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Sublingual hematoma secondary to short-acting anticoagulants such as warfarin has been labeled pseudoCLudwigs angina to distinguish it from the classic syndrome of localized infection and swelling involving the upper airway. veterinary literature.10 A large sublingual hematoma can mimic Ludwigs angina; either etiology can compromise the airway. Initial treatment includes either reversal of the bleeding diathesis for the former or appropriate antibiotic coverage for the latter. Angioedema is yet another potential cause of upper airway obstruction due to swelling, but this etiology is not typically invoked as underlying pseudoCLudwigs angina. We report a case of massive tongue swelling and impending airway compromise in the context of an intentional ingestion of the long-acting anticoagulant brodifacoum. This presentation was initially suspected to be due to local hemorrhage, consistent with coagulopathy and the previously reported pattern of pseudo-Ludwigs angina associated with warfarin misadventure. Ultimately, however, imaging excluded the presence of hematoma and the clinical course was more consistent with angioedema, temporally implicated in response to the brodifacoum ingestion. Case Report A 32-year-old African American male-to-female transgender patient presented to the emergency department, complaining of inability to swallow and difficulty speaking for the previous 2 days. She denied odynophagia, fever, trauma, seizure, or significant respiratory symptoms. Past medical history included depression, chronic pain, and a remote suicide attempt. On physical exam, she was afebrile and had a normal respiratory rate and oxygenation by pulse oximetry. The oral examination was remarkable for a massively swollen tongue, elevation of the sublingual tissue, and fullness of the anterior neck. She could not vocalize. The remainder of the physical examination was unremarkable. The patient was given empiric intravenous clindamycin to cover for possible infection and dexamethasone to reduce swelling. Anesthesia and otolaryngology services were consulted for emergent airway management and the patient was taken directly to the operating room for fiber-optic nasal intubation. While in the operating room, prior to intubation, she communicated by writing that she had swallowed a rat poison 4 weeks prior to presentation in an intentional suicide attempt. Her initial international normalization rate (INR), which returned a short GSK690693 time later, was greater than 13.7. During intubation, she was noted to have tongue, nasopharyngeal, oropharyngeal, left arytenoid, and epiglottic swelling. After intubation, she was admitted to the EIF2Bdelta intensive care unit for management of her airway. To treat her coagulopathy, she was administered high-dose vitamin K and fresh frozen plasma. Dexamethasone and clindamycin were continued. A computed tomography scan of the head was obtained on hospital day 2. This showed diffuse tongue, floor of mouth, submental, and submandibular space edema but no abnormal GSK690693 increased density that would be expected with a discrete hematoma or diffuse interstitial bleeding (Figure 1). Her airway swelling GSK690693 improved slowly and she was successfully extubated on hospital day seven. The patient was able to converse with minimal difficulty, being able to describe the brand packaging and price of the rat poison she ingested, which confirmed that it was a brodifacoum-containing product. She denied any co-ingestion or that she was taking any other daily medications at that time. The patients coagulopathy initially required vitamin K doses of 100 mg every 6 hours per feeding tube as well as intermittent fresh frozen plasma to maintain an INR less than 3. On hospital day 13, she was transferred out of the intensive care unit. Her corticosteroid therapy was tapered without recurrence of swelling. She was ultimately transitioned to vitamin K by mouth, which was safely reduced to a total daily dose of 25 mg daily. A psychiatric consultation determined that she was no longer a danger to herself and she was discharged on hospital day 17 with the plan to further taper her vitamin K by 2.5 mg every week and monitor weekly INR values. A brodifacoum level was not quantified. Figure 1. Axial contrast-enhanced computed tomography scan through the oropharynx demonstrates diffuse edema throughout the swollen tongue (*), which fills the entire oral cavity resulting in severe narrowing of the pharyngeal airway with patency maintained by … Discussion This is the first case report of airway obstruction associated with over-anticoagulation yet without hematoma. Hematoma leading to such obstruction, referred to as PseudoCLudwigs angina, is a well-established warfarin-associated phenomenon (including a case report from our own.
Category Archives: P-Glycoprotein
The five subunits of transcription factor NF-B have distinct biological functions.
The five subunits of transcription factor NF-B have distinct biological functions. than wild-type mice. Taken PP121 collectively, our data reveal a role for p50 and c-Rel in regulating epidermal proliferation and homeostasis and a profibrogenic part for c-Rel in the skin, and determine a link between epidermal c-Rel manifestation and systemic sclerosis. Modulating the actions of these subunits could be beneficial for treating hyperproliferative or fibrogenic diseases of the skin. The NF-B transcription element family regulates a large number of genes involved in a range of cellular processes that include swelling, cell cycle, cell survival, and matrix turnover. The five NF-B subunits are RelA (p65), RelB, c-Rel, p50, and p52, and these fall into two groups. Class 1 comprises p50 and p52 (encoded from the genes and gene (synonym: (the gene encoding IB; synonyms: as the gene responsible for the psoriasis susceptibility phenotype locus 2 (and mice to further elucidate the part of these proteins in pores and skin homeostasis and stress reactions. These mice17,18 develop normally, with no indications of gross epidermal problems such as those seen in mice,19 and they therefore provide an superb system for studying the part of these subunits in normal pores and skin biology and in disease. Here, we report irregular manifestation of p50 and c-Rel in both psoriatic pores and skin and pores and skin from systemic sclerosis (SSc) individuals; and mice were used to dissect the part of these subunits in normal pores and skin physiology and in disease. Although both subunits contribute to basal keratinocyte proliferation, they are Rabbit Polyclonal to CAD (phospho-Thr456). not essential for 12-mice, whereas mice developed more fibrosis, compared with wild-type (WT) mice. These data suggest that focusing on c-Rel or its downstream focuses on may be of relevance for the treatment of SSc. Materials and Methods Ethics Statement Animal experiments were approved by the local honest review committee and were performed under a United Kingdom Home Office license. Human normal pores and skin, psoriatic pores and skin, and SSc pores and skin samples were taken under full ethical authorization and with patient consent PP121 (REC referrals JLR/NJR Min ref: 95/72 and 09/H0905/11). Mouse Strains and Models Wild-type, mice on a pure C57BL/6 background were from Jorge Caamano (Birmingham University or college, Birmingham, UK). Adult male mice, 8 to 10 weeks older, were utilized for experimental models. Full-Thickness Wounding Two 6-mm punch wounds were made with sterile dermal biopsy punches on shaved backskin. Wounds were measured daily with calipers, and samples were harvested at 1, 3, 5, 7, and 10 days after wounding. TPA Model For the TPA model, mice were shaved and treated with depilatory cream; 24 PP121 hours later, either 200 L of 50 g/mL of TPA (Sigma, Poole, UK) in acetone or acetone only (vehicle) was applied to the backskin. Mice were sacrificed 72 hours after treatment. Bleomycin Model For the bleomycin model, mice were anesthetized with isoflurane, their backs were shaved, and 100 L 0.5 mg/mL bleomycin (Appollo Scientific, Cheshire, UK) in saline solution or saline solution alone (vehicle) was given via subcutaneous injection to an?area approximately 1 cm2. Injections were repeated every?other day for 4 weeks, at which point mice were sacrificed.23 Barrier Function Assay The assay was performed as explained by Hardman et?al.24 In brief, 1-day-old neonatal mice were sacrificed via ketamine overdose. Mice were washed for 1 minute in an increasing methanol series of 25%, 50%, 75%, and 100%. Mice were equilibrated in PBS, stained with 0.2% Toluidine Blue for 5 minutes, and then washed in water and destained with 90% ethanol. Cell Tradition Either main cells (passage 0) or keratinocyte cell lines (passage >10) were produced and cultured as explained previously,25 with three mice pooled per cell collection. Keratinocytes were cultured with or without 3T3-J2 feeder fibroblasts in low-calcium FAD medium (ie, Dulbeccos revised Eagles mediumCHams F12 medium, 3.5:1.1, with 0.05 mmol/L Ca2+, 10% fetal calf serum treated with 2 g Chelex 100 per 50 mL serum 4C overnight, 0.18 mmol/L adenine, 0.5 g/mL hydrocortisone, 5 g/mL insulin, 10?10 mol/L cholera toxin, 10 ng/mL epidermal growth factor, 2 mmol/L glutamine, 100 U/mL penicillin, and 100 g/mL streptomycin) and managed at 32C inside a 5% CO2Cenriched atmosphere. Main murine pores and skin fibroblasts were isolated by outgrowth from biopsies of adult mouse backskin and were used at passage 9.
