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Context.—Primary mitochondrial dysfunction is one of the most common causes of inherited disorders predominantly involving the neuromuscular system. Advances in the molecular study of mitochondrial DNA have changed our vision and our approach to primary mitochondrial disorders. Many of the mitochondrial disorders are caused by mutations in nuclear genes and are inherited in an autosomal recessive pattern. Among the autosomal inherited mitochondrial disorders, those related to DNA polymerase γ dysfunction are the most common and the best studied. Understanding the molecular mechanisms and being familiar with the recent advances in laboratory diagnosis of this group of mitochondrial disorders are essential for pathologists to interpret abnormal histopathology and laboratory results and to suggest further studies for a definitive diagnosis. Objectives.—To help pathologists better understand the common clinical syndromes originating from mutations in DNA polymerase γ and its associated proteins and u...

Research in the last decade has revolutionized the way in which we view mitochondria. Mitochondria are no longer viewed solely as cellular powerhouses; rather, mitochondria are now understood to be vibrant, mobile structures, constantly undergoing fusion and fission, and engaging in intimate interactions with other cellular compartments and structures. Findings have implicated mitochondria in a wide variety of cellular processes and molecular interactions, such as calcium buffering, lipid flux, and intracellular signaling. As such, it does not come as a surprise that an increasing number of human pathologies have been associated with functional defects in mitochondria. The difficulty in understanding and treating human pathologies caused by mitochondrial dysfunction arises from the complex relationships between mitochondria and other cellular processes, as well as the genetic background of such diseases. This review attempts to provide a summary of the background knowledge and recent developments in mitochondrial processes relating to mitochondrial-associated metabolic diseases arising from defects or deficiencies in mitochondrial function, as well as insights into current and future avenues for investigation.

Sequences in overall DNA which hybridize with ribosomal RNA are more abundant in adults than in third-instar larvae of D. melanogaster.

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Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPARγ-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPARγ-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese (III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone- and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.

Background ::: ::: Troglitazone (TRO), a thiazolidinedione (TZD) peroxisome proliferator-activated receptor γ agonist, was recently withdrawn from the market because of rare but serious hepatotoxicity. Previous studies investigating the cytotoxicity of TRO in cultured rat hepatocytes have conjectured about the role of oxidative stress in TRO-induced hepatotoxicity. Therefore, we investigated whether TRO induces oxidative stress and, if so, the portion of the TRO molecule responsible for the induction of oxidative stress. ::: ::: ::: ::: Methods ::: ::: Novikoff rat hepatoma (N1S1) cells were incubated with TRO, troglitazone quinone (TQ), thiazolidinedione-phenoxyacetic acid (TD-PAA) or rosiglitazone (RSG). Membrane peroxidation, intracellular glutathione (GSH) content, and cellular viability were monitored simultaneously by multiparameter flow cytometry. ::: ::: ::: ::: Results ::: ::: TRO and TQ increased membrane peroxidation, decreased intracellular GSH, and decreased cell viability in a concentration-dependent manner. In contrast, TD-PAA and RSG neither increased membrane peroxidation nor induced loss of cell viability. In addition, TRO caused a concentration-dependent increase in intracellular superoxide generation accompanied by a collapse in mitochondrial membrane potential. ::: ::: ::: ::: Conclusion ::: ::: Multiparameter flow cytometric evaluation of N1S1 cells indicated that the chromane ring of TRO, rather than the TZD moiety, may be responsible for oxidative stress and suggested that a direct effect on mitochondrial physiology may play a role in TRO-mediated hepatotoxicity. Cytometry Part A 52A:28–35, 2003. © 2003 Wiley-Liss, Inc.

We prove that groups acting geometrically on delta-quasiconvex spaces contain no essential Baumslag-Solitar quotients as subgroups. This implies that they are translation discrete, meaning that the translation numbers of their nontorsion elements are bounded away from zero.

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Cardiac ischemia and reperfusion promote oxidative stress, leading to the accumulation of reactive aldehydes that cause cardiac damage. Mitochondrial aldehyde dehydrogenase 2 is emerging as a key cardioprotective enzyme for its central role in the detoxification of reactive aldehydes. Mitochondrial aldehyde dehydrogenase 2 activity strongly correlates to a better cardioprotective effect, and mitochondrial aldehyde dehydrogenase 2 can be activated by several pathways. After phosphorylation, the active mitochondrial aldehyde dehydrogenase 2 can reduce the build-up of aldehydes, inhibit autophagy, inhibit opening of the mitochondrial permeability transition pore, and prevent reperfusion arrhythmias. Therefore, mitochondrial aldehyde dehydrogenase 2 activation by small molecule activators suggests a promising new direction in cardiovascular research and the development of novel cardioprotective strategies. This review will discuss the cardioprotective effects of mitochondrial aldehyde dehydrogenase 2 activation in detail. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

C1 compounds participate in various metabolic processes and regulations including DNA methylation. Formaldehyde (FA), a product of methyl group oxidation, is highly cytotoxic. In the cell, there are two pathways of its utilization: assimilation and oxidation. Formaldehyde displays cytotoxicity, and therefore its oxidation is considered as detoxification. The sensitivity to the threshold concentration of FA we regard as an indication of its major role in biosystem functioning. A model of a three-component conjugated redox system is proposed in which the methyl group oxidation pathway is an archaic and conservative donor of protons and electrons, the reduction of O2 serves as an acceptor, and the arginine amino group is used for production of both urea and nitric oxide (the donor and acceptor, respectively). The fourth component of the redox system is glutathione, which maintains redox balance. The three-level system of proton donors includes the oxidation of a methyl group (first level), the oxidation of acetate in mitochondria (second level), and glucose catabolism in the pentose phosphate pathway (third level). The whole redox system is united by the sulfhydryl groups of cysteines, glutathione, thioredoxin, and α-lipoic acid. The central regulatory role in this redox system belongs to glutathione-dependent formaldehyde dehydrogenase, which controls FA binding with tetrahydrofolic acid, arginine methylation, and denitrosation of sulfhydryl groups. The conjugated redox system was formed during evolution as a union of separate redox cycles of carbon, nitrogen, sulfur, and oxygen.

We have constructed an ALDH3a1 null mouse to investigate the role of this enzyme that comprises nearly one-half of the total water-soluble protein in the mouse corneal epithelium. ALDH3a1-deficient mice are viable and fertile, have a corneal epithelium with a water-soluble protein content approximately half that of wild-type mice, and contain no ALDH3a1 as determined by zymograms and immunoblots. Despite the loss of protein content and ALDH3a1 activity, the ALDH3a1−/− mouse corneas appear indistinguishable from wild-type corneas when examined by histological analysis and electron microscopy and are transparent as determined by light and slit lamp microscopy. There is no evidence for a compensating protein or enzyme. Even though the function of ALDH3a1 in the mouse cornea remains unknown, our data indicate that its enzymatic activity is unnecessary for corneal clarity and maintenance, at least under laboratory conditions.

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BKCa channels, originally discovered in Drosophila melanogaster as slowpoke (slo), are recognized for their roles in cellular and organ physiology. Pharmacological approaches implicated BKCa channels in cellular and organ protection possibly for their ability to modulate mitochondrial function. However, the direct role of BKCa channels in regulating mitochondrial structure and function is not deciphered. Here, we demonstrate that BKCa channels are present in fly mitochondria, and slo mutants show structural and functional defects in mitochondria. slo mutants display an increase in reactive oxygen species and the modulation of ROS affected their survival. We also found that the absence of BKCa channels reduced the lifespan of Drosophila, and overexpression of human BKCa channels in flies extends life span in males. Our study establishes the presence of BKCa channels in mitochondria of Drosophila and ascertains its novel physiological role in regulating mitochondrial structural and functional integrity, and lifespan.

Daxx-like protein (DLP), the Drosophila homolog of Daxx, binds Drosophila melanogaster p53 (Dmp53) through its C-terminal region. We generated DLP mutants and found that although DLP expression is developmentally regulated, it is not essential for the execution of the developmental program. The effects DLP mutations show in the loss of heterozygosity assay and on phenotypes resulting from Dmp53 overexpression indicate a genetic interaction between DLP and Dmp53. In contrast to Dmp53 mutants, however, loss of DLP does not result in radiosensitivity indicating that it does not play an essential role in the activation of Dmp53-dependent response after ionizing radiation, and DLP is also not required for the irradiation-induced activation of reaper. In contrast, DLP is involved in the transcriptional regulation of Ark, because Ark mRNA level is decreased in DLP mutants and increased upon ectopic overexpression of DLP. Interestingly, DLP mutants have reduced longevity and reduced female fertility. Altogether, our data suggest complex functions for DLP, which include an anti-apoptotic effect exerted through repression of some Dmp53 functions, and activation of some proapoptotic genes.

We prove that groups acting geometrically on delta-quasiconvex spaces contain no essential Baumslag-Solitar quotients as subgroups. This implies that they are translation discrete, meaning that the translation numbers of their nontorsion elements are bounded away from zero.

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Autophagy (literally 'self-eating') is an evolutionarily conserved degradation process where cytoplasmic components are engulfed by vesicles called autophagosomes, which are then delivered to lysosomes, where their contents are degraded. Under stress conditions, such as starvation or oxidative stress, autophagy is upregulated in order to degrade macromolecules and restore the nutrient balance. The source of membranes that participate in the initial formation of phagophores is still incompletely understood and many intracellular structures have been shown to act as lipid donors, including the endoplasmic reticulum, Golgi, nucleus, mitochondria and the plasma membrane. Here, we focus on the contributions of the plasma membrane to autophagosome biogenesis governed by ATG16L1 and ATG9A trafficking, and summarize the physiological and pathological implications of this macroautophagy route, from development and stem cell fate to neurodegeneration and cancer.

Autophagy is a catabolic mechanism, allowing the degradation of cytoplasmic content via lysosomal activity. Several forms of autophagy are described in mammals. Macroautophagy leads to integration of cytoplasmic portions into vesicles named autophagosomes that ultimately fuse with lysosomes. Chaperone-mediated autophagy is in contrast the direct translocation of protein in lysosomes. Macroautophagy is central to lymphocyte homeostasis. Although its role is controversial in lymphocyte development and in naive cell survival, it seems particularly involved in the maintenance of certain lymphocyte subtypes. Its importance in memory B and T cells biology has recently emerged. Moreover, some effector cells like plasma cells rely on autophagy for survival. Autophagy is central to glucose and lipid metabolism, and to the maintenance of organelles like mitochondria and endoplasmic reticulum. In addition macroautophagy, or individual components of its machinery, are also actors in antigen presentation by B cells, a crucial step to receive help from T cells, this crosstalk favoring their final differentiation into memory or plasma cells. Autophagy is deregulated in several autoimmune or autoinflammatory diseases like systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and Crohn's disease. Some treatments used in these pathologies impact autophagic activity, even if the causal link between autophagy regulation and the efficiency of the treatments has not yet been clearly established. In this review, we will first discuss the mechanisms linking autophagy to lymphocyte subtype survival and the signaling pathways involved. Finally, potential impacts of autophagy modulation in lymphocytes on the course of these diseases will be approached.

Autophagy is a major cellular recycling process that delivers cellular material and entire organelles to lysosomes for degradation, in a selective or non-selective manner. This process is essential for the maintenance of cellular energy levels, components and metabolites, as well as the elimination of cellular molecular damage, thereby playing an important role in numerous cellular activities. An important function of autophagy is to enable survival under starvation conditions and other stresses. The majority of factors implicated in ageing are modifiable through the process of autophagy, including the accumulation of oxidative damage and loss of proteostasis, genomic instability and epigenomic alteration. These primary causes of damage could lead to mitochondrial dysfunction, deregulation of nutrient sensing pathways and cellular senescence, finally causing a variety of ageing phenotypes. Remarkably, advances in the biology of ageing have revealed that ageing is a malleable process: a mild decrease in signalling through nutrient-sensing pathways can improve health and extend lifespan in all model organisms tested. Consequently, autophagy is implicated in both ageing and age-related disease. Enhancement of the autophagy process is a common characteristic of all principal, evolutionary conserved anti-ageing interventions, including dietary restriction, as well as inhibition of target of rapamycin (TOR) and insulin/IGF-1 signalling (IIS). As an emerging and critical process in ageing, this review will highlight how autophagy can be modulated for health improvement.

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Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. Metformin, a widely known anti-diabetic drug, used for patients with type 2 diabetes mellitus, is also claimed to be useful in treatment of NAFLD. However, both the clinical efficacy and the putative mechanisms underlying the clinical effects of metformin in treating NAFLD are unclear. Adenosine monophosphate‐activated protein kinase (AMPK), the primary molecular target for metformin, is a known regulator of mitochondrial function. Thus, we used a proteomic approach to investigate the effect of metformin on liver mitochondria of apolipoprotein E knockout (apoE −/− ) mice, an animal model of NAFLD. Two-dimensional electrophoresis coupled with mass spectrometry was applied to study the changes in liver mitochondrial protein expression in 6-month old metformin-treated apoE −/− mice as compared to non-treated animals. Collectively, 25 differentially expressed proteins were indentified upon metformin treatment including proteins related to metabolism, oxidative stress and cellular respiration. The most up-regulated protein was glycine N-methyltransferase (GNMT) — an enzyme, whose deficiency was shown to be directly related to the development of NAFLD. Our results clearly point to the strong mitochondrial action of metformin in NAFLD. Up-regulation of GNMT may represent an important mechanism of beneficial action of metformin in NAFLD treatment.

There is a growing body of evidence that altered functioning of apoE may aggravate cellular energy homeostasis and stress response, leading to oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress and inflammation, leading to hypercholesterolemia, dyslipidemia, liver steatosis and neurodegeneration. One of the key cellular responses to mitochondria and ER-stress related processes and cellular energy imbalance is AMP-activated protein kinase (AMPK), considered as a cellular master energy sensor and critical regulator of mitochondrial homeostasis. ::: ::: The aim of our study was to use differential proteomics and transcriptomics approach to elucidate the effect of direct AMPK activator AICAR on liver proteome in apoE−/− mice – experimental model of atherosclerosis and moderate nonalcoholic steatosis. We applied Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) labeling and two-dimensional chromatography coupled with mass spectrometry (2DLC-MS/MS) MudPIT strategy, as well as RT-PCR to investigate the changes in mitochondrial and cytosolic proteins and transcripts expression in 6-month old AICAR-treated apoE−/−. ::: ::: AICAR elicited induction of proteins related to mitochondrial β-oxidation, protein degradation and energy producing pathways (i.a. tricarboxylic acid cycle members and mitochondrial adenylate kinase 2). On the other hand, AICAR repressed inflammatory and pro-apoptotic markers in the apoE−/− mice liver, alongside reduction in several peroxisomal proteins, possibly suggesting induction of anti-oxidative pexophagy.

Combustion modes in locally stratified dual-fuel (DF) mixtures are numerically investigated for methanol/n-dodecane blends under engine-relevant pressures. In the studied constant-volume numerical setup, methanol acts as a background low-reactivity fuel (LRF) while n-dodecane serves as high-reactivity fuel (HRF), controlling local ignition delay time. The spatial distribution of n-dodecane is modeled as a sinusoidal function parametrized by stratification amplitude (Y′) and wavelength (0.01 mm

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Ischemic conditioning is an intrinsic protective mechanism in which repeated short episodes of reversible ischemia protects the tissue and increases its tolerance against a subsequent longer period of ischemia (index ischemia). Bradykinin is a physiologically and pharmacologically active peptide of the kallikrein-kinin system. Besides the involvement of bradykinin in a variety of physiological and pathological responses such as pain, inflammation and in cardiovascular system as a potent vasodilator, it also acts as an endogenous cytoprotective mediator in the ischemic tissue. Pretreatment with various pharmacological modulators of bradykinin has confirmed the involvement of bradykinin in ischemic conditioning-induced protection. The protective actions of bradykinin in three major paradigms of ischemic conditioning i.e. ischemic preconditioning, ischemic postconditioning and remote ischemic preconditioning involves activation and regulation of various endogenous signaling cascades to render the heart resistant to infarction. In ischemic preconditioning, bradykinin exerts cardioprotective effect via activation of PI3K/Akt/eNOS signaling pathway and regulation of redox state via NO release. The role of bradykinin and its B2 receptors in ischemic-postconditioning induced neuroprotection has been described mainly due to its increased redox signaling cascade and activation of mitochondrial anti-apoptotic pathway. Furthermore, its cardioprotective role during remote ischemic preconditioning has been associated with activation of B2 receptors mediated neurogenic pathway and internalization of B2 receptors along with the formation of signalosomes that activates intracellular cytoprotective transduction pathways. The present review focuses on the potential role of bradykinin in mediating different forms of ischemic conditioning (pre/post/remote)-induced cardioprotection and neuroprotection along with the possible mechanisms.

Over the past 30years the mitochondrial permeability transition - the permeabilization of the inner mitochondrial membrane due to the opening of a wide pore - has progressed from being considered a curious artifact induced in isolated mitochondria by Ca(2+) and phosphate to a key cell-death-inducing process in several major pathologies. Its relevance is by now universally acknowledged and a pharmacology targeting the phenomenon is being developed. The molecular nature of the pore remains to this day uncertain, but progress has recently been made with the identification of the FOF1 ATP synthase as the probable proteic substrate. Researchers sharing this conviction are however divided into two camps: these believing that only the ATP synthase dimers or oligomers can form the pore, presumably in the contact region between monomers, and those who consider that the ring-forming c subunits in the FO sector actually constitute the walls of the pore. The latest development is the emergence of a new candidate: Spastic Paraplegia 7 (SPG7), a mitochondrial AAA-type membrane protease which forms a 6-stave barrel. This review summarizes recent developments of research on the pathophysiological relevance and on the molecular nature of the mitochondrial permeability transition pore. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Berzelius failed to make use of Faraday's electrochemical laws in his laborious determination of equivalent weights.