Desmoplastic melanoma (DM) is certainly a rare variant of melanoma with
Desmoplastic melanoma (DM) is certainly a rare variant of melanoma with specific scientific histopathologic and immunohistochemical features. had been within 14 of 15 (93%) desmoplastic Pazopanib HCl and 4 of 20 (20%) non-desmoplastic melanomas. The high regularity of mutations in desmoplastic melanomas suggests a significant function for NF1 in the biology of the kind of melanoma. (codon V600) locus17. Lately an individual with neurofibromatosis type 1 was discovered to are suffering from a DM18. Since mutations are generally within peripheral nerve sheath tumors19 20 and provided the morphologic overlap of such tumors with DM we reasoned that mutations can also be connected with DM and for that reason examined DMs because of their mutation position and compared these to a control group of major and metastatic melanomas without desmoplasia. Components AND Strategies Sufferers The scholarly research was approved by the organization's IRB. Fifteen major desmoplastic and 20 non-desmoplastic melanomas (2 major 18 metastatic tumor examples) had been randomly selected. From the 15 DMs 7 tumors had been pure DM seen as a a pauci-cellular fibrosing malignant spindle cell proliferation. Eight tumors had been combined or mixed DM with both a classic pauci-cellular as well as a solid spindle cell tumor component (Table 1). One of the tumors was previously published as a case statement16. The non-desmoplastic melanomas included 10 superficial distributing melanomas 5 nodular 3 acral and 2 lentigo maligna melanomas. Table 1 Desmoplastic melanoma – clinical findings pathologic features and mutation status. Immunohistochemical Analysis Five micron solid sections were taken from formalin-fixed paraffin-embedded tissue and stained with an automated immunohistochemistry system according Pazopanib HCl to the manufacturer's guidelines (Ventana BenchMark XT Tucson AZ) using a standard avidin-biotin process and antibodies for S100 protein and Sox10. DNA extraction and targeted sequencing To enrich for the tumor cell populace non-tumor tissue was manually removed from formalin-fixed paraffin-embedded tissue sections and areas with at least 50% neoplastic cells were scraped into sterile Eppendorf tubes. DNA was extracted with a QIAamp DNA FFPE Tissue Kit (Qiagen) according to the manufacturer's instructions. The extracted DNA was subjected to deep-coverage targeted sequencing using an assay termed MSK-IMPACT (Memorial Sloan Kettering – Integrated Mutation Profiling of Actionable Malignancy Targets). The MSK-IMPACT assay uses target-specific oligonucleotides (NimbleGen SeqCap) to capture all protein-coding Rabbit Polyclonal to KALRN. exons and selected introns of 341 cancer-associated genes (oncogenes tumor suppressor genes and components of pathways deemed actionable by targeted therapies) and was previously described21. Briefly 250 ng genomic tumor DNA and a negative control pool of 10 "normal" blood DNAs was fragmented (Covaris E220) and used to prepare barcoded sequencing libraries (New England Biolabs Kapa Biosystems). The sequencing libraries were pooled at equimolar concentrations (100 ng per library) and used in the capture reaction (NimbleGen Pazopanib HCl SeqCap). To prevent off-target hybridization we spiked in a pool of blocker oligonucleotides complementary to the full sequences of all barcoded adaptors. The captured libraries were sequenced on an Illumina HiSeq 2500 to generate 75 bp paired-end reads generating an average protection of >500 Pazopanib HCl per tumor. Sequence Pazopanib HCl data were de-multiplexed using CASAVA and aligned to hg19 using BWA22. Local realignment and quality score recalibration were performed using the Genome Analysis Toolkit (GATK) according to GATK best practices23. Sequence data were analyzed to identify single nucleotide variants small insertions/deletions (indels) using MuTect 24 and GATK respectively. Single-nucleotide variants and indels were called if the variant allele frequency in the tumor was present in > 5% of sequencing reads and if the variant allele in the tumor was > 5 occasions higher than in the unfavorable control. We excluded variant alleles if they were present in more than 2% of reads in the unfavorable control and if they were previously reported in dpSNP25 or the 1000 genome project26. Single-nucleotide variants and indels were examined manually using the Integrative Genomics Viewer27. Oncoprints and MutationMaps were generated in the cBio portal28. RESULTS Clinical Characteristics Fifteen main cutaneous DM were analyzed. The clinical and pathologic findings are summarized in Table 1. The ages of the patients ranged from 24 – 85 (mean = 65.7 years median = 67 years). They included 10 men and 5 women. Thirteen tumors occurred in.
Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) may be the initial enzyme from the
Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) may be the initial enzyme from the hexosamine biosynthetic pathway. to bargain global (glutamine-fructose-6-phosphate transaminase 1). Mutations in result in a distinctive sub-class of CMS known as "limb-girdle CMS with tubular aggregates" [1 2 Subsequently mutations in three genes encoding enzymes from the proteins and gene encodes a homodimeric cytoplasmic enzyme that catalyses the first step from the hexosamine biosynthetic pathway [1]. GFPT1 converts fructose-6-phosphate and glutamine into glucosamine-6-phosphate and glutamate Thus; the end item of the pathway is normally uridine diphospho-and is quite comparable to CMS recommending that impaired proteins CMS. mutations. Particularly we employed mass spectrometric glycomic methodologies to characterise mutations aswell simply because myotubes obtained simply by their differentiation rigorously. As handles for these analyses we analysed myoblasts from two healthful handles and four sufferers with muscular illnesses that have not really previously been associated with glycosylation specifically CMS due to mutations in gene encoding calpain-3 and Pompe disease due to mutations in the gene encoding acidity maltase in charge Navarixin of wearing down glycogen in lysosomes. Unexpectedly no impairment of sufferers' myoblasts or myotubes. 2 Outcomes and Debate 2.1 Optimisation of Myoblast Lifestyle Conditions Because of the fact that muscle biopsies usually do not offer enough sample for glycomic analysis we initial established suitable cell culture conditions for producing the mandatory cell matters (>106) whilst minimising the quantity of foetal leg serum Rabbit polyclonal to PRKAA1. (FCS) within the culture moderate. The last mentioned was important since it is well known that FCS produced glycans often co-purify with cell-derived glycans during glycomic Navarixin analyses [5]. We discovered that culturing in mass media filled with 15% FCS was optimum for our glycomics tests (see Amount S1). 2.2 Glycomic Evaluation of Individual and Control Myoblasts Reveals no Impairment in N-Glycosylation Myoblasts had been cultured from three sufferers one individual one individual one LGMD2A individual one Pompe disease individual and two healthy handles. MALDI-TOF affected individual 3 whose myoblasts had been difficult to lifestyle. Consultant MALDI-TOF spectra from a wholesome control an individual Navarixin and the individual are proven in Amount 1. MALDI data for the various other sufferers and control are reproduced in Supplementary Details (see Number S2). Number 1 Annotated MALDI-TOF MS spectra of permethylated patient 1 (B) Navarixin and the patient (C). In each of A B and C the top panel shows the full spectrum of glycans and the bottom panel amplifies the … Number 1 demonstrates myoblast patient 1 and the patient. To investigate whether the individuals exhibited impaired myoblasts. Indeed they suggested that multiantennary glycans were probably slightly more abundant in individuals than in settings. However it is definitely important to note that increasing numbers of LacNAc devices is not necessarily indicative of improved branching because these moieties can be present in prolonged oligo-LacNAc antennae rather than as additional antennae. Indeed the MALDI data in Number 1 concur that myoblasts can handle increasing their antennae because lots of the glycans at high mass have significantly more compared to the four LacNAc moieties that will be the basis of the tetra-antennary glycan. Thankfully isomeric glycans differing in branching and oligo-LacNAc extensions could be easily recognized and their abundances likened by analysing quality fragment ions in MS/MS tests. For example Amount 4 displays MS/MS spectra extracted from the monosialylated glycan with three lacNAc systems (m/z 3055) in the MALDI data (find Amount 1) for healthful control 1 individual 1 and the individual. Two antennae agreements are in keeping with this structure: triantennary and/or biantennary with one LacNAc expansion. As proven in the annotations over the spectra as well as the cartoons in Amount 4 the MS/MS spectra are dominated by fragment ions due to loss of an individual terminal LacNAc with or without sialic acidity. These fragment ions could be based on both bi-and tri-antennary choices. Nevertheless there are many fragment ions that are diagnostic for the expanded biantennary structure. They are noticed at m/z 935 1781 and 2142. Each is minor. Their abundances in accordance with the Importantly.
The mechanism(s) where certain small peptides and peptide mimics carry large
The mechanism(s) where certain small peptides and peptide mimics carry large cargoes across membranes through exclusively non-covalent interactions continues to be difficult to solve. pre-forming a complicated with HRP. In comparison complicated formation is necessary by Pep-1. Both providers can handle forming AEE788 skin pores in membranes but our data ideas that these skin pores are not in charge of cargo transportation. Overall D9 is apparently a more powerful and flexible transporter in comparison with Pep-1 because D9 will not need an used voltage or various other forces to operate a vehicle transportation. AEE788 Hence D9 enable you to deliver cargo throughout membranes in conditions where Pep-1 will be inadequate. side from the DIB from HRP (Fig. 5). Further DLS measurements suggest that D9-NBD will not adsorb to HRP if they are incubated jointly (Desk S2). Two important tips emerge from these total outcomes. Initial interactions between HRP and D9 such as for example an incubation period aren't a prerequisite for translocation. This contrasts with Pep-1 where many literature reviews emphasize the need for both incubation as well as the peptide to cargo molar proportion. Second transportation is normally when the carrier and cargo are separated. Guanidinium-rich peptides have been completely proven to "reach across" vesicle membranes to remove large anions[9]. D9-NBD can be with the capacity of extracting large anions in cases like this carboxyfluorescein from vesicles within a concentration-dependent way (Fig. 5 inset). Our data shows that this simple idea may be extended to bigger entities such as for example whole protein. Following many of the DIB tests presented right here we imaged the catch droplet by fluorescence microscopy to measure just how much D9-NBD crossed over after translocation. Amount 5 Transport being a function of complicated development. Either Pep-1 or D9-NBD was utilized to move HRP either in the same or the contrary side from the DIB. All studies were executed at 0 mV. D9-NBD facilitates a lot more translocation when Extremely … However hardly any D9-NBD was discovered in the catch droplets (except where D9-NBD and HRP had been in split droplets) (Fig. S8). This will not always indicate that D9 cannot combination the DIB but at least it generally does not rapidly equilibrate over the membrane. Versions like floor covering toroidal pore and barrel stave are inadequate to describe the transportation of molecular cargo seen in our tests with Pep-1 and D9 as providers[16 35 We remember that both AEE788 Pep- 1[31] and D9 type skin pores in DIB membranes in the lack and existence of cargo (Fig. S7). This shows that the necessity for complicated formation (much like Pep-1)[5] may possibly not be associated with the forming of skin pores in the membrane. If therefore perhaps translocation will not happen by transferring through carrier-lined skin pores Mouse monoclonal to CD105 but rather by various other means. Including the hydrophobic parts of either D9 or Pep-1 could connect to the hydrophobic primary from the membrane as the positive locations neutralize negatively-charged areas over the cargo. The lysine-rich Pep-1 might bind detrimental residues on cargo even more weakly than guanidinium-rich D9 which can explain the necessity for voltage or lipid charge asymmetry when working with Pep-1. Up to now the DIB experiments have revealed that these two pore-forming service providers work very in a different way under well-defined conditions and AEE788 that further investigation is needed to understand these variations. Here we have shown the guanidinium-rich D9-NBD polymer can facilitate transport of a protein cargo across a lipid bilayer without the requirement of bad charge or voltage. In addition its ability to transport this protein is enhanced when the carrier-cargo is not pre-mixed demonstrating that pre-formed complexes are not required for transport. The DIB system is ideally suited for probing the mechanistic details of various service providers and enables well-defined independent variables to be analyzed in isolation which are more difficult to complete in many bulk studies. Given the complex scenery of CPP related transport or internalization we are motivated to continue studying these systems as broadly as you possibly can. The growing use of CPPs and related molecules in molecular delivery applications shows the need for more fundamental studies of the delivery mechanism. Learning how to develop more effective service providers is vital to researchers in many different fields. ? Shows We compared transport of ability guanidinium-rich vs lysine-rich membrane service providers Droplet-interface bilayer was used to quantitate protein transport across membrane Guanidinium-rich carrier did not AEE788 require force gradients to drive transport.
Schwann cells form basal laminae (BLs) containing laminin-2 (Ln-2; heterotrimer α2β1γ1)
Schwann cells form basal laminae (BLs) containing laminin-2 (Ln-2; heterotrimer α2β1γ1) and Ln-8 (α4β1γ1). full amyelination revealing Ln-2 and -8 together have a dominant role in defasciculation and that Ln-8 promotes myelination without BLs. Transgenic Ln-10 (α5β1γ1) expression also promoted myelination without BL formation. Rather than BL structure we found Ln-2 and -8 were specifically required for the increased perinatal Schwann cell Ataluren proliferation that attends myelination. Purified Ln-2 and -8 directly enhanced in vitro Schwann cell proliferation in collaboration with autocrine factors suggesting Lns control the onset of myelination Ataluren by modulating responses to mitogens in vivo. Introduction Myelin increases the speed of neural conduction in thin axons. Defects in myelination cause debilitating loss of function in a variety of congenital and acquired neurological disorders. Mechanisms coordinating myelination in the peripheral nervous system are poorly understood despite descriptions of cellular events (Martin and Webster 1973 Webster et al. 1973 and the identification of molecular cues to developing Schwann cells (Mirsky et al. 2002 We show that two members of the laminin (Ln) family of glycoproteins act in concert to regulate the onset of myelination in peripheral nerves. Peripheral myelination is a concerted process in which Schwann cell proliferation axon defasciculation and myelin assembly overlap (Webster 1971 Martin and Webster 1973 Webster et al. 1973 Stewart et al. 1993 Premyelinating Schwann cells cover fascicles of cotargeted axons. Their proliferation rate initially matches axonal growth but raises during myelination to provide Schwann cells for specific axons at perinatal age groups in rodents. Progeny invade fascicles after longitudinal department which raises Schwann cell denseness along subsets of axons. Invading cells frequently transiently ensheath many axons but retract all except one procedure and myelinate an individual axon. Recurrence of the events ultimately decreases fascicles to axons missing promyelinating signals that are defasciculated but stay unmyelinated by the final Schwann cell progeny. Webster Ataluren described the progressive defasciculation and myelination of peripheral axons as radial sorting and proposed that Schwann cell proliferation is intimately involved in the Ataluren commitment of longitudinal cohorts to defasciculate and Rabbit polyclonal to GR.The protein encoded by this gene is a receptor for glucocorticoids and can act as both a transcription factor and a regulator of other transcription factors.. ensheath subjacent axons (Webster 1971 Martin and Webster 1973 Webster et al. 1973 Although neuregulins have been identified as key signals for Schwann cell proliferation (Garratt et al. 2000 molecular mechanisms that accelerate perinatal proliferation and propel radial sorting are not known. The one factor known to have specific roles in radial sorting is Ln-2 (merosin) a major component of the Schwann cell surface basal lamina (BL). Lns comprise a family of αβγ heterotrimers. Loss of Ln-2 through mutations in the α2 chain causes a complex neuromuscular disease including peripheral dysmyelination. In the most studied and strains of Ln α2 mutant mice peripheral nerves contain bundles of unsheathed axons that resemble embryonic fascicles (Bradley and Jenkison 1973 Biscoe et al. 1974 This unique pattern of dysmyelination presumably represents incomplete radial sorting and has therefore been termed "amyelination." Mechanistic hypotheses for amyelination presume endoneurial BLs are necessary for Schwann cell motility and/or differentiation during rapid remodeling (Madrid et al. 1975 Bunge 1993 Feltri et al. 2002 Chen and Strickland 2003 Lns that self-polymerize including Ln-2 are the key structural component of BLs (Yurchenco et al. 2004 and Ln-2-deficient Schwann cells form patchy discontinuous BLs (Madrid et al. 1975 However only spinal roots and cranial nerves are severely amyelinated in and mice; sciatic nerves are partially affected and brachial Ataluren nerves are nearly normal (Bradley and Jenkison 1975 Stirling 1975 Weinberg et al. 1975 One possibility is that BL structure and Ln have limited roles in radial sorting only critical in large nerves. On the other hand lack of Ln-2 could be paid out simply by isoforms containing the α1 α4 and α5 chains partly. Ln α1 can be absent in regular nerves but can be Ataluren indicated in sciatic nerves; insufficient α1 manifestation in spinal origins may take into account serious amyelination there (Previtali et al. 2003 Ln α5 can be selectively indicated in origins (Nakagawa et al. 2001 that could hinder α1-Ln heterotrimer set up in mice in keeping with roles for.