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The proper functioning of mitochondria requires that both the mitochondrial and the nuclear genome are functional. To investigate the importance of the mitochondrial genome, which encodes only 13 subunits of the respiratory complexes, the mitochondrial rRNAs and a few tRNAs, we performed a comparative study on the 143B cell line and on its Rho-0 counterpart, i.e., devoid of mitochondrial DNA. Quantitative differences were found, of course in the respiratory complexes subunits, but also in the mitochondrial translation apparatus, mainly mitochondrial ribosomal proteins, and in the ion and protein import system, i.e., including membrane proteins. Various mitochondrial metabolic processes were also altered, especially electron transfer proteins and some dehydrogenases, but quite often on a few proteins for each pathway. This study also showed variations in some hypothetical or poorly characterized proteins, suggesting a mitochondrial localization for these proteins. Examples include a stomatin-like protein and a protein sharing homologies with bacterial proteins implicated in tyrosine catabolism. Proteins involved in apoptosis control are also found modulated in Rho-0 mitochondria.

When considering which components of the cell are the most critical to function and physiology, we naturally focus on the nucleus, the mitochondria that regulate energy and apoptotic signaling, or other organelles such as the endoplasmic reticulum, Golgi, ribosomes, etc. Few people will suggest that the membrane is the most critical element of a cell in terms of function and physiology. Those that consider the membrane critical will point to its obvious barrier function regulated by the lipid bilayer and numerous ion channels that regulate homeostatic gradients. What becomes evident upon closer inspection is that not all membranes are created equal and that there are lipid-rich microdomains that serve as platforms of signaling and a means of communication with the intracellular environment. In this review, we explore the evolution of membranes, focus on lipid-rich microdomains, and advance the novel concept that membranes serve as "capacitors for energy and metabolism." Within this framework, the membrane then is the primary and critical regulator of stress and disease adaptation of the cell.

ABSTRACTUNC-45A is an ubiquitously expressed protein highly conserved throughout evolution. Most of what we currently know about UNC-45A pertains to its role as a regulator of the actomyosin system...

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Friedreich's ataxia (FRDA) is a hereditary neurodegenerative disease that frequently culminates in cardiac failure at an early age. FRDA is believed to arise from reduced synthesis of the mitochondrial iron chaperone frataxin due to impaired gene transcription, which leads to mitochondrial iron accumulation, dysfunction of mitochondrial Fe-S containing enzymes, and increased Fenton-mediated free radical production. Recent reports have challenged this generally accepted hypothesis, by suggesting that the oxidative stress component in FRDA is minimal and thereby questioning the benefit of antioxidant therapeutic strategies. We suggest that this apparent paradox results from the radically divergent chemistries of the participating reactive oxygen species (ROS), the major cellular subcompartments involved and the overall cellular responses to ROS. In this review, we consider these factors and conclude that oxidative stress does constitute a major contributing factor to FRDA pathology. This reaffirms the idea that the rational design of specific small molecule multifunctional antioxidants will benefit FRDA patients.

Friedreich’s ataxia is an autosomal recessive disorder characterized by impaired mitochondrial function, resulting in oxidative stress. In this study, we aimed at evaluating whether tocotrienol, a ...

Fractal like morphology is a very interesting feature during electrodeposition of metals and shows pattern transition with changes in deposition conditions. In this article, we have explained the thermal effects in the two dimensional DLA morphology on the basis of thermal free energy and another free energy barrier resulting from the electric field. The results obtained from free energy hypothesis are consistent with experiments showing the transition voltage for electrodeposition of copper ions to be around 6 V.

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Mitochondrial Ca2+ accumulation and the formation of reactive oxygen species are processes dependent on the electron transport system. The production of superoxide by respiring rat heart mitochondria was decreased by either chelating extramitochondrial Ca2+ with EGTA or by blocking mitochondrial Ca2+ uptake with ruthenium red. Mitochondrial experiments with doxorubicin showed an enhanced stimulation of reactive oxygen species, which was also inhibited by EGTA or ruthenium red. Myocardial cell cultures treated with doxorubicin showed an enhanced formation of intracellular reactive oxygen species, which preceded cell damage. Ruthenium red not only attenuated the enhanced formation of intracellular reactive oxygen species, but also increased cell viability. The relationship between mitochondrial Ca2+ transport and the formation of superoxide suggests that a disruption in mitochondrial Ca2+ homeostasis by doxorubicin may be involved in the release of reactive oxygen species and its cardiotoxicity.

Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.

ABSTRACTUNC-45A is an ubiquitously expressed protein highly conserved throughout evolution. Most of what we currently know about UNC-45A pertains to its role as a regulator of the actomyosin system...

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Background A possible relationship between mitochondrial haplogroups and psychiatric diseases (e.g. schizophrenia and bipolar disorder) has been postulated, but data regarding depression is still limited. We investigated whether any mitochondrial haplogroup carried a significant higher risk of depressive symptoms in a large prospective cohort of North American people included in the Osteoarthritis Initiative. Methods Cross sectional data was derived from the Osteoarthritis Initiative. The haplogroup was assigned through a combination of sequencing and PCR-RFLP techniques. All the mitochondrial haplogroups were named following this nomenclature: H, U, K, J, T, V, SuperHV, I, W, X or Others. Depression was ascertained through the 20-item Center for Epidemiologic Studies-Depression (CES-D), with ≥16 indicating depressive symptoms. Results Overall, 3601 Caucasian participants (55.9% women), mean age of 61.7±9.3 years were included. No difference was observed in mitochondrial haplogroups frequency among those with depressive symptoms (n=285, =7.9% of the baseline population) compared to participants with no depressive symptoms (N=3316) (chi-square test=0.53). Using a logistic regression analysis, adjusted for eight potential confounders, with those having the haplogroup H as the reference group (the most common haplogroup), no significant mitochondrial haplogroup was associated with prevalent depressive symptoms. The same results were evident in secondary analysis in which we matched depressed and non-depressed participants for age and sex. Limitations Cross-sectional design; only CES-D for evaluating mood; participants not totally representative of general population. Conclusions We found no evidence of any relationship between specific mitochondrial haplogroups and depressive symptoms. Future longitudinal research is required to confirm/ refute these findings.

The human mitochondrial genome is very small and economically packed; the expression of the whole genome is essential for the maintenance of mitochondrial bioenergetic function. Mutation occurs at a much higher rate in the mitochondrial DNA (mtDNA) than in chromosomal DNA. Transient heteroplasmy of mtDNA occurs after a mutational event; the random pattern of cytoplasmic segregation that occurs during subsequent growth gives rise to a mosaic of cells. The variable proportion of mutant mitochondrial genomes per cell results in cells with a range of bioenergetic capacities. It is proposed that the accumulation of mitochondrial mutations and the subsequent cytoplasmic segregation of these mutations during life is an important contributor both to the ageing process and to several human degenerative diseases. Replacement therapy and pharmacological support may be possible for the amelioration of such disorders by means of appropriate redox compounds. Moreover, new compounds with desired redox potentials can be rationally designed for clinical use.

For transformer cooling applications, magnetic particles need to be dispersed in carrier fluids with high colloidal stability for a long period without significant degradation. However, stability of the suspension, especially the long term colloidal stability is a crucial factor for the applications in power transformers because aggregation of particles could cause clogging of micro-channels in transformers. In this article, we have reported effect of hydrodynamic size on the colloidal stability of Mn1-xZnxFe2O4 (MZ) nanoparticles (NPs)–based magnetic fluids. Lifetime of fluids has been determined from the increase in hydrodynamic size of magnetic NPs due to aggregation. Colloidal stability of fluids decreases with increase in the polydispersity of fluids caused by the enhanced dipole interactions between NPs resulting in the aggregation of NPs in chain-like structures.

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Systemic inflammatory response syndrome (SIRS) development is accompanied by mitochondrial dysfunction and excessive ROS production. Mitochondrial dysfunctions also occur in many SIRS-related diseases and may be critical for their pathogenesis; therefore, a use of mitochondria-targeted drugs is a promising trend in SIRS research and therapy. Here, we review recent studies concerning the application of the mitochondria-targeted antioxidants and uncouplers of oxidative phosphorylation in animal models of SIRS and related diseases. We propose that a new class of uncouplers of oxidative phosphorylation, lipophilic cations could be a base for a new generation of drugs for SIRS treatment. J. Cell. Physiol. 232: 904–912, 2017. © 2016 Wiley Periodicals, Inc.

Objective: Mitochondrial impairment in the skeletal muscle contributes to useless of limbs in spleen qi deficiency; however the genesis of such impairment is not clear. Herein, PTEN-induced putative kinase 1 (PINK1)-Parkin pathway and mitophagy were studied to explore the machinery of mitochondrial impairment. Methods: 16 male SD rats were randomly divided in the control group and spleen qi deficiency group (model group); transmission electron microscope was used to observe mitochondrial morphology; mitochondrial oxidative phosphorylation was assessed by testing mitochondrial membrane potential (MMP) and levels of ATP and ROS; western blot was used to analyze expressions of PINK1, Parkin, microtubule-associated protein 1 light chain 3-II (LC3-II) and p62. Results: Compared with those in the control group, mitochondria became small, less and scattered, MMP and the ATP level were reduced, the ROS level was elevated, PINK1 expression was decreased, p62 expression was increased, but Parkin and LC3-II expressions were not altered, in the model group. Conclusions: Suppression of mitophagy might be related to the mitochondrial damage in the skeletal muscle when spleen qi deficiency develops.

Berzelius failed to make use of Faraday's electrochemical laws in his laborious determination of equivalent weights.

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The cellular and molecular basis of brain stem death remains an enigma. As the origin of a “life-and-death” signal that reflects the progression toward brain stem death, the rostral ventrolateral medulla (RVLM) is a suitable neural substrate for mechanistic delineation of this phenomenon. Here, we evaluated the hypothesis that heat shock proteins (HSPs) play a neuroprotective role in the RVLM during brain stem death and delineated the underlying mechanisms, using a clinically relevant animal model that employed the organophosphate pesticide mevinphos (Mev) as the experimental insult. In Sprague-Dawley rats, proteomic, Western blot, and real-time PCR analyses demonstrated that Mev induced de novo synthesis of HSP60 or HSP70 in the RVLM without affecting HSP90 level. Loss-of-function manipulations of HSP60 or HSP70 in the RVLM using anti-serum or antisense oligonucleotide potentiated Mev-elicited cardiovascular depression alongside reduced nitric-oxide synthase (NOS) I/protein kinase G signaling, enhanced NOS II/peroxynitrite cascade, intensified nucleosomal DNA fragmentation, elevated cytoplasmic histone-associated DNA fragments or activated caspase-3, and augmented the cytochrome c/caspase-3 cascade of apoptotic signaling in the RVLM. Co-immunoprecipitation experiments further revealed a progressive increase in the complex formed between HSP60 and mitochondrial or cytosolic Bax or mitochondrial Bcl-2 during Mev intoxication, alongside a dissociation of the cytosolic HSP60-Bcl-2 complex. We conclude that HSP60 and HSP70 confer neuroprotection against Mev intoxication by ameliorating cardiovascular depression via an anti-apoptotic action in the RVLM. The possible underlying intracellular processes include enhancing NOS I/protein kinase G signaling and inhibiting the NOS II/peroxynitrite cascade. In addition, HSP60 exerts its effects against apoptosis by blunting Mev-induced activation of the Bax/cytochrome c/caspase-3 cascade.

The central nervous system plays a critical role in the normal control of arterial blood pressure and in its elevation in virtually all forms of hypertension. Mitochondrial dysfunction has been increasingly associated with the development of hypertension. Therefore, we examined whether mitochondrial dysfunction occurs in the brain in hypertension and characterized it at the molecular scale. Mitochondria from whole brain and brain stem from 12-week–old spontaneously hypertensive rats with elevated blood pressure (190±5 mm Hg) were compared against those from age-matched normotensive (134±7 mm Hg) Wistar Kyoto rats (n=4 in each group). Global differential analysis using 2D electrophoresis followed by tandem mass spectrometry–based protein identification suggested a downregulation of enzymes involved in cellular energetics in hypertension. Targeted differential analysis of mitochondrial respiratory complexes using the classical blue-native SDS-PAGE/Western method and a complementary combination of sucrose-gradient ultracentrifugation/tandem mass spectrometry revealed previously unknown assembly defects in complexes I, III, IV, and V in hypertension. Interestingly, targeted examination of the brain stem, a regulator of cardiovascular homeostasis and systemic blood pressure, further showed the occurrence of mitochondrial complex I dysfunction, elevated reactive oxygen species production, decreased ATP synthesis, and impaired respiration in hypertension. Our findings suggest that in already-hypertensive spontaneously hypertensive rats, the brain respiratory complexes exhibit previously unknown assembly defects. These defects impair the function of the mitochondrial respiratory chain. This mitochondrial dysfunction localizes to the brain stem and is, therefore, likely to contribute to the development, as well as to pathophysiological complications, of hypertension.

We report enhancement of the mechanical stability of graphene through a one-step method to disperse gold nanoparticles on the pristine graphene without any added agent.

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The role of mitochondria in haematopoietic stem-cell maintenance has not been examined in detail; here mitofusin 2, which modulates mitochondrial fusion and tethering of endoplasmic reticulum to the mitochondria, is shown to be necessary for the maintenance of haematopoietic stem cells with extensive lymphoid potential.

Mutations in the mitochondrial fusion gene Mfn2 cause the human neurodegenerative disease Charcot-Marie-Tooth type 2A. However, the cellular basis underlying this relationship is poorly understood. By removing Mfn2 from the cerebellum, we established a model for neurodegeneration caused by loss of mitochondrial fusion. During development and after maturity, Purkinje cells require Mfn2 but not Mfn1 for dendritic outgrowth, spine formation, and cell survival. In vivo, cell culture, and electron microscopy studies indicate that mutant Purkinje cells have aberrant mitochondrial distribution, ultrastructure, and electron transport chain activity. In fibroblasts lacking mitochondrial fusion, the majority of mitochondria lack mitochondrial DNA nucleoids. This deficiency provides a molecular mechanism for the dependence of respiratory activity on mitochondrial fusion. Our results show that exchange of mitochondrial contents is important for mitochondrial function as well as organelle distribution in neurons and have important implications for understanding the mechanisms of neurodegeneration due to perturbations in mitochondrial fusion.

This paper describes visual route following for a cliff-climbing, tethered mobile robot for the purpose of autonomously traversing extreme terrain in the presence of obstacles. When the robot's tether contacts an obstacle, an intermediate anchor is formed. In order to detach from intermediate anchors and avoid entanglement, the robot must backtrack along its outgoing trajectory. We use the Visual Teach & Repeat (VT&R) algorithm to autonomously repeat a manually taught path. However, our problem is complicated by the fact that the robot's tether must (i) remain taut regardless of inclination, (ii) allow the robot to drive freely, and (iii) provide motion assistance when wheel traction is reduced on steep slopes. To enable visual route following over varied terrain, we have developed a novel tether controller that selects a safe, steady-state tension based on the robot's inclination while also accounting for vehicle motion. Experiments are performed on our Tethered Robotic Explorer (TReX), which autonomously repeats paths while tethered in both flat-indoor and steep-outdoor environments in the presence of obstacles.

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Saccharomyces cerevisiae cells lacking the yeast frataxin homologue (Δyfh1) accumulate iron in the mitochondria in the form of nanoparticles of ferric phosphate. The phosphate content of Δyfh1 mitochondria was higher than that of wild-type mitochondria, but the proportion of mitochondrial phosphate that was soluble was much lower in Δyfh1 cells. The rates of phosphate and iron uptake in vitro by isolated mitochondria were higher for Δyfh1 than wild-type mitochondria, and a significant proportion of the phosphate and iron rapidly became insoluble in the mitochondrial matrix, suggesting co-precipitation of these species after oxidation of iron by oxygen. Increasing the amount of phosphate in the medium decreased the amount of iron accumulated by Δyfh1 cells and improved their growth in an iron-dependent manner, and this effect was mostly transcriptional. Overexpressing the major mitochondrial phosphate carrier, MIR1, slightly increased the concentration of soluble mitochondrial phosphate and significantly improved various mitochondrial functions (cytochromes, [Fe-S] clusters, and respiration) in Δyfh1 cells. We conclude that in Δyfh1 cells, soluble phosphate is limiting, due to its co-precipitation with iron.

BACKGROUND ::: Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntington's disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established. ::: ::: ::: RESULTS ::: To uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast model system and identify fourteen genes that, if deleted, result in higher polyglutamine toxicity. Several of these genes, like UGO1, ATP15 and NFU1 encode mitochondrial proteins, implying that a challenged mitochondrial system may become dysfunctional during polyglutamine intoxication. We further employed microarrays to decipher the transcriptional response upon polyglutamine intoxication, which exposes an upregulation of genes involved in sulfur and iron metabolism and mitochondrial Fe-S cluster formation. Indeed, we find that in vivo iron concentrations are misbalanced and observe a reduction in the activity of the prominent Fe-S cluster containing protein aconitase. Like in other yeast strains with impaired mitochondria, non-fermentative growth is impossible after intoxication with the polyglutamine protein. NMR-based metabolic analyses reveal that mitochondrial metabolism is reduced, leading to accumulation of metabolic intermediates in polyglutamine-intoxicated cells. ::: ::: ::: CONCLUSION ::: These data show that damages to the mitochondrial system occur in polyglutamine intoxicated yeast cells and suggest an intricate connection between polyglutamine-induced toxicity, mitochondrial functionality and iron homeostasis in this model system.

With the present rates of iron ore consumption, currently unusable, high-phosphorus iron ore deposits are likely to be the iron ores of the future as higher-grade iron ore reserves are depleted. Consequently, the design and timely development of environmentally-benign processes for the simultaneous beneficiation of high-phosphorus iron ores and phosphorus recovery, currently a technological challenge, might soon become a sustainability challenge. To stimulate interest in this area, phosphorus adsorption and association in iron oxides/hydroxyoxides, and current efforts at its removal, have been reviewed. The important properties of the most relevant crystalline phosphate phases in iron ores are highlighted, and insights provided on plausible routes for the development of sustainable phosphorus recovery solutions from high-phosphorus iron ores. Leveraging literature information from geochemical investigations into phosphorus distribution, speciation, and mobility in various natural systems, key knowledge gaps that are vital for the development of sustainable phosphorus removal/recovery strategies and important factors (white spaces) not yet adequately taken into consideration in current phosphorus removal/recovery solutions are highlighted, and the need for their integration in the development of future phosphorus removal/recovery solutions, as well as their plausible impacts on phosphorus removal/recovery, are put into perspective.

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Oxidative stress is one of the major causes of aging considered at both the cellular and organismal levels. There is evidence that this agent may also constitute a common element connecting the aging of cells of higher organisms with a similar process occurring in eukaryotic and prokaryotic unicellulars. The aim of this paper was to present the current state of knowledge on the role of oxidative stress in aging of human somatic cells, human as a whole as well as the yeast Saccharomyces cerevisiae and bacteria Caulobacter crescentus, and Escherichia coli.

Skin aging is a complex process which involves all the layers of the epidermis and dermis. In order to slow skin aging, methods are researched which would strengthen and protect skin stem cells. Science is in search of the right method to stimulate the proliferation of epidermal stem cells. Plant stem cells show outstanding anti-aging properties, as they can, among other activities, stimulate fibroblasts to synthesise collagen, which, in turn, stimulates skin regeneration. One of the most important agents which give anti-aging properties to plant stem cell extracts is kinetin (6-furfuryladenine). This compound belongs to a cytokine group and is considered to be a strong antioxidant which protects protein and nucleic acids from oxidation and glycoxidation processes. It enables cells to remove the excess of free radicals to protect them from oxidative stress.

All organisms must display a certain degree of environmental adaptability to survive and reproduce. Growth and reproduction are metabolically expensive and carry other costs that contribute to aging. Therefore, animals have developed physiologic strategies to assess the harshness of the environment before devoting resources to reproduction. Presumably, these strategies maximize the possibility for offspring survival. Current views of aging reflect a trade-off between reproductive fitness and somatic maintenance whereby environmental stress induces an adaptive metabolic response aimed at preserving cellular integrity while inhibiting growth, whereas favorable environmental conditions (abundance of food and water, and optimal temperature, etc.) promote growth and reproductive maturity but simultaneously increase cellular damage and aging. Here we propose that the prevalence of infectious pathogens in a given niche represents an additional environmental factor that, via innate immune pathways, actively shifts this balance in favor of somatic maintenance at the expense of reproduction and growth. We additionally propose the construction of a genetic model system with which to test this hypothesis.

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When endothelial cells from different vascular beds are grown in culture they show a limited capacity to divide, eventually entering into a permanent and phenotypically distinctive non-dividing state referred to as ‘replicative senescence’. Replicative senescence is thought to result from progressive shortening of telomeric DNA and consequent telomere dysfunction. More recently, it has been realised that senescence can also be induced by a variety of insults, including those causing intracellular oxidative stress. In this report, we review evidence for the occurrence of endothelial cell senescence in vivo. We will also examine the causes, mechanisms and regulation of this process as they emerge from our studies in cell culture, focusing in particular on the roles of oxidative stress, telomerase, growth factors and nitric oxide.

In a previous study, we demonstrated that endothelial microvesicles (eMVs) have a well-developed enzymatic team involved in reactive oxygen species detoxification. In the present paper, we demonstrate that eMVs can synthesize the reducing power (NAD(P)H) that nourishes this enzymatic team, especially those eMVs derived from senescent human umbilical vein endothelial cells. Moreover, we have demonstrated that the molecules that nourish the enzymatic machinery involved in NAD(P)H synthesis are blood plasma metabolites: lactate, pyruvate, glucose, glycerol, and branched-chain amino acids. Drastic biochemical changes are observed in senescent eMVs to optimize the synthesis of reducing power. Mitochondrial activity is diminished and the glycolytic pathway is modified to increase the activity of the pentose phosphate pathway. Different dehydrogenases involved in NADPH synthesis are also increased. Functional experiments have demonstrated that eMVs can synthesize NADPH. In addition, the existence of NADPH in eMVs was confirmed by mass spectrometry. Multiphoton confocal microscopy images corroborate the synthesis of reducing power in eMVs. In conclusion, our present and previous results demonstrate that eMVs can act as autonomous reactive oxygen species scavengers: they use blood metabolites to synthesize the NADPH that fuels their antioxidant machinery. Moreover, senescent eMVs have a stronger reactive oxygen species scavenging capacity than young eMVs.

We prove that groups acting geometrically on delta-quasiconvex spaces contain no essential Baumslag-Solitar quotients as subgroups. This implies that they are translation discrete, meaning that the translation numbers of their nontorsion elements are bounded away from zero.

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Publisher Summary This chapter reviews the literature on the application of organ culture to the study of vitamins and hormones. The organ culture technique enables part of a complicated problem to be isolated from the general confusion of the body so that it may be studied under controlled, simplified-and yet abnormal conditions. Seeking for the primary cause of some phenomenon in vivo is often like looking for a needle in a haystack. In organ culture, the main object is to preserve the characteristic structure and functional activities of tissues in a condition resembling as closely as possible that of the same organ in the body. Used in this way, as an ancillary technique to studies on the intact animal, organ culture is an extremely valuable tool for a wide variety of problems.

In the 50 years since we described cell death as 'programmed,' we have come far, thanks to the efforts of many brilliant researchers, and we now understand the mechanics, the biochemistry, and the genetics of many of the ways in which cells can die. This knowledge gives us the resources to alter the fates of many cells. However, not all cells respond similarly to the same stimulus, in either sensitivity to the stimulus or timing of the response. Cells prevented from dying through one pathway may survive, survive in a crippled state, or die following a different pathway. To fully capitalize on our knowledge of cell death, we need to understand much more about how cells are targeted to die and what aspects of the history, metabolism, or resources available to individual cells determine how each cell reaches and crosses the threshold at which it commits to death.

Age serves as a basis for assigning status and regulating social interaction across all societies. Members of the cultural group socialize new members into the rules and roles that are associated w...

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We used Au nanoparticles (Au-NPs) as a model for studying particle-specific effects of manufactured nanomaterials (MNMs) by examining the toxicogenomic responses in a model soil organism, Caenorhabditis elegans . Global genome expression for nematodes exposed to 4-nm citrate-coated Au-NPs at the LC(10) level (5.9 mg·L(-1)) revealed significant differential expression of 797 genes. The levels of expression for five genes (apl-1, dyn-1, act-5, abu-11, and hsp-4) were confirmed independently with qRT-PCR. Seven common biological pathways associated with 38 of these genes were identified. Up-regulation of 26 pqn/abu genes from noncanonical unfolded protein response (UPR) pathway and molecular chaperones (hsp-16.1, hsp-70, hsp-3, and hsp-4) were observed and are likely indicative of endoplasmic reticulum stress. Significant increase in sensitivity to Au-NPs in a mutant from noncanonical UPR (pqn-5) suggests possible involvement of the genes from this pathway in a protective mechanism against Au-NPs. Significant responses to Au-NPs in endocytosis mutants (chc-1 and rme-2) provide evidence for endocytosis pathway being induced by Au-NPs. These results demonstrate that Au-NPs are bioavailable and cause adverse effects to C. elegans by activating both general and specific biological pathways. The experiments with mutants further support involvement of several of these pathways in Au-NP toxicity and/or detoxification.

In Caenorhabditis elegans, heterochronic genes constitute a developmental timer that specifies temporal cell fate selection. The heterochronic gene lin-42 is the C. elegans homolog of Drosophila and mammalian period, key regulators of circadian rhythms, which specify changes in behavior and physiology over a 24 hr day/night cycle. We show a role for two other circadian gene homologs, tim-1 and kin-20, in the developmental timer. Along with lin-42, tim-1 and kin-20, the C. elegans homologs of the Drosophila circadian clock genes timeless and doubletime, respectively, are required to maintain late-larval identity and prevent premature expression of adult cell fates. The molecular parallels between circadian and developmental timing pathways suggest the existence of a conserved molecular mechanism that may be used for different types of biological timing.

We report enhancement of the mechanical stability of graphene through a one-step method to disperse gold nanoparticles on the pristine graphene without any added agent.

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The transformation of 2,3-oxidosqualene to lanosterol is catalyzed by a microsomal enzyme (cyclase) which can be obtained in soluble and partially purified form by treatment of liver microsomes with deoxycholate as previously shown. The catalytic and physical properties of the soluble enzyme are determined by ionic strength. In 0.4 M KCl the cyclase exists largely in a dissociated, enzymatically active form. Solutions of low ionic strength (0.1 M KCl or less) cause enzyme aggregation and loss of activity. The anionic detergent deoxycholate is essential for cyclase activity, but is effective only in a narrow concentration range.

Parkinson's disease (PD) is a neurodegenerative disorder marked by the selective degeneration of dopaminergic neurons in the nigrostriatal pathway. Several lines of evidence indicate that mitochondrial dysfunction contributes to its etiology. Other studies have suggested that alterations in sterol homeostasis correlate with increased risk for PD. Whether these observations are functionally related is, however, unknown. In this study, we used a toxin-induced mouse model of PD and measured levels of nine sterol intermediates. We found that lanosterol is significantly (∼50%) and specifically reduced in the nigrostriatal regions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, indicative of altered lanosterol metabolism during PD pathogenesis. Remarkably, exogenous addition of lanosterol rescued dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in culture. Furthermore, we observed a marked redistribution of lanosterol synthase from the endoplasmic reticulum to mitochondria in dopaminergic neurons exposed to MPP+, suggesting that lanosterol might exert its survival effect by regulating mitochondrial function. Consistent with this model, we find that lanosterol induces mild depolarization of mitochondria and promotes autophagy. Collectively, our results highlight a novel sterol-based neuroprotective mechanism with direct relevance to PD.

We prove that groups acting geometrically on delta-quasiconvex spaces contain no essential Baumslag-Solitar quotients as subgroups. This implies that they are translation discrete, meaning that the translation numbers of their nontorsion elements are bounded away from zero.

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Chronic alcoholism causes a variety of ultrastructural, biochemical and functional alterations in the myocardium, but the underlying mechanisms are not well understood. Molecular changes that developed in the left ventricles of rats fed for 1 to 24 weeks on liquid diets containing ethanol as 36% of total calories were analyzed. Total tissue RNA and DNA were chemically extracted and measured by spectroscopic methods; mitochondrial DNA and mitochondrially-coded ribosomal RNA were measured at the 12s rRNA region by a quantitative polymerase chain reaction method; mitochondrial protein and enzyme activities were assayed. Ethanol-fed rats had 83.9±2.9% (mean±S.E.M.) as much DNA/g tissue and 74.7±3.9% as much total left ventricle DNA as pair-fed controls (P

AIMS ::: Alcoholic cardiomyopathy (ACM) presents as decreased myocardial contractility, arrhythmias and secondary non-ischemic dilated cardiomyopathy leading to heart failure. Mitochondrial dysfunction is known to have a significant role in the development and complications of ACM. This study investigated if chronic ethanol feeding promoted myocardial mitochondrial topoisomerase dysfunction as one underlying cause of mitochondrial DNA (mtDNA) damage and mitochondrial dysfunction in ACM. ::: ::: ::: METHODS ::: The impact of chronic ethanol exposure on the myocardial mitochondria was examined in both neonatal cardiomyocytes using 50 mM ethanol for 6 days and in rats assigned to control or ethanol feeding groups for 4 months. ::: ::: ::: RESULTS ::: Chronic ethanol feeding led to significant (P < 0.05) decreases in M-mode Fractional Shortening, ejection fraction, and the cardiac output index as well as increases in Tau. Ethanol feeding promoted mitochondrial dysfunction as evidenced by significantly decreased left ventricle cytochrome oxidase activity and decreases in mitochondrial protein content. Both in rats and in cultured cardiomyocytes, chronic ethanol presentation significantly increased mtDNA damage. Using isolated myocardial mitochondria, both mitochondrial topoisomerase-dependent DNA cleavage and DNA relaxation were significantly altered by ethanol feeding. ::: ::: ::: CONCLUSION ::: Chronic ethanol feeding compromised cardiovascular and mitochondrial function as a result of a decline in mtDNA integrity that was in part the consequence of mitochondrial topoisomerase dysfunction. Understanding the regulation of the mitochondrial topoisomerases is critical for protection of mtDNA, not only for the management of alcoholic cardiomyopathy, but also for the many other clinical treatments that targets the topoisomerases in the alcoholic patient.

We describe a method which allows isolation of deletions within hybrid plasmids. It is based on the fact that the tetracycline resistance (Tc R ) gene of pBR322 can be inactivated by inserting foreign DNA into its Hin dIII site, and that the easily selectable Tc R mutants of such plasmids are generally (>90%) due to deletions of certain hybrid plasmid sequences. We have found that Tc R mutants are usually maintained within the cell recombined with the parental Tc S plasmids. Such heterodimers dissociate in both Rec + and in recA hosts. Parental rather than mutant plasmids are then retained by the host cell.

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Periodontitis, the most prevalent chronic inflammatory disease, has been related to cardiovascular diseases. Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway. The aim of this research was to study the role of autophagy in peripheral blood mononuclear cells from patients with periodontitis and gingival fibroblasts treated with a lipopolysaccharide of Porphyromonas gingivalis. Autophagy-dependent mechanisms have been proposed in the pathogenesis of inflammatory disorders and in other diseases related to periodontitis, such as cardiovascular disease and diabetes. Thus it is important to study the role of autophagy in the pathophysiology of periodontitis. Peripheral blood mononuclear cells from patients with periodontitis (n = 38) and without periodontitis (n = 20) were used to study autophagy. To investigate the mechanism of autophagy, we evaluated the influence of a lipopolysaccharide from P. gingivalis in human gingival fibroblasts, and autophagy was monitored morphologically and biochemically. Autophagosomes were observed by immunofluorescence and electron microscopy. We found increased levels of autophagy gene expression and high levels of mitochondrial reactive oxygen species production in peripheral blood mononuclear cells from patients with periodontitis compared with controls. A significantly positive correlation between both was observed. In human gingival fibroblasts treated with lipopolysaccharide from P. gingivalis, there was an increase of protein and transcript of autophagy-related protein 12 (ATG12) and microtubule-associated protein 1 light chain 3 alpha LC3. A reduction of mitochondrial reactive oxygen species induced a decrease in autophagy whereas inhibition of autophagy in infected cells increased apoptosis, showing the protective role of autophagy. Results from the present study suggest that autophagy is an important and shared mechanism in other conditions related to inflammation or alterations of the immune system, such as periodontitis.

Experiments with isolated mitochondria have established that these organelles are pivotal intracellular sources of superoxide in a variety of pathophysiological conditions. Recently, a novel fluoroprobe MitoSOX Red was introduced for selective detection of superoxide in the mitochondria of live cells and was validated with confocal microscopy. Here we show approximately 3-7 fold dose- and time-dependent increase in mitochondrial superoxide production (measured by MitoSOX using flow cytometry and confocal microscopy) in rat cardiac derived H9c2 myocytes and/or in human coronary artery endothelial cells triggered by Antimycin A, Paraquat, Doxorubicin or high glucose. These results establish a novel, quantitative method for simple detection of mitochondrial superoxide generation simultaneously in a large population of live cells by flow cytometry. This method can also be adapted for immune cell studies with mixed population of T or B cells or their subsets to analyze mitochondrial superoxide levels using multiple labeled surface markers in individual populations.

Berzelius failed to make use of Faraday's electrochemical laws in his laborious determination of equivalent weights.

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Alpha synuclein protein may play an important role in familial and sporadic Parkinson's disease pathology. We have induced G209A mutant or wild-type alpha-synuclein expression in stable HEK293 cell models to determine if this influences markers of oxidative stress and damage under normal conditions or in the presence of dopamine or paraquat. Induced wild-type or mutant alpha-synuclein expression alone had no effect upon levels of oxidative stress or damage, as measured by glutathione levels or aconitase activity. Both wild-type and mutant alpha-synuclein expression decreased the oxidative damage induced by paraquat, although the protection was less marked with mutant alpha-synuclein expression. This suggests that alpha-synuclein expression may either have anti-oxidant properties or may upregulate cellular antioxidant levels, a function that was diminished by the G209A mutation. However, mutant but not wild-type alpha-synuclein expression specifically enhanced dopamine associated oxidative damage. Non-expressing cells treated with reserpine to inhibit the vesicular monoamine compartmentalisation produced similar results. However, consistent with the hypothesis that mutant alpha-synuclein disrupts vesicular dopamine compartmentalization, this effect was diminished in cells expressing mutant alpha-synuclein. This may result in increased dopamine metabolism and cause selective oxidative damage to dopaminergic cells. (C) 2004 Elsevier Ltd. All rights reserved.

Alpha-synuclein is the major protein component of Lewy bodies, a cardinal pathological feature of the degenerating Parkinsonian brain. Alpha-synuclein has been reported to be able to intercalate into membranes via formation of an alpha-helical structure at its N-terminal end. Recent in vitro studies from various laboratories have demonstrated that alpha-synuclein can physically associate with mitochondria and interfere with mitochondrial function. α-Syn predominantly associates with the inner mitochondrial membrane, where it can apparently interact with complex I resulting in reduced mitochondrial complex I activity and increased free radical production. However, the effect of in vivo alpha-synuclein accumulation within dopaminergic neurons on mitochondrial function has not been thoroughly studied. Examination of transgenic animals which overexpress the familial mutant A53T form of the protein selectively within dopaminergic neurons reveals that A53T localizes to the mitochondrial membranes as monomers and oligomers particularly under conditions of proteasomal inhibitory stress, and that this localization coincides with a selective age-related mitochondrial complex I inhibition and decreased substrate-specific respiration along with increases in mitochondrial autophagy (mitophagy).