mTOR is a central integrator of metabolic and immunological stimuli dictating
mTOR is a central integrator of metabolic and immunological stimuli dictating defense cell activation proliferation and differentiation. into long-lived cells that communicate high levels of Bcl-2 CD25 and CD62L. Furthermore mTORlo T cells have a greater propensity to differentiate into suppressive Foxp3+ T regulatory cells and this paradigm was also observed in human being CD4+ T cells. Overall Micafungin these studies provide the opportunity to track the development of effector and memory space T cells from na?ve precursors as well as facilitate the interrogation of immunologic and metabolic programs that inform these fates. Intro The evolutionarily conserved serine/threonine kinase mammalian Target of Rapamycin (mTOR) is definitely a central integrator of environment cues and intracellular stress signals dictating the course of cellular growth proliferation and differentiation [1]. The mTOR kinase forms two unique signaling complexes mTORC1 and mTORC2 with unique upstream activators and discrete downstream focuses on [2]. mTORC1 characterized by the scaffolding proteins Raptor and PRAS40 along with mLST8 and Deptor is definitely canonically triggered upon activation of PI3-kinase [3]. This happens in part through the phosphorylation and inactivation of the mTORC1-inhibitory proteins TSC1/2 [2 4 5 These events result in the phosphorylation of the canonical mTORC1 substrates S6 kinase and 4EBP1 leading to improved translation of mRNA transcripts with Best or TOP-like motifs elevated mitochondrial biogenesis and improved expression from the vital metabolic transcription elements Micafungin Myc and HIF-1α [6-9]. mTORC1 activity performs a critical function in regulating cell size especially to advertise the upsurge in cell size upon activation [10]. In T cells the kinase activity of mTOR provides been shown to become modulated by many immunological stimuli including TCR ligation co-stimulation/co-inhibition cytokine/chemokine publicity and adhesion molecule engagement [11]. Certainly mTOR offers emerged as an important integrator of cues from your immune microenvironment Micafungin to guide T cell effector and memory space differentiation [12 13 In the case of CD4+ T cells pharmacological inhibition of mTOR signaling or genetic deletion of the mTOR gene results in a severe defect in the ability of a na?ve CD4+ T cell to adopt an effector phenotype following activation [14-18]. Instead CD4+ T cells triggered in the absence of mTOR signaling adopt a default Foxp3+ regulatory cell phenotype [14]. In contrast studies utilizing CD4+ T cells lacking components of Micafungin either the mTORC1 or mTORC2 complex possess revealed that mTORC1 signaling is required for the development of IFN-gamma generating Th1 cells and IL-17 generating Th17 cells while mTORC2 is required for the development of IL-4 generating Th2 cells [19 20 In addition to regulating CD4+ T cell effector differentiation mTOR offers been shown to play a central part in regulating the development of long-lived memory space CD8+ T cells [21-23]. The data derived from knockout mice and pharmacologic inhibitors suggests Micafungin that the differential activation of mTOR signaling during an immune response plays an important part in dictating fate decisions for activated T cells. To this end we wanted to identify cells based on their level of mTOR activity CASP12P1 and then track their fate. With this study we demonstrate that cell size can be used like a surrogate indication of mTOR activity in recently triggered T cells allowing for the isolation of mTORhi and mTORlo populations with divergent differentiation metabolic and survival potential. CD4+ mTORhi T cells preferentially develop into short-lived terminally differentiated effector cells having a powerful metabolic phenotype and large proliferative capacity. On the other hand mTORlo CD4+ T cells are less proliferative less glycolytic and demonstrate a long lived phenotype. We also find that enriched within this human population of mTORlo cells are suppressive Foxp3+ regulatory T cells and this getting was recapitulated in human being CD4+ T cells. Materials and Methods Animals Mice were kept in accordance with guidelines of the Johns Hopkins University or college Institutional Animal Care and Use Committee. 5c.c7 Rag-/-and OT-II mice were purchased from Taconic. C57BL/6 mice CD90.1 mice CD4 Cre recombinase mice Foxp3GFP+ mice and mice with alleles were from Jackson Laboratories. Mice with alleles were generated from the laboratory of M. Gambello [24]. 5c.c7 Rag-/-mice were derived from a B10.A background while all other WT and OT II+ mice.
The insulin-like growth factor-I receptor (IGF-IR) plays a key role in
The insulin-like growth factor-I receptor (IGF-IR) plays a key role in regulating Beta-Lapachone mammalian development and growth and is generally deregulated in cancer adding to tumor initiation and progression. endocytosis and trafficking into early endosomes IGF-IR proteins appearance and IGF-I intracellular signaling and natural results including cell proliferation migration and colony development. These biological replies had been inhibited by DDR1 silencing and improved by DDR1 overexpression. Tests in mouse fibroblasts co-transfected using the individual IGF-IR and DDR1 provided similar outcomes and indicated that in the lack of IGF-IR collagen-dependent phosphorylation of DDR1 is normally impaired. These outcomes demonstrate a crucial function of DDR1 in the legislation of IGF-IR actions and recognize DDR1 being a book important focus on for breast malignancies that overexpress IGF-IR. PLA) that allows quantification and localization of protein-to-protein connections with one molecule quality in cells. PLA verified that both substances interact in intact MCF-7 cells and that interaction elevated after IGF-I arousal (Amount ?(Amount2c).2c). Beta-Lapachone No appreciable indication was discovered when the precise antibodies had been omitted confirming the specificity of constitutive and IGF-I-stimulated DDR1-IGF-I connections. In contract with immunoprecipitation research IGF-IR-DDR1 association considerably elevated after 5 min IGF-I publicity and dropped after 15 min (Amount ?(Amount2c2c). As demonstrated in transiently transfected R? fibroblasts (Number ?(Number2d 2 remaining panel) the constitutive association between IGF-IR and DDR1 was confirmed after expressing a kinase-inactive IGF-IR/K1003R mutant and DDR1 (Number ?(Number2d 2 remaining panel). The connection was also detectable between the IGF-IR and the kinase-inactive DDR1/K618A mutant which is not phosphorylated upon collagen activation [29] as demonstrated in transfected R+ cells (Number ?(Number2d 2 right panel). PLA studies using both IGF-IR Beta-Lapachone crazy type and IGF-IR/K1003R mutant indicated that a practical IGF-IR is required to fully sustain IGF-I-enhanced DDR1-IGF-IR connection (Number ?(Figure2e2e). These results indicate that IGF-IR associates with DDR1 constitutively Collectively. Nevertheless this association is enhanced by IGF-I stimulation. IGF-I induces DDR1 phosphorylation and an operating IGF-IR plays a significant function in collegen-dependent DDR1 tyrosine-phosphorylation DDR1 binds to and it is activated by several types of collagen [30 17 22 within an integrin-independent style [29]. Because DDR1 was within anti-pY immunoprecipitates from IGF-II activated cells [13] and interacted using the IGF-IR (Amount ?(Amount2)2) we evaluated whether IGF-I arousal might affect DDR1 phosphorylation. As proven by ELISA assay (Amount ?(Figure3a) 3 Beta-Lapachone in MCF-7 cells DDR1 phosphorylation was barely detectable in unstimulated cells but was significantly induced by IGF-I stimulation peaking at 5-30 min and slowly declining thereafter (Figure ?(Figure3a).3a). Arousal with collagen IV (10 μg/ml) and orthovandate (1 mM) was utilized as positive control. Data had been confirmed by traditional western blotting evaluation (Amount ?(Figure3b3b). Amount 3 IGF-I induces collagen-independent DDR1 phosphorylation Very similar studies were executed in DDR1-transfected mouse fibroblasts. In R+ cells harboring the IGF-IR DDR1 phosphorylation was induced by IGF-I using a optimum at 10-30 min and by collagen IV needlessly to say (Amount ?(Amount3c3c and ?and3d).3d). On the other hand in R? cells missing the IGF-IR aswell such as R? cells transfected using the IGF-IR/K1003R mutant IGF-I marketed a small Beta-Lapachone however not significant DDR1 phosphorylation (Amount ?(Amount3c3c and ?and3d) 3 which is probable because of IGF-I binding Beta-Lapachone to insulin receptors (IR) expressed in R? cells. Intriguingly DDR1 phosphorylation in response to collagen IV was severely impaired in R also? and GHRP-6 Acetate in R?/IGF-IR/K1003R cells although leftover even now significant when assessed using the delicate ELISA assay (Amount ?(Amount3c).3c). Once again we can not exclude that DDR1 connections with IRs portrayed in R? cells may are likely involved in regulating collagen-dependent DDR1 activation in the lack of an operating IGF-IR (Amount ?(Amount3c3c and ?and3d3d)..