We prove that groups acting geometrically on delta-quasiconvex spaces contain no essential Baumslag-Solitar quotients as subgroups. This implies that they are translation discrete, meaning that the translation numbers of their nontorsion elements are bounded away from zero.

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Oxidative stress has been suggested to contribute to the development of diabetic nephropathy. Manganese superoxide dismutase (MnSOD) protects the cells from oxidative damage by scavenging free radi ...

This study characterizes mitochondria isolated from livers of Sod2(-/+) and Sod2(+/+) mice. A 50% decrease in manganese superoxide dismutase (MnSOD) activity was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice, with no change in the activities of either glutathione peroxidase or copper/zinc superoxide dismutase. However, the level of total glutathione was 30% less in liver mitochondria of the Sod2(-/+) mice. The reduction in MnSOD activity in Sod2(-/+) mice was correlated to an increase in oxidative damage to mitochondria: decreased activities of the Fe-S proteins (aconitase and NADH oxidoreductase), increased carbonyl groups in proteins, and increased levels of 8-hydroxydeoxyguanosine in mitochondrial DNA. In contrast, there were no significant changes in oxidative damage in the cytosolic proteins or nuclear DNA. The increase in oxidative damage in mitochondria was correlated to altered mitochondrial function. A significant decrease in the respiratory control ratio was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice for substrates metabolized by complexes I, II, and III. In addition, mitochondria isolated from Sod2(-/+) mice showed an increased rate of induction of the permeability transition. Therefore, this study provides direct evidence correlating reduced MnSOD activity in vivo to increased oxidative damage in mitochondria and alterations in mitochondrial function.

This study characterizes mitochondria isolated from livers of Sod2(-/+) and Sod2(+/+) mice. A 50% decrease in manganese superoxide dismutase (MnSOD) activity was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice, with no change in the activities of either glutathione peroxidase or copper/zinc superoxide dismutase. However, the level of total glutathione was 30% less in liver mitochondria of the Sod2(-/+) mice. The reduction in MnSOD activity in Sod2(-/+) mice was correlated to an increase in oxidative damage to mitochondria: decreased activities of the Fe-S proteins (aconitase and NADH oxidoreductase), increased carbonyl groups in proteins, and increased levels of 8-hydroxydeoxyguanosine in mitochondrial DNA. In contrast, there were no significant changes in oxidative damage in the cytosolic proteins or nuclear DNA. The increase in oxidative damage in mitochondria was correlated to altered mitochondrial function. A significant decrease in the respiratory control ratio was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice for substrates metabolized by complexes I, II, and III. In addition, mitochondria isolated from Sod2(-/+) mice showed an increased rate of induction of the permeability transition. Therefore, this study provides direct evidence correlating reduced MnSOD activity in vivo to increased oxidative damage in mitochondria and alterations in mitochondrial function.

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Large-conductance Ca 2+ -activated K + channels (BK channels) are widely expressed throughout the vertebrate nervous system, and are involved in the regulation of neurotransmitter release and neuronal excitability. Here, the neuroprotective effects of NS11021, a selective and chemically unrelated BK channel activator, and potential molecular mechanism involved have been studied in rat cortical neurons exposed to glutamate in vitro. Pretreatment with NS11021 significantly inhibited the loss of neuronal viability, LDH release and neuronal apoptosis in a dose-dependent manner. All these protective effects were fully antagonized by the BK-channel inhibitor paxilline. NS11021-induced neuroprotection was associated with reduced oxidative stress, as evidenced by decreased reactive oxygen species (ROS) generation, lipid peroxidation and preserved activity of antioxidant enzymes. Moreover, NS11021 significantly attenuated the glutamate-induced endoplasmic reticulum (ER) calcium release and activation of ER stress markers, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12. Pretreatment with NS11021 also mitigated the mitochondrial membrane potential (MMP) collapse, cytochrome c release, and preserved mitochondrial Ca 2+ buffering capacity and ATP synthesis after glutamate exposure. Taken together, these results suggest that activation of BK channels via NS11021 protects cortical neurons against glutamate-induced excitatory damage, which may be dependent on the inhibition of ER stress and preservation of mitochondrial dysfunction.

Mitochondria are as highly specialized organelles and masters of the cellular energy metabolism in a constant and dynamic interplay with their cellular environment, providing adenosine triphosphate, buffering Ca2+ and fundamentally contributing to various signaling pathways. Hence, such broad field of action within eukaryotic cells requires a high level of structural and functional adaptation. Therefore, mitochondria are constantly moving and undergoing fusion and fission processes, changing their shape and their interaction with other organelles. Moreover, mitochondrial activity gets fine‐tuned by intra‐ and interorganelle H+, K+, Na+, and Ca2+ signaling. In this review, we provide an up‐to‐date overview on mitochondrial strategies to adapt and respond to, as well as affect, their cellular environment. We also present cutting‐edge technologies used to track and investigate subcellular signaling, essential to the understanding of various physiological and pathophysiological processes.

We prove that groups acting geometrically on delta-quasiconvex spaces contain no essential Baumslag-Solitar quotients as subgroups. This implies that they are translation discrete, meaning that the translation numbers of their nontorsion elements are bounded away from zero.

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Numerous human pathologies result from unrepaired oxidative DNA damage. Base excision repair (BER) is responsible for the repair of oxidative DNA damage that occurs in both nuclei and mitochondria. Despite the importance of BER in maintaining genomic stability, knowledge concerning the regulation of this evolutionarily conserved repair pathway is almost nonexistent. The Saccharomyces cerevisiae BER protein, Ntg1, relocalizes to organelles containing elevated oxidative DNA damage, indicating a novel mechanism of regulation for BER. We propose that dynamic localization of BER proteins is modulated by constituents of stress response pathways. In an effort to mechanistically define these regulatory components, the elements necessary for nuclear and mitochondrial localization of Ntg1 were identified, including a bipartite classical nuclear localization signal, a mitochondrial matrix targeting sequence and the classical nuclear protein import machinery. Our results define a major regulatory system for BER which when compromised, confers a mutator phenotype and sensitizes cells to the cytotoxic effects of DNA damage.

Reactive oxygen species (ROS) are generated as by-products of respiration and are used as signal transducing intermediates in out-in signaling pathways. ROS are also generated during inflammatory responses and it has been shown that hydrogen peroxide may trigger activation of B-lymphocytes, similar to cross-linking of surface immunoglobulins. On the other hand, both exogenous and endogenous generated ROS are a major source of nuclear and mitochondrial DNA (mtDNA) damage. The base excision repair (BER) enzyme APE/Ref-1 normally repairs small nuclear DNA lesion such as oxidized or alkylated bases. It is not clear though whether DNA repair mechanisms able to abolish oxidative damage from nuclear DNA are present into mitochondria too. Here we show by confocal microscopy and Western blot analysis that in the B-lymphocyte Raji cell line a fraction of APE/Ref-1 rapidly re-localizes into mitochondria following H(2)O(2) activation. Targeting of APE/Ref-1 to mitochondria is not associated with cytochrome-c loss or apoptosis induction. These findings indicate that the APE/Ref-1 translocates to mitochondria in response to oxidative stress and thereby it might exert a protective function.

We prove that groups acting geometrically on delta-quasiconvex spaces contain no essential Baumslag-Solitar quotients as subgroups. This implies that they are translation discrete, meaning that the translation numbers of their nontorsion elements are bounded away from zero.

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Although valproic acid (VPA) a proven anticonvulsant agent thought to have relatively few side-effects VPA has been referred as the third most common xenobiotic suspected of causing death due to liver injury. In this study the cellular pathways involved in VPA hepatotoxicity were investigated in isolated rat hepatocytes. Accelerated cytotoxicity mechanism screening (ACMS) techniques using fluorescent probes including, ortho-phthalaldehyde, rhodamine 123 and acridine orange were applied for measurement of ROS formation, glutathione depletion, mitochondrial membrane potential and Lysosomal membrane damage, respectively. Our results showed that cytotoxic action of VPA is mediated by lysosomal membrane leakiness along with reactive oxygen species (ROS) formation and decline of mitochondrial membrane potential before cell lysis ensued. Incubation of hepatocytes with VPA also caused rapid hepatocyte glutathione (GSH) depletion which is another marker of cellular oxidative stress. Most of the VPA induced GSH depletion could be attributed to the expulsion of GSSG. Our results also showed that CYP2EI is involved in the mechanism of VPA cytotoxicity. We finally concluded that VPA hepatotoxicity is a result of metabolic activation by CYP2E1 and ROS formation, leading to lysosomal labialization, mitochondrial/lysosomal toxic cross-talk and finally general cellular proteolysis in the rat hepatocytes.

Palladium (Pd) accumulates in many organs and renders many deleterious effects. Although the Pd toxicity has been documented, the precise mechanism of Pd toxicity still needs to be elucidated. In the current research, a hepatotoxicity mechanism of Pd has been investigated. Our findings clearly indicate that Pd induces reactive oxygen species (ROS) formation and oxidative stress, mitochondrial and lysosomal injury and finally cell death. These effects are reversed by antioxidants and ROS scavengers, mitochondrial permeability transmission [1] pore sealing agent, ATP progenitor, and lysosomotropic agent. Pretreatment of hepatocytes with ROS scavengers and MPT pore sealing agents reduced cell death which explains the role of oxidative stress and mitochondrial pathway of ROS formation in Pd hepatocytes cell toxicity. Overall, the results have distinctly determined the mechanism by which Pd-induced toxicity in the isolated rat hepatocytes. Keywords : Palladium; rat hepatocytes; reactive oxygen species; mitochondria; lysosome.

Valproic acid (VPA) is a widely used antiepileptic drug to treat epilepsy and psychiatric disorders, but potentially causes idiosyncratic liver injury. Alpers-Huttenlocher syndrome (AHS), a neurometabolic disorder caused by mutations in mitochondrial DNA polymerase gamma (POLG), is associated with an increased risk of developing fatal VPA hepatotoxicity. However, the mechanistic link of this clinical mystery remains unknown. Here, we established an induced pluripotent stem cell （iPSC） toxicity model to explore the mechanism behind the high risk of VPA-induced liver injury in AHS. By this model, we demonstrated that AHS iPSCs-hepatocytes are more sensitive to VPA-induced mitochondrial-dependent apoptosis than controls. Furthermore, Superoxide flashes, spontaneous bursts of superoxide generation, caused by opening of the mitochondrial permeability transition pore (mPTP), occur more frequently in AHS iPSCs-hepatocytes, and the mPTP inhibitor, cyclosporine A, is able to rescue VPA-induced apoptotic sensitivity. In addition, carnitine and N-acetylcysteine, which has been used to treat VPA-induced liver injury, also rescue VPA-induced apoptotic sensitivity.

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A degeneration-like order for modules

Degenerations and other partial orders on the space of representations of algebras

Familial longevity is characterized by high circadian rhythmicity of serum cholesterol in healthy elderly individuals

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Protein phosphatase 4 regulates apoptosis in leukemic and primary human T-cells

The control of T-cell survival is of overwhelming importance for preventing leukemia and lymphoma. The present report demonstrates that the serine/threonine protein phosphatase PP4 regulates the survival of both leukemic T-cells and untransformed human peripheral blood T-cells, particularly after treatment with anti-leukemic drugs and other cytotoxic stimuli. PP4-induced apoptosis is mediated, at least in part, through de-phosphorylation of apoptosis regulator PEA-15, previously implicated in the control of leukemic cell survival. PP4 activity significantly affects the mutation rate in leukemic T-cells, indicating that PP4 dysfunction may be important in the development and progression of leukemia.

A recurring problem in forensic medicine is the need to fix the time of death within the limits of probability. Errors in overestimating and underestimating the post-mortem interval based on body cooling is common. Post-mortem biochemistry has become a potent additional procedure in forensic death investigation. However, in our experiment, to determine the post-mortem interval we investigated the ATPase activity. The investigation was performed on the liver tissue of 25 corpses (21 men and four women) of age ranging between 40–60 years. The study of ATPase enzymatic activity shows that there is a considerable drop in the levels of ATPase activity with increasing post-mortem interval up to 24 h and this is one of the most reliable methods for estimating time of death.

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Reactive Oxygen Species Regulation of Autophagy in Skeletal Muscles

Abstract Objective: To evaluate the effects of physiological levels of mitochondrial-derived reactive oxygen species (ROS) on skeletal muscle autophagy, a proteolytic pathway designed to regulate contractile and myofilament homeostasis and to recycle long-lived proteins and damaged organelles. Results: Basal levels of autophagy and autophagy triggered by 1.5 to 4 h of acute nutrient deprivation, rapamycin treatment, or leucine deprivation were measured in differentiated C2C12 myotubes using long-lived protein degradation assays, LC3B lipidation, autophagy-related gene expression, and electron microscopy. Preincubation with the general antioxidants tempol (superoxide dismutase mimic) and N-acetyl cysteine (NAC) or the mitochondria-specific antioxidants mito-tempol and SS31 significantly decreased the rates of long-lived protein degradation and LC3B flux and blocked the induction of autophagy-related gene expression. Mitochondrial ROS levels significantly increased in response to acute nutrient deprivation ...

E-mail: [email protected] February 2, 2011, Accepted February 3, 2012Key Words : Chromatin immunoprecipitation, Protein kinase A, Osteoblast, OsteopontinVitamin D receptor (VDR) is a member of nuclear receptorfamily of transcription factors and mediates the molecularactions of 1,25-dihydroxyvitamin D

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What are guanosine triphosphate-binding proteins doing in mitochondria?

The discovery of GTP-binding proteins in mitochondria is a recent event. These regulatory proteins may be participating in membrane fusion and thereby playing important roles in the physiology of the mitochondrion. So far, it has been proposed that GTP-binding protein mediated membrane fusion may be involved in protein import, steroid hormone production and mitochondrial amalgamation during spermatogenesis.

Abstract Preeclampsia is a multisystem disorder unique to human pregnancy, characterized by abnormal placentation. Although its causes remain unclear, it is known that the expression of several transporters is altered. Transient receptor potential vanilloid 1 (TRPV-1) is a nonselective cation channel, present in human placenta. Here, we evaluated the expression of TRPV-1 in preeclamptic placentas. We observed a deregulation in TRPV-1 expression in these placentas which may explain the impaired Ca 2+ homeostasis found in preeclampsia.

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Principal component analysis: a review and recent developments

What is principal component analysis?

Mitochondrial bioenergetics decay in aging: beneficial effect of melatonin

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Sex differences in longevity and aging are seen throughout the animal kingdom. These are likely to result, in part, from sex differences in endocrinology. In the nematode Caenorhabditis elegans, males are the longer-lived sex. Here we explore the possibility that sex differences in insulin/insulin-like growth factor 1 (IGF-1) and steroid endocrinology contribute to this sex difference in aging by studying C. elegans populations in liquid culture. We report that in hermaphrodite populations, mutational loss of the DAF-12 steroid receptor affected life span as in previous plate-culture studies: mutant longevity is suppressed in a weak daf-2 insulin/IGF-1 receptor mutant but enhanced in a stronger daf-2 mutant. However, in males, mutation of daf-12 had little effect on aging in either weak or strong daf-2 mutants. Moreover, while mutation of daf-12 marginally reduced life span in daf-2(+) hermaphrodites, as in plate-cultured populations, it did not in daf-2(+) males. These results could imply that in C. elegans, as in mammals, sex differences in steroid endocrinology contribute to sex differences in aging.. Title: Pedestrian Detection via Periodic Motion Analysis

Sterol-sensing nuclear receptors and insulin-like growth factor signaling play evolutionarily conserved roles in the control of aging. In the nematode Caenorhabditis elegans, bile acid-like steroid hormones known as dafachronic acids (DAs) influence longevity by binding to and regulating the activity of the conserved nuclear receptor DAF-12, and the insulin receptor (InsR) ortholog DAF-2 controls life span by inhibiting the FoxO transcription factor DAF-16. How the DA/DAF-12 pathway interacts with DAF-2/InsR signaling to control life span is poorly understood. Here we specifically investigated the roles of liganded and unliganded DAF-12 in life span control in the context of reduced DAF-2/InsR signaling. In animals with reduced daf-2/InsR activity, mutations that either reduce DA biosynthesis or fully abrogate DAF-12 activity shorten life span, suggesting that liganded DAF-12 promotes longevity. In animals with reduced DAF-2/InsR activity induced by daf-2/InsR RNAi, both liganded and unliganded DAF-12 promote longevity. However, in daf-2/InsR mutants, liganded and unliganded DAF-12 act in opposition to control life span. Thus, multiple DAF-12 activities influence life span in distinct ways in contexts of reduced DAF-2/InsR signaling. Our findings establish new roles for a conserved steroid signaling pathway in life span control and elucidate interactions among DA biosynthetic pathways, DAF-12, and DAF-2/InsR signaling in aging.. Title: A phospholipid transfer function of ER-mitochondria encounter structure revealed in vitro

Females live longer than males in many species, including humans. We have traced a possible explanation for this phenomenon to the beneficial action of estrogens, which bind to estrogen receptors and increase the expression of longevity-associated genes, including those encoding the antioxidant enzymes superoxide dismutase and glutathione peroxidase. As a result, mitochondria from females produce fewer reactive oxygen species than those from males. Administering estrogens has serious drawbacks, however--they are feminizing (and thus cannot be administered to males) and may increase the incidence of serious diseases such as uterine cancer in postmenopausal women. Phytoestrogens, which are present in soy or wine, may have some of the favorable effects of estrogens without their undesirable effects. Study of gender differences in longevity may help us to understand the basic processes of aging and to devise practical strategies to increase the longevity of both females and males.. Title: Why females live longer than males: control of longevity by sex hormones.

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Chaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolic proteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-control systems. We have previously found that CMA activity declines in aged organisms and have proposed that this failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormal cellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determine whether these negative features of aging can be prevented by maintaining efficient autophagic activity until late in life, in this work we have corrected the CMA defect in aged rodents. We have generated a double transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shown to decrease in abundance with age, can be modulated. We have analyzed in this model the consequences of preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular and organ levels. We show here that CMA activity is maintained until advanced ages if the decrease in the receptor abundance is prevented and that preservation of autophagic activity is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function.. Title: Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury.

Mutant dwarf and calorie-restricted mice benefit from healthy aging and unusually long lifespan. In contrast, mouse models for DNA repair-deficient progeroid syndromes age and die prematurely. To identify mechanisms that regulate mammalian longevity, we quantified the parallels between the genome-wide liver expression profiles of mice with those two extremes of lifespan. Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice. Subsequent analysis of significantly over-represented biological processes revealed suppression of the endocrine and energy pathways with increased stress responses in both delayed and premature aging. To test the relevance of these processes in natural aging, we compared the transcriptomes of liver, lung, kidney, and spleen over the entire murine adult lifespan and subsequently confirmed these findings on an independent aging cohort. The majority of genes showed similar expression changes in all four organs, indicating a systemic transcriptional response with aging. This systemic response included the same biological processes that are triggered in progeroid and long-lived mice. However, on a genome-wide scale, transcriptomes of naturally aged mice showed a strong association to progeroid but not to long-lived mice. Thus, endocrine and metabolic changes are indicative of "survival" responses to genotoxic stress or starvation, whereas genome-wide associations in gene expression with natural aging are indicative of biological age, which may thus delineate pro- and anti-aging effects of treatments aimed at health-span extension.. Title: Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients.

Liver is a vital organ with many important functions, and the maintenance of normal hepatic function is necessary for health. As an essential mechanism for maintaining cellular homeostasis, autophagy plays an important role in ensuring normal organ function. Studies have indicated that the degeneration of hepatic function is associated with autophagic deficiency in aging liver. However, the underlying mechanisms still remain unclear. The serine protease Omi/HtrA2 belongs to the HtrA family and promotes apoptosis through either the caspase-dependent or caspase-independent pathway. Mice lacking Omi/HtrA2 exhibited progeria symptoms (premature aging), which were similar to the characteristics of autophagic insufficiency. In this study, we demonstrated that both the protein level of Omi/HtrA2 in liver and hepatic function were reduced as rats aged, and there was a positive correlation between them. Furthermore, several autophagy-related proteins (LC3II/I, Beclin-1 and LAMP2) in rat liver were decreased significantly with the increasing of age. Finally, inhibition of Omi/HtrA2 resulted in reduced autophagy and hepatic dysfunction. In conclusion, these results suggest that Omi/HtrA2 participates in age-related autophagic deficiency in rat liver. This study may offer a novel insight into the mechanism involved in liver aging.. Title: Omi/HtrA2 Participates in Age-Related Autophagic Deficiency in Rat Liver

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Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging. " Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people. The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging. This article reports the main outcomes of this session.. Title: Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

During aging, the mechanisms that normally maintain health and stress resistance strikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how this decline occurs is unknown. Changes in transcriptional networks and chromatin state lie at the heart of age-dependent decline. These epigenomic changes are not only observed during aging but also profoundly affect cellular function and stress resistance, thereby contributing to the progression of aging. We propose that the dysregulation of transcriptional and chromatin networks is a crucial component of aging. Understanding age-dependent epigenomic changes will yield key insights into how aging begins and progresses and should lead to the development of new therapeutics that delay or even reverse aging and age-related diseases.. Title: The Aging Epigenome.

The concept of frailty as a medically distinct syndrome has evolved based on the clinical experience of geriatricians and is clinically well recognizable. Frailty is a nonspecific state of vulnerability, which reflects multisystem physiological change. These changes underlying frailty do not always achieve disease status, so some people, usually very elderly, are frail without a specific life threatening illness. Current thinking is that not only physical but also psychological, cognitive and social factors contribute to this syndrome and need to be taken into account in its definition and treatment. Together, these signs and symptoms seem to reflect a reduced functional reserve and consequent decrease in adaptation (resilience) to any sort of stressor and perhaps even in the absence of extrinsic stressors. The overall consequence is that frail elderly are at higher risk for accelerated physical and cognitive decline, disability and death. All these characteristics associated with frailty can easily be applied to the definition and characterization of the aging process per se and there is little consensus in the literature concerning the physiological/biological pathways associated with or determining frailty. It is probably true to say that a consensus view would implicate heightened chronic systemic inflammation as a major contributor to frailty. This review will focus on the relationship between aging, frailty and age-related diseases, and will highlight possible interventions to reduce the occurrence and effects of frailty in elderly people.. Title: Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process

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causes of death with parkinson's

Parkinson's disease is not fatal in itself, and many people with Parkinson's have a normal lifespan. But depending on your symptoms, Parkinson's disease can increase the risk of dying from complications such as falls, choking, and pneumonia.

causes of parkinson s disease parkinson s disease is caused by a loss of nerve cells in the part of the brain called the substantia nigranerve cells in this part of the brain are responsible for producing a chemical called dopaminearkinson s disease is caused by a loss of nerve cells in the part of the brain called the substantia nigra

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diseases caused by dysfunctional cells

Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell.itochondrial diseases as a rule are worse when the defective mitochondria are present in the muscles, cerebrum, or nerves, because these cells use more energy than most other cells in the body.

Mitochondrial diseases result from failures of the mitochondria, specialized compartments present in every cell of the body except red blood cells. Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth.itochondrial diseases result from failures of the mitochondria, specialized compartments present in every cell of the body except red blood cells. Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth.

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is coenzyme q a protein

Coq10, a mitochondrial coenzyme Q binding protein, is required for proper respiration in Schizosaccharomyces pombe. Cui TZ(1), Kawamukai M. Author information: (1)Department of Applied Bioscience and Biotechnology, Faculty of Life and Environmental Science, Shimane University, Matsue, Japan.

1 Coenzyme Q10 (commonly known as CoQ10) is a compound that is made naturally in the body. 2 The body uses it for cell growth and to protect cells from damage that could lead to cancer (see Question 1). coenzyme helps an enzyme do its job. An enzyme is a protein that speeds up the rate at which natural chemical reactions take place in cells of the body. The body's cells use CoQ10 to make energy needed for the cells to grow and stay healthy. The body also uses CoQ10 as an antioxidant.

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Animal Models of OXPHOS Disorders

Dysfunction of the mitochondrial respiratory chain has been associated with a wide range of human diseases ranging from diabetes to cardiomyopathy. Mutations in a number of nuclear as well as mitochondrial genes have been implicated in causing these diseases. Several animal models have now been created which reproduce some of the clinical pathology observed in human patients suffering from OXPHOS disorders. In this chapter we review some of these animal models of OXPHOS disorders and how they have led to a further understanding of both mitochondrial respiratory chain function and dysfunction.

Meerkats, Oreo the raccoon and cosy craft sessions are on offer to keep the kids entertained over half-term at Sandwell’s Oak House Museum.

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Smoking cessation increases the resistance of low-density lipoprotein to oxidation

Abstract The effects of smoking cessation on the susceptibility to oxidation of low-density lipoprotein (LDL) was investigated in 14 men who quit smoking for 3 months. LDL was isolated and susceptibility of LDL to V-70 (4-methoxy-2,4-dimethylvalerinitrile)-mediated oxidation was assessed by measuring conjugated diene production at 234 nm, the lag phase being a measure of the resistance of LDL to oxidation. The mean duration of the lag phase became 1.9-fold longer after 3 months ( P

Abstract To identify changes in proteins accompanying transformation of normal lung epithelial cells to cancer cells, we performed a comparative proteomic study using two cell lines representing matching normal and cancer cells. Strikingly, a good number of detected actin cytoskeletal proteins were preferentially downregulated in cancer cells, while similar numbers of proteins in other organelles were up or downregulated. We also found that the formation of stress fibers and focal adhesions were substantially decreased in cancer cells. Protein network analysis showed that the altered proteins are highly connected. These results provide novel insights into the molecular mechanism promoting lung cancer progression.

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Apoptotic mechanisms in mutant LRRK2-mediated cell death.

Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinson's disease. The pathological mutations have been associated with an increase of LRRK2 kinase activity, although its physiological substrates have not been identified yet. The data we report here demonstrate that disease-associated mutant LRRK2 cell toxicity is due to mitochondria-dependent apoptosis. Transient transfection of mutant LRRK2 leads to neuronal death with clear apoptotic signs. Soluble caspase inhibitors or the genetic ablation of Apaf1 protects cells from apoptotic death. Moreover, we explored the function of two protein domains in LRRK2 (LRR and WD40) and demonstrate that the lack of these protein domains has a protective effect on mitochondria dysfunctions induced by mutant LRRK2.

Introduction ::: Left atrium (LA) mechanical functions and atrial electromechanical delay (AEMD) times were considered independent predictors of cardiovascular morbidity in general population. Data are scant about these parameters in end-stage renal disease (ESRD) patients receiving hemodialysis (HD) and peritoneal dialysis (PD). We aimed to evaluate AEMD times and LA mechanical functions and associated risk factors in HD and PD patients.

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Clinical Features of Rhabdomyolysis After Open and Laparoscopic Roux-en-Y Gastric Bypass

Background ::: Rhabdomyolysis (RML) is caused by muscle injury, this may cause kidneys overload and lead to acute renal failure (ARF). The risk factors for RML in bariatric surgery (BS) are operative time (OT) >4 h and high BMI. The frequency of RML in BS varies from 12.9 to 37.8%. This study has the objective of describing the characteristics associated with RML and ARF in BS.

Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinson's disease. The pathological mutations have been associated with an increase of LRRK2 kinase activity, although its physiological substrates have not been identified yet. The data we report here demonstrate that disease-associated mutant LRRK2 cell toxicity is due to mitochondria-dependent apoptosis. Transient transfection of mutant LRRK2 leads to neuronal death with clear apoptotic signs. Soluble caspase inhibitors or the genetic ablation of Apaf1 protects cells from apoptotic death. Moreover, we explored the function of two protein domains in LRRK2 (LRR and WD40) and demonstrate that the lack of these protein domains has a protective effect on mitochondria dysfunctions induced by mutant LRRK2.

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Autophagy and Inflammatory Cell Death, Partners of Innate Immunity

Alas, it is the law of the evolutionary jungle that any host defen! se mechanism that efficiently kills microbes also exerts a strong selective pressure for tolerant variants to emerge. A silver lining in this otherwise dark cloud is that pathogens can be exploited as powerful tools to examine host defense mechanisms. Recent studies of the confrontation between macrophages and the opportunistic pathogen Legionella pneumophila have revealed a regulatory mechanism that may link autophagy to pyroptosis. Building from the extensive literature on autophagy, cell death, and innate immunity, we propose here a testable model in which the NOD-LRR protein Naip5 dictates whether macrophages elevate autophagy or pyroptosis as a barrier to infection.

AbstractBackground: Application of hepatoprotectants, such as drugs or cytokines, can reduce drug-induced hepatotoxicity (DIH). Due to species-specific differences and abnormal cell polarity and dr...

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Programmed cell death: Superman meets Dr Death

This year's Cold Spring Harbor meeting on programmed cell death (September 17-21, 2003), organised by Craig Thompson and Junying Yuan, was proof that the 'golden age' of research in this field is far from over. There was a flurry of fascinating insights into the regulation of diverse apoptotic pathways and unexpected non-apoptotic roles for some of the key apoptotic regulators and effectors. In addition to their role in cell death, components of the apoptotic molecular machinery are now known to also function in a variety of essential cellular processes, such as regulating glucose homeostasis, lipid metabolism, cell proliferation and differentiation.

Over the past several years, a number of clinical prediction rules have been developed to estimate mortality and determine appropriate disposition to

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Mitochondrial dysfunction and cell senescence: cause or consequence?

The mitochondrial theory of aging remains to date one of the most popular theories of aging. One major model of aging is replicative senescence, where the irreversible loss of division potential of somatic cells occurs after a more or less constant number of cell divisions. Few data are available concerning the role of mitochondria in this model. Here, we review evidence supporting the involvement of mitochondria in replicative senescence and a possible link to telomere biology. Moreover, we suggest that this process might be more complex than originally formulated, because variations in nuclear gene expression involved in mitochondrion nucleus cross-talk are observed in both senescence and immortalization.

Technology scaling has enabled increased speed, lower energy consumption and lower die cost. However, new reliability issues appear in these deep sub-micron technologies. The aging of devices during circuit operation will have to be considered during the circuit design phase, so that models that represent the modified behaviour of devices will be needed. In this work, the wear-out of the gate dielectric of MOS devices during electrical stress and its impact on the performance of devices and circuits are addressed. As an example of gate degradation impact on circuits, the wear-out effects in an inverter have been studied.

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A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations

The majority of mitochondrial DNA (mtDNA) mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA mutations would be expected to be severe. To determine the fate of the more severe mtDNA mutations, we introduced mtDNAs containing two mutations that affect oxidative phosphorylation into the female mouse germ line. The severe ND6 mutation was selectively eliminated during oogenesis within four generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, severe mtDNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.

Author contributions ::: ::: GH helped design the study, establish the animal model, collect and analyze samples, and write the manuscript. YY and DH helped establish the animal model, performed Western blotting, immunohistochemistry analyses. YY and DH also helped analyse data and revise the manuscript. QYW and JK contributed to study planning, analyse and interpret data, review and revise the manuscript. All authors have approved the final version of this article to be published and agreed to be accountable for all aspects of the work in ensuring the questions related to the accuracy or integrity of any part of the work. ::: ::: ::: ::: Disclosure ::: ::: The authors report no conflicts of interest in this work.

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Non-identical twins Evelyn and Edith born 1909 when Edward VII on throne . World's oldest twins will celebrate their 104th birthdays on Friday . Lives have seen two World Wars, discovery of penicillin and moon landing . Between them they have eight children, 21 grandchildren, 47 great-grandchildren, and six great-great grandchildren .

By . Chris Pleasance . PUBLISHED: . 11:39 EST, 10 November 2013 . | . UPDATED: . 12:20 EST, 10 November 2013 . In 1909 Queen Victoria had been dead for eight years, her successor Edward VII was on the throne and World War I was still five years from starting. That year also saw the birth of Evelyn and Edith in Scotland, the world's oldest surviving twins, who will celebrate their 104th birthdays on Friday. However the sisters, who live in the same retirement home, may have to spend it apart as one of them is in hospital. Evelyn Middleton (left) and her sister Edith Ritchie are the world's oldest surviving twins and will celebrate their 104th birthdays on Friday . Edith, the older of the two sisters . by 90 minutes, is currently recovering from a operation . after she broke her hip. Her son Nathaniel Ritchie explained that major celebrations at the Bonnyton Care Home in Ellon, Aberdeenshire, where the twins live together, are on hold until his mother returns there. Nathaniel, from nearby Mintlaw, said: 'My mum is doing really well. We were worried when she broke her hip. The doctors said there was no choice but to operate but we were told there were risks for someone of her age. In the early part of the 20th century Ernest 'Biggie' Shackleton was attempting to reach the South Pole, the Panama Canal started construction and future Poet Laureate John Betjeman had just been born . 'Others younger than her had been refused the procedure because their hearts were not strong enough. Obviously hers is. 'She is just waiting for a special bed to be delivered to Bonnyton so that she can go back there. 'If it doesn't arrive before the birthday, we'll be taking a cake with 'Happy 104th birthday' on it into hospital.' Through the course of their life the ladies have seen artist Picasso produce his finest work, watched as silent film star Charlie Chaplin rose to fame and witnessed DH Lawrence's book Lady Chatterly's Lover scadalise England. They have also lived through both World Wars, watched men walk on the moon and seen the coronation of our Queen, Elizabeth II. After the passing of their husbands the sisters helped to look after one-another and as Evelyn's eyesight failed Edith, who puts her longevity down to hard work and a bowl of porridge every morning, started reading the paper to her. Evelyn married William Middleton and had four children, 12 grandchildren, 26 great-grandchildren and three great-great grandchildren. Edith married Nathaniel Ritchie and had four children, nine grandchildren, 21 great-grandchildren and three great-great grandkids. Evelyn's daughter Eveline, 83, from Cruden Bay, said: 'My mum and her sister just get on with life. They really are amazing.'