Mint adaptor protein bind towards the membrane-bound amyloid precursor proteins (APP)
Mint adaptor protein bind towards the membrane-bound amyloid precursor proteins (APP) and affect the creation of pathogenic amyloid-beta (Aβ) peptides linked to Alzheimer's disease (AD). that Mints get excited about APP intracellular trafficking which affects Aβ era. Here we present that APP endocytosis was attenuated in Mint knockout neurons disclosing a job for Mints in APP trafficking. We also present the fact that Atractylodin endocytic APP sorting procedures are governed by Src-mediated phosphorylation of Mint2 which internalized APP is certainly Atractylodin differentially sorted between autophagic and recycling trafficking pathways. A Mint2 phospho-mimetic mutant preferred endocytosis of APP along the autophagic sorting pathway resulting in elevated intracellular Aβ deposition. Conversely the Mint2 phospho-resistant mutant elevated APP localization towards the recycling pathway and back again to the cell surface area thereby improving Aβ42 secretion. These outcomes demonstrate that Src-mediated phosphorylation of Mint2 regulates the APP endocytic sorting pathway offering a system for regulating Aβ secretion. endosomes (Koo and Squazzo 1994 Band et al. 2007 Cirrito et al. 2008 The sorting indication that regulates endocytic handling Atractylodin of APP necessary for Aβ era is based on the extremely conserved YENPTY series (Haass et al. 1994 This YENPTY motif of APP interacts with phosphotyrosine-binding (PTB) domains of adaptor protein such as for example Mint protein (Borg et al. 1996 Each one CMH-1 of the three Mint family includes an isoform-specific N-terminus and a conserved C-terminus which has a PTB area which binds APP and two PDZ domains that bind several protein including presenilins (Okamoto and Südhof 1997 1998 Lau et al. 2000 Biederer et al. 2002 We've previously shown the fact that APP-Mint interaction is certainly biologically relevant as lack of specific Mint proteins delays the age-dependent creation of amyloid plaques in transgenic mouse types of Advertisement (Ho et al. 2008 Nevertheless the molecular and cellular mechanisms underlying Mints influence on APP handling remain unclear. Elevated tyrosine phosphorylation mediated by Src category of tyrosine kinases has a central function in Advertisement (Williamson et al. 2002 Gianni et al. 2003 Lee 2005 Specifically Src-mediated tyrosine phosphorylation is in charge of regulating the sorting of several cell-surface proteins along the clathrin-mediated endocytic pathway (Wilde et al. 1999 Kametaka et al. 2005 Delom and Fessart 2011 Also the phosphorylation condition of APP and/or its interacting protein has an important function in APP sorting and Aβ creation (Bonifacino and Taub 2003 Herein we demonstrate that APP endocytosis is certainly reduced in neurons missing Mint proteins recommending that Mints are essential regulators of APP endocytosis. We present that Mints are differentially phosphorylated with the Src category of kinases which Src-mediated phosphorylation of Mint2 regulates the sorting of intracellular APP which modulates the creation of secreted Aβ. These results reveal a job for phosphorylation of Mint2 in regulating APP sorting and secreted Aβ creation that are highly relevant to Advertisement pathogenesis. Components and Strategies Plasmids dynamic pUSEamp-Src Con527F plasmid was extracted from Upstate Biotechnology Constitutively. pCMV5-Fyn pCMV5-Lyn pCMV5-Yes pCMV5-Shc pCMV5-Dab1 and pCMV-c-Src had been supplied by Dr. Uwe Beffert (Boston Atractylodin School). pCMV5 rat Mint1 pCMV5 rat Mint2 pCMV5 rat Mint3 pCMV5 individual APP695 and pCMV5 individual APP formulated with the Swedish mutation plasmids had been kindly supplied by Dr. Thomas Südhof (Stanford School). All Mint2 plasmids had been produced from rat Mint2 cDNA. Atractylodin Mint2 phospho-mutants had been produced using the QuikChange XL package (Stratagene La Jolla CA) to mutate tyrosine residues 86 110 and 193 to glutamic acidity (Y3E) or phenylalanine (Y3F). Causing cDNAs had been placed into pEGFP-C3 (Invitrogen) to synthesize EGFP-Mint2 wild-type (EGFP-Mint2-WT) EGFP-Mint2-Y3E or EGFP-Mint2-Y3F plasmids. For lentivirus creation Mint2-WT Mint2-Y3E or Mint2-Y3F was placed in to the pLitmusIRES shuttle vector using a 5′ IRES and eventually placed into pFUW-NLS-EGFP-to generate pFUW-EGFP–IRES-Mint2-WT -Mint2-Y3E and -Mint2-Y3F plasmids. To create GST-Mint2 peptides for phosphorylation evaluation PCR was utilized to amplify the rat Mint2 N-terminal area (Mint2-N; residues 1-399) the Mint2 N-terminal area formulated with Y3F mutations (Mint2-N-Y3F; residues.