Living to the ripe old age of 500 might be a possibility if the science shown to extend worms' lives can be applied to humans, scientists have said. U.S. researchers tweaked two genetic pathways in the tiny lab worm Caenorhabditis elegans and boosted the creature's lifespan by a factor of five. The research raises the prospect of anti-ageing treatments based on genetic interactions, they said. U.S. scientists tweaked two genetic pathways in the tiny lab worm Caenorhabditis elegans (pictured) and boosted the creature's lifespan by a factor of five . ‘What we have here is a synergistic five-fold increase in lifespan,’ said lead scientist Dr Pankaj Kapahi, from the Buck Institute of Age Research, Novato, California. ‘The two mutations set off a positive feedback loop in specific tissues that amplified lifespan. ‘Basically these worms lived to the human equivalent of 400 to 500 years.’ Living to the age of 500 might be a possibility if the science shown to extend worms' lives can be applied to humans, scientists said. Two mutations set off a positive feedback loop in specific tissues that enabled worms to live to the human equivalent of 400 to 500 years . While it could take years of research to . extend humans’ lives dramatically, the study raises the prospect of . anti-ageing treatments informed by genetic interactions, according to Dr . Kapahi. ‘In the early years, cancer researchers focused on mutations in single genes, but then it became apparent that different mutations in a class of genes were driving the disease process,’ he said. While it could take years of research to extend humans' lives, the study raises the prospect of anti-ageing treatments informed by genetic interactions . ‘The same thing is likely happening in ageing,’ he added. C. elegans, the first animal to have its whole genome (or genetic code) mapped, has been widely used in studies of ageing and lifespan. The new research, reported in the journal Cell Reports, involved blocking key molecules that affect the action of insulin and a nutrient signalling pathway called Target of Rapamycin (TOR). Single mutations in the TOR pathway were known to extend the lifespan of C. elegans by 30 per cent, while insulin-signalling mutations could double the amount of time they lived. Adding the two together might have been expected to extend longevity by 130 per cent, but the combined impact turned out to be much greater. The research may explain why it has proved so difficult to identify single genes responsible for the long lives enjoyed by human centenarians. ‘It's quite probable that interactions between genes are critical in those fortunate enough to live very long, healthy lives,’ said Dr Kapahi. Future research is expected to use mice to see if the same effects occur in mammals. ‘The idea would be to use mice genetically engineered to have suppressed insulin signalling and then treat them with the drug rapamycin, which is well-known to suppress the TOR pathway,’ Dr Kapahi said. Earlier this year British scientists captured death spreading like a wave through the body of a worm, by studying the blue fluorescence that travels cell-to-cell until the whole organism is dead. Researchers from the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC) likened the spread of the blue glow travelling through the worm's body to that of the Grim Reaper, stalking death. They believe that the research could eventually prove to be a useful model to understanding death in people and perhaps even lead to an increase in life expectancy. When individual cells die, they trigger a chemical chain reaction that leads to the breakdown of cell components and a build-up of molecular debris. The molecular mechanisms of this are reasonably well understood at a cellular level but we know much less about how death spreads throughout an organism at the end of its life. In worms, the spread of death can be seen easily under a microscope as a wave of blue fluorescence travelling through the gut of the worm. The study, published in PLoS Biology, reveals that this fluorescence is caused by a cell death pathway called necrosis and its spread throughout the organism is dependent on calcium signalling. In worms, the spread of death can be seen easily under a microscope as a wave of blue fluorescence travelling through the gut of the worm (pictured). This fluorescence is caused by a cell death pathway called necrosis and its spread throughout the organism is dependent on calcium signalling .

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bone broth..chicken carcass, lamb bones with some meat left out for 3 hours from pressure cooking I left my bone broth out after pressure cooking for 3 hours. It was warm when I got home and consisted of a chicken carcass, lamb bones with a bit of meat and the second boiling of marrow beef bones with some vinegar. It gelled so perfectly in the fridge but should we eat it? Would boiling it again for a while make it safe?

How do I know if food left at room temperature is still safe to eat? If I left food out of the refrigerator for some period of time, is it still safe? If I left it out too long, can I salvage it by cooking it more?

why do chaperones bring protein into mitochondria? why would mitochondria need protein? Sounds trivial? Please help to sort out. I saw this picture while looking at dehydration reactions and cell revision. And proceeded to the Protein Folding and Processing in the ER: Various changes occur to proteins in the ER. Chaperones and Folding: Polypeptides must assume the correct folding pattern in order to function properly. The correct folding of a protein is mediated by chaperones (they also are proteins--chaperones are abundant in the ER lumen). A completed polypeptide will assume the correct folding pattern spontaneously, however before translation is complete, it could assume an incorrect formation or it could aggregate with other partially made polypeptides. To prevent this, chaperones in the ER (and cytosol) bind to the nascent polypeptide and keep it from interacting with anything until the polypeptide is completely synthesized. (Chaperones bind to polypeptides destined for mitochondria then release them as they pass through the mitochondrial membranes. Chaperones on the inside of mitochondria bind until these polypeptides have completely entered.) With regards to protein synthesis and folding, this kind of info is not in my textbook. Not in couple of the online open textbooks either. I even search for where do protein fold? to find out if there was a relationship. It doesn't say protein fold in mitochondria and turns out it's a question most scientist are looking for answers. For whatever protein synthesis I have learnt so far, there was no mentioning of protein strands going into mitochondria but mitochondria as a power houses. What's going on here? Why would a protein go into a mitochondria? How does it exit and where to?

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What was Daenerys Targaryen's motive in the final chapter of A Game of Thrones? If you haven't read the book massive spoilers ahead... It's been years since I've read the book but is it ever explicitly said what Daenerys' motive was for putting the dragon eggs, Mirri Maz Duur, and herself into Drogo's funeral pyre? Did she know this would hatch the dragon eggs? Suspect it? Or was it pure grief and desperation?

Was Daenerys actually trying to hatch the eggs? I was reading @Aegon' s response and I realized that I've never been clear on whether Dani was intentional in her pyre building to do blood magic and wake the dragons, or if she was just grieving Drogo and killing Mirri and her statement about "only death can pay for life" was a slap in the Maegi's face, since in the end she sacrificed her unborn child for the husk of Drogo. I know she had tried baking the eggs previously and had felt like they could hatch then, but was clearly disappointed and chastised herself for foolishness when they did not. I don't recall inner monologue or statements after that where she said, "ya know what I should have done..." I guess what I'm asking is whether there is evidence outside her statement to the Maegi that she was intentional in her blood magic rite or if the miracle was a happy accident?

why do chaperones bring protein into mitochondria? why would mitochondria need protein? Sounds trivial? Please help to sort out. I saw this picture while looking at dehydration reactions and cell revision. And proceeded to the Protein Folding and Processing in the ER: Various changes occur to proteins in the ER. Chaperones and Folding: Polypeptides must assume the correct folding pattern in order to function properly. The correct folding of a protein is mediated by chaperones (they also are proteins--chaperones are abundant in the ER lumen). A completed polypeptide will assume the correct folding pattern spontaneously, however before translation is complete, it could assume an incorrect formation or it could aggregate with other partially made polypeptides. To prevent this, chaperones in the ER (and cytosol) bind to the nascent polypeptide and keep it from interacting with anything until the polypeptide is completely synthesized. (Chaperones bind to polypeptides destined for mitochondria then release them as they pass through the mitochondrial membranes. Chaperones on the inside of mitochondria bind until these polypeptides have completely entered.) With regards to protein synthesis and folding, this kind of info is not in my textbook. Not in couple of the online open textbooks either. I even search for where do protein fold? to find out if there was a relationship. It doesn't say protein fold in mitochondria and turns out it's a question most scientist are looking for answers. For whatever protein synthesis I have learnt so far, there was no mentioning of protein strands going into mitochondria but mitochondria as a power houses. What's going on here? Why would a protein go into a mitochondria? How does it exit and where to?

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Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase

The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death Pathways

studies rethinking bank efficiency and regulation : how off - balance - sheet activities make a difference .

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Everything Hertz: methodological issues in short-term frequency-domain HRV

The LF/HF ratio does not accurately measure cardiac sympatho-vagal balance

Candida albicans Triggers NLRP3-Mediated Pyroptosis in Macrophages

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Substrate Integrated Waveguide (SIW) Monopulse Slot Antenna Array

A broadband substrate integrated waveguide (SIW) filter

Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils

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The BCL-2 (B cell CLL/Lymphoma) family is comprised of approximately twenty proteins that collaborate to either maintain cell survival or initiate apoptosis(1). Following cellular stress (e.g., DNA damage), the pro-apoptotic BCL-2 family effectors BAK (BCL-2 antagonistic killer 1) and/or BAX (BCL-2 associated X protein) become activated and compromise the integrity of the outer mitochondrial membrane (OMM), though the process referred to as mitochondrial outer membrane permeabilization (MOMP)(1). After MOMP occurs, pro-apoptotic proteins (e.g., cytochrome c) gain access to the cytoplasm, promote caspase activation, and apoptosis rapidly ensues(2). In order for BAK/BAX to induce MOMP, they require transient interactions with members of another pro-apoptotic subset of the BCL-2 family, the BCL-2 homology domain 3 (BH3)-only proteins, such as BID (BH3-interacting domain agonist)(3-6). Anti-apoptotic BCL-2 family proteins (e.g., BCL-2 related gene, long isoform, BCL-xL; myeloid cell leukemia 1, MCL-1) regulate cellular survival by tightly controlling the interactions between BAK/BAX and the BH3-only proteins capable of directly inducing BAK/BAX activation(7,8). In addition, anti-apoptotic BCL-2 protein availability is also dictated by sensitizer/de-repressor BH3-only proteins, such as BAD (BCL-2 antagonist of cell death) or PUMA (p53 upregulated modulator of apoptosis), which bind and inhibit anti-apoptotic members(7,9). As most of the anti-apoptotic BCL-2 repertoire is localized to the OMM, the cellular decision to maintain survival or induce MOMP is dictated by multiple BCL-2 family interactions at this membrane. Large unilamellar vesicles (LUVs) are a biochemical model to explore relationships between BCL-2 family interactions and membrane permeabilization(10). LUVs are comprised of defined lipids that are assembled in ratios identified in lipid composition studies from solvent extracted Xenopus mitochondria (46.5% phosphatidylcholine, 28.5% phosphatidylethanoloamine, 9% phosphatidylinositol, 9% phosphatidylserine, and 7% cardiolipin)(10). This is a convenient model system to directly explore BCL-2 family function because the protein and lipid components are completely defined and tractable, which is not always the case with primary mitochondria. While cardiolipin is not usually this high throughout the OMM, this model does faithfully mimic the OMM to promote BCL-2 family function. Furthermore, a more recent modification of the above protocol allows for kinetic analyses of protein interactions and real-time measurements of membrane permeabilization, which is based on LUVs containing a polyanionic dye (ANTS: 8-aminonaphthalene-1,3,6-trisulfonic acid) and cationic quencher (DPX: p-xylene-bis-pyridinium bromide)(11). As the LUVs permeabilize, ANTS and DPX diffuse apart, and a gain in fluorescence is detected. Here, commonly used recombinant BCL-2 family protein combinations and controls using the LUVs containing ANTS/DPX are described.. Title: Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.

Apoptosis that proceeds via the mitochondrial pathway involves mitochondrial outer membrane permeabilization (MOMP), responsible for the release of cytochrome c and other proteins of the mitochondrial intermembrane space. This essential step is controlled and mediated by proteins of the Bcl-2 family. The proapoptotic proteins Bax and Bak are required for MOMP, while the antiapoptotic Bcl-2 proteins, including Bcl-2, Bcl-xL, Mcl-1, and others, prevent MOMP. Different proapoptotic BH3-only proteins act to interfere with the function of the antiapoptotic Bcl-2 members and/or activate Bax and Bak. Here, we discuss an emerging view, proposed by Certo et al. in this issue of Cancer Cell, on how these interactions result in MOMP and apoptosis.. Title: Updated energy budgets for neural computation in the neocortex and cerebellum.

Proteasome inhibitors induce rapid death of cancer cells. We show that in epithelial cancer cells, such death is associated with dramatic and simultaneous up-regulation of several BH3-only proteins, including BIK, BIM, MCL-1S, NOXA, and PUMA, as well as p53. Elevated levels of these proteins seem to be the result of direct inhibition of their proteasomal degradation, induction of transcription, and active translation. Subsequent cell death is independent of BAX, and probably BAK, and proceeds through the intrinsic mitochondrial apoptosis pathway. We identify the cascade of molecular events responsible for cell death induced by a prototypical proteasome inhibitor, MG132, starting with rapid accumulation of BH3-only proteins in the mitochondria, proceeding through mitochondrial membrane permeabilization and subsequent loss of DeltaPsi(m), and leading to irreversible changes of mitochondrial ultrastructure, degradation of mitochondrial network, and detrimental impairment of crucial mitochondrial functions. Our results also establish a rationale for the broader use of proteasome inhibitors to kill apoptosis-resistant tumor cells that lack functional BAX/BAK proteins.. Title: BAX/BAK-independent mitoptosis during cell death induced by proteasome inhibition?

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Sterol-sensing nuclear receptors and insulin-like growth factor signaling play evolutionarily conserved roles in the control of aging. In the nematode Caenorhabditis elegans, bile acid-like steroid hormones known as dafachronic acids (DAs) influence longevity by binding to and regulating the activity of the conserved nuclear receptor DAF-12, and the insulin receptor (InsR) ortholog DAF-2 controls life span by inhibiting the FoxO transcription factor DAF-16. How the DA/DAF-12 pathway interacts with DAF-2/InsR signaling to control life span is poorly understood. Here we specifically investigated the roles of liganded and unliganded DAF-12 in life span control in the context of reduced DAF-2/InsR signaling. In animals with reduced daf-2/InsR activity, mutations that either reduce DA biosynthesis or fully abrogate DAF-12 activity shorten life span, suggesting that liganded DAF-12 promotes longevity. In animals with reduced DAF-2/InsR activity induced by daf-2/InsR RNAi, both liganded and unliganded DAF-12 promote longevity. However, in daf-2/InsR mutants, liganded and unliganded DAF-12 act in opposition to control life span. Thus, multiple DAF-12 activities influence life span in distinct ways in contexts of reduced DAF-2/InsR signaling. Our findings establish new roles for a conserved steroid signaling pathway in life span control and elucidate interactions among DA biosynthetic pathways, DAF-12, and DAF-2/InsR signaling in aging.. Title: A phospholipid transfer function of ER-mitochondria encounter structure revealed in vitro

Mutations in daf-2 and age-1 cause a dramatic increase in longevity as well as developmental arrest at the dauer diapause stage in Caenorhabditis elegans. daf-2 and age-1 encode components of an insulin-like signaling pathway. Both daf-2 and age-1 act at a similar point in the genetic epistasis pathway for dauer arrest and longevity and regulate the activity of the daf-16 gene. Mutations in daf-16 cause a dauer-defective phenotype and are epistatic to the diapause arrest and life span extension phenotypes of daf-2 and age-1 mutants. Here we show that mutations in this pathway also affect fertility and embryonic development. Weak daf-2 alleles, and maternally rescued age-1 alleles that cause life span extension but do not arrest at the dauer stage, also reduce fertility and viability. We find that age-1(hx546) has reduced both maternal and zygotic age-1 activity. daf-16 mutations suppress all of the daf-2 and age-1 phenotypes, including dauer arrest, life span extension, reduced fertility, and viability defects. These data show that insulin signaling, mediated by DAF-2 through the AGE-1 phosphatidylinositol-3-OH kinase, regulates reproduction and embryonic development, as well as dauer diapause and life span, and that DAF-16 transduces these signals. The regulation of fertility, life span, and metabolism by an insulin-like signaling pathway is similar to the endocrine regulation of metabolism and fertility by mammalian insulin signaling.. Title: A molecular framework for plant regeneration.

Longevity is regulated by the daf-2 gene network in Caenorhabditis elegans. Mutations in the daf-2 gene, which encodes a member of the insulin receptor family, confer the life extension (Age) phenotype and the constitutive dauer (a growth-arrested larval form specialized for dispersal) formation phenotype. The Age phenotype is mutually potentiated by two life extension mutations in the daf-2 gene and the clk-1 gene, a homologue of yeast CAT5/COQ7 known to regulate ubiquinone biosynthesis. In this study, we demonstrated that the daf-2 mutation also conferred an oxidative stress resistance (Oxr) phenotype, which was also enhanced by the clk-1 mutation. Similar to the Age phenotype, the Oxr phenotype was regulated by the genetic pathway of insulin-like signaling from daf-2 to the daf-16 gene, a homologue of the HNF-3/forkhead transcription factor. These findings led us to examine whether the insulin-like signaling pathway regulates the gene expression of antioxidant defense enzymes. We found that the mRNA level of the sod-3 gene, which encodes Mn-superoxide dismutase (SOD), was much higher in daf-2 mutants than in the wild type. Moreover, the increased sod-3 gene expression phenotype is regulated by the insulin-like signaling pathway. Although the clk-1 mutant itself did not display Oxr and the increased sod-3 expression phenotypes, the clk-1 mutation enhanced them in the daf-2 mutant, suggesting that clk-1 is involved in longevity in two ways: clk-1 composes the original clk-1 longevity program and the daf-2 longevity program. These observations suggest that the daf-2 gene network controls longevity by regulating the Mn-SOD-associated antioxidant defense system. This system appears to play a role in efficient life maintenance at the dauer stage.. Title: YOKO HONDA AND SHUJI HONDA 1

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Molecular mechanisms leading to myocardial injury during warm or cold ischemia are insufficiently understood. Although proteasomes are thought to contribute to myocardial ischemia-reperfusion injury, their roles during the ischemic period remain elusive. Because donor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation, we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts in context of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiac proteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of hearts in University of Wisconsin (UW) solution for up to 48h. Addition of the specific proteasome inhibitor epoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reduced edema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified 20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to a subset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATP negatively regulates its activity and that maximal activation occurs at ATP concentrations in the low mumol/L range. These data suggest that proteasome activation is a pathophysiologically relevant mechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be a cell-destructive protease that is activated as ATP levels decline. Proteasome inhibition during cold ischemia preserves the ultrastructural integrity of the cardiomyocyte.. Title: A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes to myocardial injury during cold ischemia.