La Crosse virus (LACV) is a leading cause of pediatric encephalitis
La Crosse virus (LACV) is a leading cause of pediatric encephalitis and aseptic meningitis in the midwestern and southern United States where it is considered an emerging human pathogen. is the primary mechanism of orthobunyavirus entry and identified key cellular factors in this process. First we demonstrated that LACV colocalized with clathrin shortly after infection in HeLa cells; we then confirmed the functional requirement of dynamin- and clathrin-mediated endocytosis for orthobunyavirus entry using several independent assays and importantly extended these findings to primary neuronal cultures. We also determined that macropinocytosis and caveolar endocytosis both established routes of virus entry are not critical for cellular entry of LACV. Moreover we demonstrated that LACV infection is dependent on Rab5 which plays an important regulatory role in early endosomes but not on Rab7 which is associated with late endosomes. These findings provide the first description of bunyavirus entry into cells of the central nervous system where infection can cause severe neurological LY450108 disease and will aid in the design and development of LY450108 antivirals and therapeutics that may be useful in the treatment of LACV and more broadly arboviral infections of the central LY450108 nervous system. INTRODUCTION In the past decade arthropod-borne viruses (arboviruses) have been responsible for approximately 30% of all emerging infectious diseases highlighting their potential global impact as human and veterinary pathogens (21 28 60 The are the largest family of viruses comprising five genera (and are the number of cells and nuclei respectively. RESULTS Entry and early infection occasions of LACV are dynamin and clathrin reliant in HeLa cells and major rat neurons. Earlier tests demonstrating the level of sensitivity of LACV to lysosomotropic real estate agents (46) recommended that LACV gets into sponsor cells by receptor-mediated endocytosis (5 13 17 53 Nevertheless the exact mechanism and especially any relevance to neuronal cells Igfbp2 is not examined. To see whether LACV gets into cells in CCVs HeLa cells and major rat neuronal ethnicities had been incubated with LACV (MOI >10) on snow for 90 min and consequently LY450108 shifted to a 37°C incubator permitting the moderate to gradually warm. Following pathogen adsorption on snow cells had been set at regular intervals (up to 20 min) as the moderate warmed and had been stained with particular antibodies against LACV Gc and clathrin heavy chain. Primary rat neuronal cultures were also stained with anti-MAP2 antibody followed by anti-chicken Cy5 antibody (not shown). In both HeLa cells and primary rat neuronal cultures LACV colocalized with clathrin shortly after the onset of infection (Fig. 1A; 20-min time point shown) suggesting LACV enters cells in CCVs. Fig 1 LACV LY450108 requires dynamin- and clathrin-mediated endocytosis during early infection in HeLa cells and primary neurons. (A) Colocalization of LACV with clathrin shortly after LACV internalization. LACV (MOI >10) was incubated with either HeLa cells … Nevertheless colocalization does not automatically indicate a functional role for CME in LACV entry. Therefore the effects of well-described inhibitors of dynamin and CME dynasore (DYN) chlorpromazine (CPZ) and hypertonicity were tested in this system. DYN is a specific inhibitor of the GTPase activity of dynamins (34 41 thus inhibiting CME. CPZ inhibits CME by interfering with clathrin disassembly and receptor recycling to the plasma membrane (22 59 while hypertonic medium blocks and removes membrane-associated clathrin lattices (19 20 The internalization of Alexa Fluor 594-conjugated transferrin (TF-594) which is mediated by CME was used as a positive control. DYN CPZ and LY450108 hypertonicity indeed reduced the uptake of TF-594 (Fig. 1B). Murine leukemia virus (MLV) pseudotype particles incorporating LACV M segment constructs [MLV(LACV)] prepared using a previously described three-plasmid system (44 45 56 were then used in a previously described entry assay (44 45 CHME-5 cells were transduced with MLV(LACV) pseudotypes in the presence of DYN CPZ or hypertonic medium and then stained for ?-galactosidase to quantify the expression of the indicator enzyme (44 45 MLV(LACV) pseudotypes transduced CHME-5 cells significantly less well (Fig. 1C) in the presence of DYN CPZ or hypertonicity than the control DMSO treatment. These experiments showed that inhibitors of CME have a marked effect on entry mediated by the LACV glycoproteins. To further demonstrate.


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Operating in a deep lying role specifically designed to maximize his previously stifled talents, Andrea Pirlo was unquestionably the heartbeat for both Marcello Lippi's Azzurri and Carlo Ancelotti's Rossoneri between 2003 and 2007.
11x2 is a community of awesome people posting and discussing the latest football news. It's part of NewsBoiler, a network of social news sites covering today's pop culture.

subset: commoncrawl


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Ronny Extra Tall Spectator Height Stool by Amisco
The Ronny Extra Tall Stool features a steel frame that is coated to protect it from scratches. The steel frame doesn't necessarily mean that it will look metallic, as you may choose from a range of frame finishes. You may like the pictured metallic style frame, or you may choose a different earthy finish to sedate or bright solid color lighten the frame. The Ronny Extra Tall Stool features a cushioned seat and seatback to deliver comfort during ball games, parties or billiards games. For added support, the stool has a footrest that wraps around the full base of the stool. The footrest comes in handy when the person seated engages in the fun of the 360-degree swivel seat mechanism! Extra tall stools are used when a bar top or countertop is set higher than the average bar. Or, they are frequently placed in game rooms, flanking billiards tables and other standing game tables so that while waiting your turn, gamers have somewhere to sit and observe. Does the Ronny need to come and give your game room a facelift? Check out the available fabric and frame combinations!
Item # 41442-34
Frame Steel
Seat Cushioned
Swivel Yes
Width 20.75''
Length 19.25''
Height 44''
Weight 42 lbs
Finish You choose. Please view options below!
Cushion Color You choose. Please view options below!
This item ships via UPS / FedEx. Most delivery times within the Continental U.S for in stock bar stools range from 2-5 business days depending on location. All in stock bar stool orders ship direct from American Heritage or Family Leisure and usually ship within 48 hours from the time of purchase. Shipping Details & Conditions.


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Customer Reviews
I have an OG Minaal Carry-On which is fantastic for travelling, but can be overkill for day-to-day use. This is why I purchased the Daily and have really enjoyed the more compact size.
The bag is definitely 5 stars, however I don't like the water bottle pocket and would prefer it if this was removed on future versions. The pocket is too small for my bottle and ends up being a waste of space/material.
Beyond that, you've crushed it with this bag!
Carry-on 2.0 Bag – Refurbished
Carry-on 2.0 Bag – Refurbished
I purchased the Carry-on as a "carrot" to help me do more solo traveling, and it worked! It's so easy to pack everything I want and need to take, and the combination of the pockets and packing cubes helps me keep everything organized for my entire time away. It's great for short or long trips and my partner and I have even shared it for a weekend away. It's sturdy and dependable and fulfills all my luggage needs!
I loved this bag until the back zipper failed at the top corners. This very quick caused the bag to open flat while on trip. I used this everyday and on many short trips. I now have no usable bag and miss the daily 2.0. In the end, I would love another but won't pay a premium price for a failed bag.
In short the bag simply ticks all my boxes of my dream backpack. Quality materials, timeless design and so urban looking yet would fit in just about any occasion be it a quick stop by for a meeting or outdoor city or even country adventure. This bag is simply fulfilled my needs and beyond. Perfectly executed travel backpack I'd say.
• Net Weight: 1.415kg / 3.12lb
• LxWxH: 55 x 35 x 20 cm / 21.6 x 13.7 x 7.87 in (fully packed)
• Capacity: 35L –learn more
• Made of high quality 600D nylon fabric, augmented with 1000D nylon in high-abrasion areas to extend your bag's lifespan
• Fitted with durable Woojin & Duraflex buckles
• Includes patented DeviceNest™ shock-proof device sleeve which fits 16" laptops & 11" devices in a dedicated compartment
• Compliant with both US and European airline carry-on limits
• Switch to briefcase-style business mode by zipping away the shoulder straps
• Quick-access bottle holder with adjustable bungee cord
• Lockable YKK zippers for added security
• Seam-sealed rain cover included
• Lie-flat clamshell scoop increases capacity and helps with faster packing and unpacking
• 4-point harness adjustment system for extra comfort and body-type adaptation
• Works with other Minaal accessories such as attachable hip pads, packing cubes, shirt protectors, and extender straps
We offer a lifetime guarantee against all manufacturing defects. If your gear has a defect, we'll organise a repair or send you a replacement – anywhere in the world.
Find out more here.
All our gear comes with a lifetime warranty.
We call it the Kauri Guarantee – inspired by the enormous, venerable tree of that name found in New Zealand.


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The Sleep Deep Method® 10 Day Sleep Challenge
I help people
Join us for this 10 Day Sleep Challenge to improve your skills of quieting your mind, sleeping peacefully and waking up both mentally and physically so you can be productive every single day.
Over this short video course Beatrix is going to bust a few myths about sleep, and give you the best and simplest tips she leant from years of working with private clients on their sleep problems.
Are you up for a challenge?
As a World Sleep Day Ambassador, sleep coach, speaker and the author of The Sleep Deep Method ®, I'm excited to take on an even bigger role in helping tired people to recharge this year.
When we sleep better, we live better, so getting quality sleep is about so much more that how your feel when you first open your eyes in the morning. Great sleep means better physical health, mental health, relationships, and increased productivity.
So let me tell you about what I will be teaching you in this year's Sleep Challenge, and how it will improve your whole life, not just one aspect of it.
What is inside of this 10 Day Sleep Challenge?
This sleep challenge consists of easy to follow video lectures or modules with simple action steps to address the most common sleep related issues that I come across when working with CEOs, Senior executives and Entrepreneurs.
Day 1 - How To Keep A Sleep Diary
I will demonstrate how a sleep diary helps, when you keep one in the right way. You will learn how to keep one of your own and use the information you gather to aid your own individual sleep problems. You may be surprised what you uncover!