Mitochondrial permeability transition pore (mPTP) is involved in cardiac dysfunction during chronic β-adrenergic receptor (β-AR) stimulation. The mechanism by which chronic β-AR stimulation leads to mPTP openings is elusive. Here, we show that chronic administration of isoproterenol (ISO) persistently increases the frequency of mPTP openings followed by mitochondrial damage and cardiac dysfunction. Mechanistically, this effect is mediated by phosphorylation of mitochondrial fission protein, dynamin-related protein 1 (Drp1), by Ca2+/calmodulin-dependent kinase II (CaMKII) at a serine 616 (S616) site. Mutating this phosphorylation site or inhibiting Drp1 activity blocks CaMKII- or ISO-induced mPTP opening and myocyte death in vitro and rescues heart hypertrophy in vivo. In human failing hearts, Drp1 phosphorylation at S616 is increased. These results uncover a pathway downstream of chronic β-AR stimulation that links CaMKII, Drp1 and mPTP to bridge cytosolic stress signal with mitochondrial dysfunction in the heart.. Title: CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation

The principal function of the proteasome is targeted degradation of intracellular proteins. Proteasome dysfunction has been observed in experimental cardiomyopathies and implicated in human congestive heart failure. Measures to enhance proteasome proteolytic function are currently lacking but would be beneficial in testing the pathogenic role of proteasome dysfunction and could have significant therapeutic potential. The association of proteasome activator 28 (PA28) with the 20S proteasome may play a role in antigen processing. It is unclear, however, whether the PA28 plays any important role outside of antigen presentation, although up-regulation of PA28 has been observed in certain types of cardiomyopathy. Here, we show that PA28α overexpression (PA28αOE) stabilized PA28β, increased 11S proteasomes, and enhanced the degradation of a previously validated proteasome surrogate substrate (GFPu) in cultured neonatal rat cardiomyocytes. PA28αOE significantly attenuated H(2)O(2)-induced increases in the protein carbonyls and markedly suppressed apoptosis in cultured cardiomyocytes under basal conditions or when stressed by H(2)O(2). We conclude that PA28αOE is sufficient to up-regulate 11S proteasomes, enhance proteasome-mediated removal of misfolded and oxidized proteins, and protect against oxidative stress in cardiomyocytes, providing a highly sought means to increase proteasomal degradation of abnormal cellular proteins.. Title: The NBS1–Treacle complex controls ribosomal RNA transcription in response to DNA damage

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In this review I summarize interrelations between bioenergetic processes and such programmed death phenomena as cell suicide (apoptosis and necrosis) and mitochondrial suicide (mitoptosis). The following conclusions are made. (I) ATP and rather often mitochondrial hyperpolarization (i.e. an increase in membrane potential, ΔΨ) are required for certain steps of apoptosis and necrosis. (II) Apoptosis, even if it is accompanied by ΔΨ and [ATP] increases at its early stage, finally results in a ΔΨ collapse and ATP decrease. (III) Moderate (about three-fold) lowering of [ATP] for short and long periods of time induces apoptosis and necrosis, respectively. In some types of apoptosis and necrosis, the cell death is mediated by a ΔΨ-dependent overproduction of ROS by the initial (Complex I) and the middle (Complex III) spans of the respiratory chain. ROS initiate mitoptosis which is postulated to rid the intracellular population of mitochondria from those that are ROS overproducing. Massive mitoptosis can result in cell death due to release to cytosol of the cell death proteins normally hidden in the mitochondrial intermembrane space.. Title: Bioenergetic aspects of apoptosis, necrosis and mitoptosis

The bulk of ATP consumed by various cellular processes in higher eukaryotes is normally produced by five multimeric protein complexes (I-V) embedded within the inner mitochondrial membrane, in a process known as oxidative phosphorylation (OXPHOS). Maintenance of energy homeostasis under most physiological conditions is therefore contingent upon the ability of OXPHOS to meet cellular changes in bioenergetic demand, with a chronic failure to do so being a frequent cause of human disease. With the exception of Complex II, the structural subunits of OXPHOS complexes are encoded by both the nuclear and the mitochondrial genomes. The physical separation of the two genomes necessitates that the expression of the 13 mitochondrially encoded polypeptides be co-ordinated with that of relevant nuclear-encoded partners in order to assemble functional holoenzyme complexes. Complex biogenesis is a highly ordered process, and several nuclear-encoded factors that function at distinct stages in the assembly of individual OXPHOS complexes have been identified.. Title: Oxidative phosphorylation: synthesis of mitochondrially encoded proteins and assembly of individual structural subunits into functional holoenzyme complexes.

Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of β-oxidation flux by labeled palmitate demonstrates that tBid inhibits β-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on β-oxidation. The unexpected role of tBid in the regulation of lipid β-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.. Title: Hallmarks of Cancer: The Next Generation

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Autophagy plays a central role in regulating important cellular functions such as cell survival during starvation and control of infectious pathogens. Recently, it has been shown that autophagy can induce cells to die; however, the mechanism of the autophagic cell death program is unclear. We now show that caspase inhibition leading to cell death by means of autophagy involves reactive oxygen species (ROS) accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Inhibition of autophagy by chemical compounds or knocking down the expression of key autophagy proteins such as ATG7, ATG8, and receptor interacting protein (RIP) blocks ROS accumulation and cell death. The cause of abnormal ROS accumulation is the selective autophagic degradation of the major enzymatic ROS scavenger, catalase. Caspase inhibition directly induces catalase degradation and ROS accumulation, which can be blocked by autophagy inhibitors. These findings unveil a molecular mechanism for the role of autophagy in cell death and provide insight into the complex relationship between ROS and nonapoptotic programmed cell death.. Title: Autophagic programmed cell death by selective catalase degradation.

Reactive oxygen species (ROS) are potentially harmful to cells because of their ability to oxidize cell constituents such as DNA, proteins, and lipids. However, at low levels, and under tight control, this feature makes them excellent modifiers in a variety of signal transduction pathways, including autophagy. Autophagy was traditionally associated with oxidative stress, acting in the degradation of oxidized proteins and organelles. Recently, a signaling role was suggested for ROS in the regulation of autophagy, leading, under different circumstances, either to survival or to death. To study the effects of ROS on this pathway, one must determine the localization, intensity, kinetics, and essentiality of the oxidative signal in autophagy. Moreover, once characterized, detection and manipulation of ROS formation could be used to monitor and control autophagic activity. In this chapter we discuss methods to examine ROS in the context of autophagy.. Title: Monitoring starvation-induced reactive oxygen species formation.

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.. Title: Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications for Treatment of Latent Infection

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what does ap biology involve

Develop advanced reasoning and inquiry skills as you design experiments, collect and analyze data using mathematics and other methods, and interpret that data to draw conclusions. AP Biology Course Overview (PDF) AP Biology Course & Exam Description (PDF)

Apoptosis (from Ancient Greek ἀπόπτωσις falling off) is a process of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation, and global mRNA decay. Between 50 and 70 billion cells die each day due to apoptosis in the average human adult.

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what is iphlpapi.dll

Iphlpapi.dll is a type of DLL file associated with MSDN Disc 1550 developed by Microsoft for the Windows Operating System. The latest known version of Iphlpapi.dll is 1.0.0.0, which was produced for Windows. This DLL file carries a popularity rating of 1 stars and a security rating of UNKNOWN.

Inositol trisphosphate or inositol 1,4,5-trisphosphate (also commonly known as triphosphoinositol; abbreviated InsP3 or Ins3P or IP3), together with diacylglycerol (DAG), is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells.n the nervous system, IP 3 serves as a second messenger, with the cerebellum containing the highest concentration of IP 3 receptors. There is evidence that IP 3 receptors play an important role in the induction of plasticity in cerebellar Purkinje cells.

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what is pqq used for

PQQ offers a viable alternative. The enormous amount of energy generated within the mitochondria exposes them to constant free radical activity. The resulting mitochondrial decay is a hallmark of aging. PQQ protects and augments delicate mitochondrial structures to promote youthful cellular function in three distinct ways: Antioxidant power.

Rating Newest Oldest. Best Answer: Opurt is correct, however it is a bit of an interesting story. PQ was always used until the separatist Pari Quebecois became the government. They insisted that 'PQ' be changed to 'QC' and to delete reference that Québec was only the province of a country. Source(s):

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The Australian experience in organ donation--2003.

A Systematic Literature Review and Research Agenda for Organ Donation Decision Communication

1954 The Pure Theory of Public Expenditure

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Council aides did not have a total for the savings that would be realized in city agency legal departments through its plan.

A savings would be realized in city legal departments if the plan was implemented.

The plan would bring no savings to the city agency legal departments.

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99 on the voucher by transposing the seven and the one, the approving official and the certifying officer, who might generally expect much lower taxi fares, would have no basis to assess the reasonableness of the claim.

Certifying officers would often expect taxi fares to be much lower.

Certifying officers have all of the evidence they need to assess the claims.

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1. Deputy Director Maxim Thorne says the plan would threaten innovative programs that have expanded the range of services offered, and won awards and broad community support.

The Deputy Director won awards for his statements about the new plan.

There was no plan being proposed, especially not one that would have any effect on current programs.

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Just before the R97 case was filed, when many in the community were concerned about the size of the Service's request, I suggested that a case calling for rates to be phased--in over time might help avoid the rate shock that comes with large, double digit increases.

The community was concerned about the size of the Service's request.

The size of the Service's request had no effect on the R97 case.

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For example, an LSC grantee could represent a welfare claimant who argued that an agency made an erroneous factual determination or that an agency misread or misapplied a term contained in an existing welfare statute.

They can represent claimants that say the agency has made a mistake.

The LSC grantees are prevented from making claims.

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While preserving the neighborhood groups' own boards of directors, the proposed plan makes them accountable to one central LSNY board for decisions like staffing and budgets.

The suggested plan makes them accountable to a board.

The suggested plan makes them accountable to no one.

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The propertyrelated fee increase requires voter approval under Proposition 218, a process Tulare County Water Works officials started after they learned the outcome of Alpaugh Irrigation's vote.

Prop 218 requires voter approval for fee increase.

Fee increases can happen at any time if the board says so.

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Cell-based leakage power reduction priority (CBLPRP) optimization methodology for designing SOC applications using MTCMOS technique

This paper describes a straightforward cell-based leakage power reduction priority (CBLPRP) optimization methodology for designing highspeed low-power SOC applications using MTCMOS technique. The CBLPRP methodology is based on the cell swapping priority depending on the total leakage power reduction for a cell changing from LVT type to HVT type. Experimental results show that by employing CBLPRP Methodology on the ISCAS benchmark circuits, a 10-20% reduction in the leakage power consumption could be achieved as compared to the one using the GDSPOM technology.

With a huge budget, the sloping land conversion program(SLCP)has profound significance in china. We evaluate the economics theoretical basis of SLCP and reveal the internal economics logic of SLCP in a framework of mainstream economics. Firstly, we discuss the limitation of beginning to collect Pigou taxes in the framework of externality theory and point out that it is difficult to achieve good results of sloping land conversion through voluntary transaction of Coase theorem. Secondly, we illustrate the reasons of urban residents paying a price of SLCP through a game model of public goods, and by using of optimal tax theory we analyze that the policy of the theory will lead to a high social cost. As a substitution mechanism, the principal- agent of SLCP is a way of cutting down the social cost. Lastly, we put forward some proposals of public policy.

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Parliament and Non-Sovereign Law-Making Bodies

In my last chapter I dwelt upon the nature of Parliamentary sovereignty; my object in this chapter is to illustrate the characteristics of such sovereignty by comparing the essential features of a sovereign Parliament like that of England with the traits which mark non-sovereign law-making bodies.

Thousands turned out last weekend to protest at cuts, deficits, and increasing private sector involvement in the NHS. ::: ::: The “Day of Action” was organised by NHS Together, a collaboration of health service unions, NHS staff …

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Addressing Health and Social Care in Easington: Partnership in Practice

This Case Study examines a practical example of joint commissioning in action, in Easington, County Durham. It explores the collaborative processes and particularly the contribution of groups operating at strategic (district) and operational (village) levels. Key individuals made important contributions to the development of a truly ‘partnership’ way of working. Impacts on services began to be made but in the period of study this was more ad hoc than systematic. In spite of some tensions between the different levels of decision making and in the face of further organisational change, the challenge for Easington is to sustain the progress made and to move forward by making further inroads into needs which span various agencies' responsibilities.

Constituents will get the chance to chat with their local MP at his regular ‘shoppers surgery’ to be held at the Sainsbury’s store on Wetherby Road ...

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British IVF clinics on a "gravy train": Robert Winston

People are being sucked into IVF without a full recognition of exactly how low the success rate is.

Abstract It would seem that many industrial companies in the UK, even though their profit margins are being squeezed, still have money to burn, literally. Although fuel prices have escalated quite sharply over the past two decades, the cost of energy is not yet high enough to force companies to implement conservation measures as a matter of course. Energy managers have been appointed throughout the country, but they have mostly proved ineffective. Gopal Srinivasan urges UK industry to consider heat recovery projects.

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Council seeking views on proposed Public Spaces Protection Order

The proposed PSPO seeks to replace and consolidate a number of existing orders that are in place in Cheltenham.

The offence of controlling or coercive behaviour came into effect in England and Wales in December 2015, and related offences have since been enacted in Scotland and Ireland. To date, there has bee...

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Contingent or Structural Crisis in British Agriculture

The British agricultural sector is either already in or rapidly approaching some sort of crisis. Two features are particularly significant in the political response to the current situation. First, there is an increasingly neoliberal approach to agricultural policy. Sec end, agricultural policy per se is being subsumed with wider rural policies. In this paper we question the rationality of both these trends, both theoretically through 'new wave regulation theory' and by relating the British situation to the recent experiences of the agricultural sectors in Australia and New Zealand.

Building socialism new countryside needs finance support,but the shortage of present countryside cpital is a factor of hindering countryside development.adds vigour to the development of countryside society and economy,but as the lack of law and government protection to countryside finance,the irregular countryside finance develops irregularly.It is an important meaning to guide irregular countryside finance to serve countryside development with regulation finance.

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The Outlook for State and Local Government Finances

City? (Washington, D.C.: The Urban Institute, October 1972). 10. Leona Vogt, et al., Health Start: Final Report of the Evaluation of the Second Year Program (Washington, D.C.: The Urban Institute, December 1973). 11. Bayla White, et al., The Atlanta Project: How One Large School System Responded to Performance Information (Washington, D.C.: The Urban Institute, March 1974). 12. John Waller, et aL, Monitoring for Criminal Justice Planning Agencies (Washington, D.C.: The Urban

EDITOR—I received 21 items of correspondence about my personal view on separating the NHS from direct government involvement, mostly supporting the idea and many urging me to take it further.1 I have worked in the NHS for 28 years and my conclusions are based on first hand experience of the waste associated with massive bureaucracy to support edicts from the top, short term solutions to …

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Turnaround of the Indian Railways: a public ownership saga

The reported turnaround of the Indian Railways (IR) has attracted wide notice. This article locates the enterprise within the broader Indian public sector and explores the factors that led to the turnaround from a low performing organisation to a high performing one. The case study method is used, with the developing theory of enterprise turnaround underpinning the case study. The theory suggests that turnaround successes need to be understood in terms not only of managerial actions, but also of favourable environmental conditions. This study reveals that both managerial leadership and good luck contributed to the turnaround success of the IR. There was no element of privatisation (apart from some limited outsourcing) within this turnaround. All happened within the context of full public (governmental) ownership. An underlying suggestion is that more such studies could help authorities assess and improve public enterprise performance.

Thousands turned out last weekend to protest at cuts, deficits, and increasing private sector involvement in the NHS. ::: ::: The “Day of Action” was organised by NHS Together, a collaboration of health service unions, NHS staff …

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What does a colour TV licence cost?

Official TV Licensing website - TV Licence types and costs / TV Licence types and costs TV Licence types and costs It costs £145.50 for a colour and £49.00 for a black and white TV Licence. In some cases, you may be entitled to a reduced fee TV Licence (see table below). You’re entitled to a 50% reduction in your TV Licence fee if you’re certified as blind (severely sight impaired). Cost of a TV Licence to cover multiple units Cost of a TV Licence to cover multiple units Some businesses can apply for a TV Licence to cover a number of accommodation or mobile units (for hotels, hostels, mobile units and campsites), or entertainment units (for hospitality areas). For more information, visit the pages below: The licence fee will be based on the number of units offered where a TV receiver is installed or used. To cover up to 15 units You only need to pay one fee of £145.50. To cover more than 15 units You pay one fee for the first 15 units and an additional fee of £145.50 for every extra 5 units or fewer. If you still have questions take a look at TV Licensing FAQs where you can find all the answers in one place.

Michael Howard - ORG Wiki Michael Howard Michael Howard MP (Conservative) former MP for Folkestone & Hythe. Former leader of the Conservative Party. Issues Freedom of Information Signed Early Day Motion 2699 Freedom of Information 10 December 2006 That this House welcomes the finding of the Constitutional Affairs Committee (HC991) that the Freedom of Information Act has `already brought about the release of significant new information and....this information is being used in a constructive and positive way' and the committee's conclusion that it sees `no need to change' the Act's charging arrangements; views with concern reports that the Government is considering changing these arrangements to permit an application fee to be charged for all requests or to allow authorities to refuse, on cost grounds, a significant proportion of requests which they currently must answer; and considers that such changes could undermine the Act's benefits of increased openness, accountability and trust in the work of public authorities. Links

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Which two words complete the names of these financial institutions Furness, Principality and Skipton?

Savings compensation and protection: Bank ownership and licences | This is Money comments The way you spread out your savings is crucial in terms of protection and compensation, but it is also a system that can be difficult to navigate. We explain who covers what Protected against a bust: Make sure your savings are safe by not putting more than £85,000 into each authorised bank The UK's level of savings compensation is currently £75,000 - or £150,000 for joint accounts - as of 1 January 2016. This is lower than the £85,000 of protection offered to savers between 2011 to 2015. The change was made to put the UK safety net in line with that enjoyed throughout the rest of Europe.  The Bank of England deemed it necessary due to changes in the exchange rate between sterling and the euro, which meant the previous £85,000 limit is now worth more than the European limit of 100,000 euros.   More... How to avoid a banking nightmare: Your rights, fraud and how to complain when things go wrong You only receive this £75,000 protection once under each bank or building society's 'compensation licence'. Each bank usually has its own authorisation, but those that operate different brands often share them. It is best to spread your savings over as many savings institutions as possible - never holding more than £75,000 - under each authorisation. Yet a series of mergers, takeovers, joint ventures and subsidiaries has created an impenetrable web for savers to negotiate. Below, we reveal who owns who to make sure you don't unwittingly bank savings twice with the same institution. However, the issue of savings compensation is a complicated one: there are a number of banks that are owned by the same banking group but which are separately licenced.  This means you can have deposits with, for example, NatWest and with its owner RBS and be covered under the FSCS for both accounts separately, meaning total coverage of £150,000. Also, those with savings at AA could now be covered under different licences.  If you opened an account with AA Savings before 7 October 2015, then your money is under a banking licence with Halifax (which also covers Bank of Scotland, BM Savings, Birmingham Midshires, Intelligent Finance and Saga.) Essential guide:  How to save safely with banks and building societies    For more updates sign up to our newsflash or newsletter.   If you need to open a new account our savings tables have the web's best advice on rates and our savings tool allows you to do your own research. Below is the web's most comprehensive guide to savings compensation. The name of the bank is listed next to its licence. If the ownership of the bank is different to the licence-holder, this is noted in brackets. But the licence-holder is the most important information. Which depositor protection scheme are your savings covered by? Name

Somerset Conservatives | Covering the Bridgwater & West Somerset, Somerton & Frome, Taunton Deane, Wells, and Yeovil parliamentary constituencies Covering the Bridgwater & West Somerset, Somerton & Frome, Taunton Deane, Wells, and Yeovil parliamentary constituencies Main navigation Hill Farms ‘Must be Ring-Fenced Against Change’ Tuesday, 17 January, 2017 MP Ian Liddell-Grainger has warned Ministers hill farmers must be ‘absolutely’ protected after Brexit if the UK is to avoid an environmental disaster. Helping people get on in life Latest figures from the Office for National Statistics show that more people are in work than ever before and wages are still rising – good news for Britain’s families.The number of people in w View all Our Map We are responsible for political activity across the county of Somerset on behalf of the Conservative Party. This covers the five parliamentary constituencies of Bridgwater & West Somerset, Somerton & Frome, Taunton Deane, Wells and Yeovil. The map shows events and news articles happening near you. Individual events and news articles are represented by pins of different colours and you will be able to click on them to find out more information.

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How much good the Norplant option would do is debatable.

It is questionable how much benefit the Norplant option will provide.

Everyone know that the Norplant option is very beneficial.

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it's going to be reduced right uh-huh

It'll be reduced.

It will be expanded.

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It is designed to give the utilities flexibility in determining how and where to achieve the reductions.

Utilities will have flexibility in determining how to reduce rates.

Utilities only want to raise their rates.

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The results are in quadrillion Btu in both the reference case and each of the four policy scenarios.

The results are present in the policy scenarios.

The results were not relevant to them.

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defending the decision to deny benefits will deliver the government's message in the litigation.

The governments message will be delivered by defending the decision to deny benefits.

The governments message was to deny benefits.

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This process would yield an estimate for cases that are funded exclusively with LSC resources.

The process would yield an estimate

The process wouldn't yield an estimate

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The new policy narrows the definition to providing legal advice or representation to people who cannot afford it.

The recent changes in policy allow better access for legal advice for those who are short-handed.

The new policy makes it harder for poor people to get legal advice.

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Not surprisingly, the push for a shrinkocracy has gained little support.

Shrinkocracy has gained little help despite the push for it.

Shrinkocracy has gained massive support.

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The reconfiguration is part of a nationwide effort by LSC to boost cost-effectiveness by reducing the number of providers through a competitive bidding process imposed by Congress under a 1996 law.

LSC believes it's important to limit the number of providers via a competitive bidding process.

It was imposed by Congress under a 1941 law.

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This risk can be acceptably mitigated if the plan calls for invoice examination to be commensurate with the risk to the government.

There is a practical way to mitigate the risk.

There is no way to mitigate the risk.

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Smaller towns will have a syndicat d'initiative, which provides the same services.

The syndicat d'initiative in smaller towns give the same services.

Smaller towns will not be able to offer similar services.

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There would be no government second guessing and lengthy permit reviews.

The government cannot change their mind.

The government can change their mind.

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Passaic Legal Aid argues that LSC used the consolidation process to deny funding based on performance without a required hearing.

LSC can deny funding.

LSC doesn't have the ability to deny funding.

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Does Performance Pay Increase Job Satisfaction?

Effects Of Devolved Government Practices On Health Service Provision In Pastoral Communities: A Case Study Of Wajir County

It is premature to test older drivers with the SIMARD-MD

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If there are no applicable domestic studies, there are many ways to utilize the international literature to conduct benefit transfer (BT). In the health economics literature simple unit transfer methods, rather than function-based methods, are the most commonly used. In this chapter we utilize a large database of Value of a Statistical Life (VSL) estimates, derived from stated preference studies worldwide, to investigate the reliability of meta-analytic BT (MA-BT) and compare this method with simple unit transfers in a case study illustration. Meta-regression analysis is a way to estimate how different policy-relevant factors affect VSL and is thought to improve accuracy in BT. We discuss in particular how different quality criteria to screen available studies and VSL estimates may influence BT accuracy. Results show that quality screened MA-BT models give lower transfer errors, and in the case study example MA-BT methods achieve accuracy gains over the use of unit transfer methods. However, the unscreened MA-BT method achieved around the same accuracy as the best unit transfers based on quality screened data . Hence, transfer accuracy may in some contexts depend as much on the quality of the underlying data as on the BT method itself.

Cost-Benefit Analysis is a method to assess the effects of policies and projects on social welfare. CBAs are usually applied in a top-down approach, in the sense that a decision-making body first decides on which policies or projects are to be considered, and then applies a set of uniform criteria to identifying and valuing relevant cost and benefit flows. This paper investigates the possible advantages, prerequisites and limitations of applying CBA in what may be considered an alternative, “bottom-up” manner. Instead of starting out with a pre-defined policy option, the suggested approach begins with the underlying environmental problem, and then assesses costs and benefits of strategies and solutions as identified by local and directly affected stakeholders. For empirical case studies concerning two river catchments in Sweden and Latvia, the bottom-up CBA approach utilises local knowledge, assesses plans which are not only developed for local conditions but are also likely to be more acceptable to local society, and sheds additional light on possible distributional effects. By not only benefitting from, but also supporting participatory environmental planning, bottom-up CBA is in line with the growing trend of embedding stakeholder participation within environmental policy and decision-making.

Berzelius failed to make use of Faraday's electrochemical laws in his laborious determination of equivalent weights.

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In this report, the results of interviews with sixty local health care politicians in southern Sweden will be presented. It is evident from the material that despite their formal responsibility, the politicians are of the opinion that other actors exert greater influence upon the allocation of resources. They do not think that health care expenditure need be extended, whereas fields such as care of the elderly and preventive medicine ought to receive extended contributions at the expense of other publicly financed activities such as general mammography and in vitro fertilization. Somewhat more than a third of the politicians hold that the goal stipulated in the Swedish Health Care Act, i.e. to provide good health and care on equal terms, has not been fulfilled. Their attitudes towards priority criteria such as personal responsibility, age, life expectancy, parenthood and productivity differ from case to case, and there is no clear-cut consensus. However, approximately half of the respondents agree wholly or partly that a person who promises to alter his or her unhealthy habits should be treated before someone who does not make such a promise. The same applies to the principle that those employed ought to be given priority in operating queues, and in consequence of this utility perspective there are also increased demands upon the physicians to take economy into consideration in treating an individual patient.

In both English and Swedish health care, there is currently much interest in encouraging public consultation and participation in public service planning in order to improve quality, enhance local accountability, and help to inform and legitimize difficult decisions about health care priorities. This article explores the progress of local budget holders for health services in the two countries—primary care groups/trusts in England and county councils and municipalities in Sweden—in developing consultative and participative processes. Using secondary and primary research methods, the study identified much activity among English primary care groups/trusts, although with less certainty of outcome. In Sweden, initiatives were limited to a few county councils, were more distinctive, and in the case of one county council, resulted in the sustained channeling of citizens' views. In comparing and contrasting the approaches in the two countries, the authors note the importance of political cultures and institutional arrangements as well as, more generally, the complexities and challenges of consultation and participation in health care planning.

Every function of n inputs can be efficiently computed by a complete network of n processors in such a way that: If no faults occur, no set of size t n /2 of players gets any additional information (other than the function value), Even if Byzantine faults are allowed, no set of size t n /3 can either disrupt the computation or get additional information. Furthermore, the above bounds on t are tight!

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Prior to 2008, reference to green infrastructure (GI) in Irish planning, advocacy and guidance documentation had been limited. However, by November 2011, GI was referenced in statutory guidance at national, regional and local levels, while also enjoying reference in many non-statutory planning policy and advocacy documents. ::: ::: This thesis seeks to examine and explain the processes which facilitated the rapid emergence, evolutionary trajectory and institutionalisation of GI planning policy in Ireland. Specifically, the investigation seeks to critically examine why and how GI was introduced, interpreted and advanced in planning policy formulation in Ireland between November 2008 and November 2011. Situated within the field of interpretive policy analysis, the thesis adopts a discourse centred approach focused on the context sensitive constitution of the ‘meaning(s)’ of GI. The potential implications of such meaning(s) are also examined. The research involves extensive documentary analysis of both Irish and international planning policy related material. The investigation also involves the analysis of semi-structured interviews with 52 interviewees from the public, private and voluntary sectors. Information obtained from participant observation at 2 planning workshops is scrutinised. ::: ::: The thesis provides a number of original empirical and theoretical contributions to knowledge. This is achieved by presenting a critical interpretive analysis of policy dynamics in a context where attention to ‘meaning-making’ is largely absent in academic literature regarding landuse planning. The research identifies, examines and discusses the influential roles played by planning rationalities, motivated agents, professional networks and timing in the dissemination and institutionalisation of a new policy initiative within Irish landuse governance. The thesis also provides a broader contribution to understandings of the policy process by presenting an innovative theoretical explanation of how representation and interpretation may shape the content, currency and consequences of policy.

The urban heat island effect, in which cities are hotter than surrounding rural areas, will be exacerbated by climate change impacts for many Australian cities. Heatwaves already kill more people than other natural disasters, and have significant impacts on productivity and liveability. Vegetation is one of the most effective mitigation options for the urban heat island effect. However, in many Australian cities, green space is under increasing pressure from urban densification and sprawl. To date, green space planning has a relatively weak role in urban planning, and the links between urban planning and provision of urban green space, and its broader urban liveability contributions, are largely missing. This paper provides an overview of the urban heat island effect, and urban greenery's role in its mitigation. Following this, it presents an analysis framework to assess the effectiveness of Australian policies in retaining and maximising urban greenery. The framework utilises research on sustainability transitions to structure the criteria for analysing policies. The framework focuses on policy processes and content to assess policy effectiveness and to define policy 'success'. We propose that a key component of policy effectiveness is gaining cross-organisational 'ownership' and agency for policy implementation from across multiple departments within the policy's jurisdiction. Reflecting urban greenery's multi-functionality, we propose that policy success is associated with it being integrated and embedded across departments within an organisation (for example transport, recreation, open space, strategic planning, assets management, etc.); and when a range of urban greenery's multiple contributions are actively and intentionally utilised.

Blunt trauma abdomen rarely leads to gastrointestinal injury in children and isolated gastric rupture is even rarer presentation. We are reporting a case of isolated gastric rupture after fall from height in a three year old male child.

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Case Study on Power Quality Improvement of Thirty Bus System with UPFC

The unified power flow controller (UPFC) is a pair of back to back power electronic inverters which controls the real and reactive power flow in a transmission line. This paper describes the modeling and simulation of IEEE 30 bus system employing UPFC. Simulink models are developed for IEEE 30 bus system with and without UPFC. Digital simulation using MATLAB/SIMULINK is done with these models and the results are presented. The effect of UPFC on real power, reactive power and the voltage is also presented. Index Terms—FACTS, UPFC, Power Quality, MATLAB, SIMULINK

In urban-rural planning,tenure is a very important and unavoidable issue.On the mode of the system of rural collective construction land tenure,in the town planning area turns right concessions were took,but outside of town planning protect right concessions were took.Sense of profit is very obvious in the mode of the system."The visible hand" of the government plays a tremendous role.The power of the government should be restricted in order to liberate the local government from the "land fiscal",to make the local government lose interests impulse and turn to rationality.The concomitant reforms of rural collective construction land need to be proceeded.In the hook pilot of urban and rural construction land need to be proceeded,the farmer's right to know and decide should be respeeted,the "land ticket" transactional model could be drew lessons from to realize the same right and the same profit.

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Extra-constitutionalism, the Human Rights Act and the Labour 'Rebels' : applying Prof. Tushnet's theories in the UK.

The control of executive power during periods of emergency is important but complicated. One key problem arises from the need to guarantee that the executive does not abuse its power at a time when there can be considerable pressure to act, while at the same time ensuring that the courts do not prevent the executive from maintaining the security of the state. This article aims to examine Prof Mark Tushnet’s emerging theory of extra-constitutionalism and apply it to the UK. The article will consider the response of the UK government to judicial criticism of its anti-terror legislation in light of s.4 of the Human Rights Act, 1998 (HRA). Finally, the feasibility of adopting Tushnet’s proposed control of the executive by the legislature and public will be discussed. In particular consideration will be given to the effectiveness of such non-judicial forms of review within the framework of the UK’s electoral and Parliamentary systems.

In urban-rural planning,tenure is a very important and unavoidable issue.On the mode of the system of rural collective construction land tenure,in the town planning area turns right concessions were took,but outside of town planning protect right concessions were took.Sense of profit is very obvious in the mode of the system."The visible hand" of the government plays a tremendous role.The power of the government should be restricted in order to liberate the local government from the "land fiscal",to make the local government lose interests impulse and turn to rationality.The concomitant reforms of rural collective construction land need to be proceeded.In the hook pilot of urban and rural construction land need to be proceeded,the farmer's right to know and decide should be respeeted,the "land ticket" transactional model could be drew lessons from to realize the same right and the same profit.

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Increasing the benefits of chemotherapy by ameliorating the adverse effects.

When cancer is first diagnosed in most patients, it is usually incurable. Chemotherapy can cause remissions, prolonged disease-free survival, and prolonged survival in general, but it is associated with considerable toxicity to the physical and mental well-being of the patient. The number of side-effects increases when multiple drug combinations are used. In addition, financial and social problems add to the stress of coping with a fatal disease. Therefore both patients and physicians have asked whether survival (sometimes for extra months) with added side-effects of chemotherapy is worthwhile. The "soft" index of quality of life has been measured by many investigators, and a variety of interventions have been found to alleviate some distress.

Purpose – The purpose of this paper is to shed light onto the policy context of mainstreaming community-based adaptation (CBA) in Nepal. Scaling up CBA needs strong policy support. Design/methodology/approach – The content and processes of Nepal’s development policies and climate change policies and programmes were examined. The policy analysis was supported by a literature review, review of policy documents and interviews and discussions undertaken with policy-makers, practitioners and communities. Findings – Findings show that despite a lack of clear focus on climate change, the decentralization provisions and bottom-up practices within Nepal’s development policies and plans could be the entry points for mainstreaming CBA. However, experience shows that decentralization alone is insufficient because it benefits only a few institutions and individuals, while marginalizing the real beneficiaries. One of the policy conditions to mainstreaming CBA in development is to ensure that there are specific provisio...

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Development of a plug-and-play multiple RTU coordination control algorithm for small/medium commercial buildings

There have been very few advanced control algorithms developed for small commercial buildings due to practical difficulties such as the spatial comfort variations, significant disturbances, high sensor costs, and high cost of site-specific engineering solutions. High implementation cost has been a major impediment to successful market penetration. The focus of this work is to develop and demonstrate plug-and-play optimal coordination of multiple roof top units (RTUs). The goal is to minimize the time required to configure the control strategy in order to enable a more cost effective control implementation for small commercial building applications.

In urban-rural planning,tenure is a very important and unavoidable issue.On the mode of the system of rural collective construction land tenure,in the town planning area turns right concessions were took,but outside of town planning protect right concessions were took.Sense of profit is very obvious in the mode of the system."The visible hand" of the government plays a tremendous role.The power of the government should be restricted in order to liberate the local government from the "land fiscal",to make the local government lose interests impulse and turn to rationality.The concomitant reforms of rural collective construction land need to be proceeded.In the hook pilot of urban and rural construction land need to be proceeded,the farmer's right to know and decide should be respeeted,the "land ticket" transactional model could be drew lessons from to realize the same right and the same profit.

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LONG-TERM DURABILITY OF CONCRETE ---NORDIC CONCRETE RESEARCH

The objective of the present project is to investigate the long-term durability characteristics of various types of concrete exposed to various environments. The project is carried out as a semi-full scale project with a total concrete volume of 2 cu m for each of the 16 different types of concrete. The activities with respect to the full-scale specimens include destructive as well as non-destructive testing. In addition to the larger specimens a number of laboratory specimens were cast in order to provide initial data on the quality of the concrete.(a) for the covering abstract see IRRD 816919.

In urban-rural planning,tenure is a very important and unavoidable issue.On the mode of the system of rural collective construction land tenure,in the town planning area turns right concessions were took,but outside of town planning protect right concessions were took.Sense of profit is very obvious in the mode of the system."The visible hand" of the government plays a tremendous role.The power of the government should be restricted in order to liberate the local government from the "land fiscal",to make the local government lose interests impulse and turn to rationality.The concomitant reforms of rural collective construction land need to be proceeded.In the hook pilot of urban and rural construction land need to be proceeded,the farmer's right to know and decide should be respeeted,the "land ticket" transactional model could be drew lessons from to realize the same right and the same profit.

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