Day 2 - The 4 Pillars Of Great Sleep
There are 4 very clear pillars, or aspects, to great sleep. We all have 1 pillar that gives us the most trouble. So identifying and focussing on that gets you ahead on dealing with your sleep problems.
Day 3 - What 'Good Sleep' Means To You
We are each a little different. Without getting hung up on the number of hours a magazine article tells us we should get, we should instead listen to our body. Maybe sleeping through the night undisturbed is more important for you then an extra 30 minutes in bed.
Day 4 - The 7 Areas Of Life Affecting Your Sleep
There are 7 areas of life that affect our sleep, and that are in turn affected by our sleep, or lack of it. We will look at the areas that typically trigger sleep issues with some examples to give you guidance.
Day 5 - Bad Sleep vs. Sleep Disorders
There are many sleep disorders affecting people all over the world. But for most of us, our sleep is bad but not technically disordered. The key is to not self diagnose. We will talk more about what to be aware of.
Day 6 - Create A Suitable Sleep Environment
There are more distractions in your bedroom that you realise, and some things you may never even think of. From temperatures and textures to memory-evoking keepsakes, I will explain how to make your bedroom a safe sleep space.
Day 7 - Design A Great Bedtime Routine
Many people think they have a good bedtime routine, perhaps because they are following some general advice. If yours isn't working well then your routine isn't personalised to your needs and personality. I explain how to do this.
Day 8 - Maintain Your Daytime Energy
Lack of quality sleep and daytime tiredness is a vicious cycle. For example, when we are tired we make bad food choices, not getting the nutrition we need, and causing more tiredness in the long run. We will talk about breaking that cycle.
Day 9 - Daytime Stressors That Stop You Sleeping Well
There are physical, mental and emotional stressors that keep us awake at night. Sure, we can't avoid bad feelings – this is not the goal. Instead, you need time to process stress before winding down to sleep at night.
Day 10 - How To Achieve Peak Performance
With great sleep comes great productivity. Sleeping well is something you can train yourself to do. I like my clients to think of sleep as a skill to be refined. Then once refined, productivity and mental clarity is better than ever.
I help people
Join us for this 10 Day Sleep Challenge to improve your skills of quieting your mind, sleeping peacefully and waking up both mentally and physically so you can be productive every single day.
One Payment of £ 10.00


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It took me a while this year to go through the dozens of Thin Mints, Do-Si-Dos, and Samoas I secured last spring. I remember how hard I fought with empty promises and unconvincing pouts for just "one more box", how I pleaded and bargained with those little evil cookie-keeper brats and their greedy families. I even stashed my very favorite Tagalongs in various hidden locations around the house so they would last longer. I was not letting anybody else, at least willingly, participate on that forbidden pleasure of licking layer after layer of sugary goodness.
At the very end, just before that last sinful bite, I paused full of doubt. I looked at that delicious cookie with anticipated regret for a while. But I could not help it. I gulped it just like all the ones before it. Just as last year, all good things get to an end. Would they taste as good if I had them all year round? Probably not.
The 7 Evil Projects
New project ideas are kind of like cookies. They are fresh and delicious when you first get them and start working on them. But if you let them linger for too long, they become stale. The year just started and I find myself with seven projects that need finishing before they get too musty. Some of them are new ideas, others are not so fresh anymore, but I need to finish them all as soon as possible.
To do just that I have devised a devious strategy that, I am sorry to inform, may involve audience participation. Let me introduce you both the projects and the plan.
The Plan
You all know by now the iOS developer community is chock full of awesome individuals, people that share a passion for what they do and have no problems sharing it with others, helping them get aboard and get better at it, honestly asking and answering questions that range from technical issues, to business practices, and even how much they are making. In other types of business maybe trade secrets, envy, and contempt for the competition are the norm, but not here! I am proud to be part of such group.
There is a thing though, that not many people talk about even in this community: projects in development. And sure, I worked for years in advertising agencies, I have been a business owner before, and totally understand the "competitive advantage means secrecy" point of view. Is just that, as an indie game developer, I don't think is doing much for me. I do want to talk about what I am doing; I like to get input from all of you. Because I'm finding that, more often than not, your feedback points me in directions that I had not even considered before, and at the end make for a better product.
So talking this out with my friend George, we decided we were going to develop our next personal game project totally in the open. We will talk about anything that comes up: game mechanics, design issues, technical problems, marketing, motivation, etc. from beginning to end, and let people give us feedback at every step. George started this Monday, so go check out his Fairie's Journey.
That was the plan until I realized I don't have one game project, but seven Evil Projects in waiting. So if I am going to do one, why not all of them? Some are more interesting than others, so today I just wanted to show you what there is, and get your feedback on what aspects of these projects are you interested in knowing more about (use the comments below, or find me on Twitter!) I have grouped them in 2 sections, so let's start with…
Motivational Tools with None of the Bullshit
and Other Web Projects
As I was saying last week, the Habit to Procrastinate is strong on this one. I would feel ashamed if it was not so common. What is to keep me from taking a nap right now, instead of writing this elaborate post? Only one thing: that you guys keep me in check. That was the whole idea behind iDevBlogADay: I need to blog; somebody needs to publicly lash me if I don't; at the end you get some interesting articles published that would probably have never seen the light otherwise.
Evil Project #1: iDevBlogADay Redesign
iDevBlogADay has grown from its humble beginning when Chris Waite and me were sharing that same sentiment on Twitter, to a list of almost 70 people engaged in this weird blogging support group, plus thousands of readers that consider what we collectively write worth their attention.
The original website has not changed much from that hasty first week implementation. Sure it has worked well until now, but some of the upkeep is too cumbersome: every time somebody wants either off the list or into it, I have to manually sort things out; there is not even a page that explains how the whole thing works, or how to solve common problems. Last year I started working on some tools to help me out, plus a more professional look for it all. You can see the working prototype right here: http://idevblogaday.com/v2.php
What needs to be done?
- If you were in your iPhone when trying to access that page, you didn't see much. First thing that needs to happen is for the new design to work properly on small screens (is an iOS-related site, for God's sake!).
- I still need to implement info pages, and some forms for people to sign up into the waiting list without having to contact me on Twitter.
- When somebody doesn't publish on his day, the site should at least notify me, then make it easier for me to move people around from the main list into the waiting list and vice-versa.
- With currently 54 people in the waiting list, the question comes now and then… why not have more than 2 persons per day? Is the moment to decide, because if I finally go with this design that change is going to be more difficult in the future. Is that a sign that the design is not too restrictive?
What can I write about?
Not sure if web development is an area enough readers are interested about, so probably I can write about design considerations, both the graphic design and why I think iDevBlogADay works as nicely as it does. Anything else you want to know?
Evil Project #2: iDevTracker
After the unexpected success of iDevBlogADay I kept wondering… will this same strategy work applied to other areas? As you can see today, the "open development" plan has lots in common: I need to finish my projects, and get feedback; somebody needs to call me a lazy git1 if I don't; you get hopefully useful information that you may not get otherwise.
How many people out there are in this same situation? They are maybe starting their indie development on the side, cannot spend too much time on it, then get distracted reading blogs, playing World of Warcraft, or taking care of the kids, and end up with stale projects that they abandon at the end? If I had to guess, lots. And you know what? Some of those projects are probably rubbish, but others… gosh, I wish there were more of the others!
So iDevTracker in a few words: you need to finish a project; somebody needs to show you how bad you are doing it this week compared with all the other cool indie guys out there; we get more awesome games! And in a few more words, here is the abstract from the site:
Submit your indie project. Tell us how far along you think you are. Add a small blurb about your progress if you want. Continue updating your project to get historical data and ballpark info about your effectiveness, inform the community about your progress, and see how you compare with other indie developers.
What needs to be done?
- Some forms still need designing and implementing, I am half the way there.
- I would like to have a beta of this one out soon. Is going to be really simple to start with: just add your progress, see how you are doing in comparison, browse projects by company, maybe some Google-powered charts.
What can I write about?
No idea. If you want to know more, or you have ideas about how this can help you, or what kind of information you want to track, comments are open.
Evil Project #3: Notedo
Tomorrow the Mac App Store opens to the public, and although I had been thinking for a while if releasing Pip for Mac was worth it (I already had it working with even iChat Theater support early last year), I decided against it.
All the same, I have been a Mac developer for longer than anybody without a product out there should be, so it was frustrating not to make something, anything, for this unique occasion. Anyway, I am kind of old-fashioned, certainly not cool enough to write a Twitter client; so what other app idea could I come up with that has been done a few thousand times before? Of course, a note taking/to-do application!
Noel talked before about how valuable having immediate access to writing a quick note and going back to coding was for him. I always found also that I liked the minimal structure of having to-dos and notes organized only by projects, maybe priority, but not other hierarchies. Chris has also been developing BrainWave, a light weight project management tool, because he could not find something that fulfilled his simple requirements. So with all this in mind I decided to do a really simple application with a minimum of features:
- It slides out of one side of the screen, activated by a global hot key. Same hot key hides it.
- It handles multiple projects, but you can only see and manipulate one at a time.
- You organize to-dos by dragging them up and down in the list, no folders or categories.
- You can collect pieces of information, either writing quick notes, or dragging images, URLs, etc. into the notes section of the project. To-dos and notes are separate tabs. That way you can keep all your ideas together.
- Everything can be controlled with the keyboard. Should be as easy as possible to activate, write a few to-dos, and deactivate, without using the mouse.
So is there no application out there already that does all this? Not that I have found. I am using a mix of web apps (Trac), Yojimbo, JustNotes, and others, so all the little pieces of information about a project end up all over the place.
What can I write about?
Although iOS developers will be familiars with the environment, Mac development has its own set of nuances. This application makes extensive use of Core Data, bindings, global events (that I had to get from Carbon and not Cocoa!), etc. If you get into non-game Mac development, you are going to find that although you get lots of stuff for free, some of the things interface elements that you would consider standard are not there. Making these behave appropriately writing them from scratch is what differentiates the good from the excellent. I am not sure if utility applications are something you guys are interested in though.
Evil Project #4: Mystery Coconut's Site
This one is probably the less interesting for the readers. I have to change the site's design, basically because I am not a one-product company anymore. I want to reflect that, make the blog easier to read, have a repository of sample code for people to download, and maybe even advertise my free-lancing services.
At the same time, I would like to keep the cartoony casual style. Even if I do serious (read boring) to-do applications, I want the company (read me) to concentrate on the fun stuff (read games), and a light-hearted theme can do wonders for how you think about yourself, your company, and your products.
What can I write about?
Apart from design issues or marketing, not sure what else will come out of this one. Any ideas?
But Didn't You Say You Were a Game Company?
Finally we get to the interesting part: the 3 evil games.
Evil Project #5: Casey's Contraptions
As you may already know, I am collaborating with Noel Llopis in this project. This should actually be Evil Project #1, because it is the one that I am working the most on, and that needs to be out faster.
This project was kind of a surprise for me. After working on the prototype for a while and decide he wanted to go ahead with the project, Noel had difficulties finding an artist whose style fit his idea. I suggested a 50s style Hanna Barbera or Warner Bros. could work, and Noel asked me if I was interested in giving it a try.
Now, I have worked as a graphic designer before, but not as an illustrator. I was also ready to go on my own doing game programming, and was even thinking of outsourcing the art. But I had bought a Wacom Tablet a year back and had fun doing Mystery Coconut's site header graphics, so I reluctantly agreed.
Now, after Casey went public, lots of people have commented on how much they love the art style. Some even offered me work as illustrator for their games! All I have to say is that I am glad you guys like it, but I am not a professional artist by far. I am slow, and I don't have the training, and more important, the confidence, that is achieved through experience. For now, I will continue drawing because is fun, and kind of relaxing. But not sure I see it as an important part of my freelancing services. Time will tell, I guess.
What can I write about?
Noel was supposed to write weekly about our progress, but he has been too busy, so I guess I can do it instead. Some people have also asked me about how I get the brush style of these illustrations, what programs I use (Adobe Illustrator mainly), etc. so if that is something that interests you I can probably write a post about the whole process. We also ended up with lots of interface designs that we are not going to use in the final product, so a roundup of what was discarded and why may also be interesting.
Evil Project #6:
Legend of Robin Hood
Number 6 is finally the one that I was supposed to talk about today! Basically is a turn-by-turn strategy game, in which you either control Robin Hood and his Merry Men, or the Sheriff of Nottingham and his Men at Arms. The gameplay started as something loosely based on the old board game "The Legend of Robin Hood". This game is from 1979 and was published by Avalon Hill, so the rules are pretty wargamy. Although I played it just a couple of times a while ago with my good friend José Miguel Ramírez, my interest in this game was picked up again when I discovered a full print-n-play version was available online: you can get it, plus a plethora of other nicely designed board game aids, in the Headless Hollow site.
My goals with this game were:
- To create an easy to play game, that could interest equally strategy gamers and a more casual ones. The theme here was important, and so is the art style. So Robin Hood with Playmobil style chubby characters, including warriors in hobby horses, seemed like a win2.
It had to follow in general the main events in the Robin Hood legend: things like the archery contest, assaulting castles, disguising and infiltration, robbery and collecting taxes, recruiting your men, and even public executions. Most of these things are in the original board game, and is what makes it the best Robin Hood board game ever published.
- It had to have randomly generated mini-adventures, but not be a rogue-like or a twitch game. I wanted a slow paced turn by turn strategy game, but it needed both short term and long term goals. Players will have multiple of these goals, each one rewarding different amounts of victory points depending on difficulty, and will be able to choose what ones the pursue.
- I wanted it to be asynchronous multiplayer, but better than to have to wait for your opponent to do its turn it will play entirely against the game's AI for the short term goals, and only the long term goals and story line will be affected by what other players do. On that end, all the players playing the same side will be affected by how well everybody playing the game is doing, and will have to decide on the right tactics for their side to win the game. The game will work in "seasons", and although any player will be able to join at any time, the overall winner will be decided at either the end of the season or when a side has obtained enough victory points. At that moment the game will start over from the beginning; a new battle of wits between Robin Hood and the Sheriff will ensue, and players will be able to change sides if they want.
Does that sound like a difficult one to pull off? That's why we also have Evil Project #7!
What can I write about?
This one is very much in the planning phase, so I will pretty much write about the whole process. The first posts will probably explain the game mechanics in more detail, but feel free to ask whatever you want to know!
Evil Project #7: Elephant Racing
The last project is my attempt to create a fast to develop, casual game. It all started when my friend José Luis Laviña sent me a Christmas card with a photo of him and his wife vacationing in Thailand, mounted on an elephant. I could not stop thinking about the elephant for rest of the day and the result is this crazy game idea.
- The player is participating in the annual racing-through-the-jungle-on-your-elephant competition.
- He has pole at the end of which dangles a banana. Player uses the banana as bait to steer his elephant through the path in the jungle. Path contains traps, impassable rocks, and other obstacles.
- Player has to balance steering where he wants to go with moving the banana away from the elephant's trunk; if he grabs it, he stops to eat!
- You have a supply of bananas, that you can use to replace your bait, or to throw at the elephants of the other participants.
- There are also banana trees, that you either need to avoid (the elephant will stop), or use to replenish your supply. Some of the trees contain tigers that will attack you too!
- Other things that can be used to scare elephants away (like when you are done replenishing your supply of bananas), are mice, or loud noises (trumpet? Shotgun?). All these can be used on your opponents too.
That's it! I love the steering mechanic (having to balance where you want to go with avoiding the elephant's trunk), as well as the interesting possibilities that using your resources on yourself or on your opponents open.
What can I write about?
This one is even more green than the previous one, but probably needs a prototype right away to check if the main mechanic is as sound as it… sounds… on paper. I was thinking of using only Core Animation for rendering both this and the Robin Hood game (no OpenGL, no Cocos, or external frameworks). I can write quite a few posts about how to get graphic atlases, frame-by-frame animations, and how to integrate it all into the main game loop. Core Animation is a pretty powerful, ready to use, rendering engine, and I think is time it stops being relegated to match-3 games.
To Be Continued
So there you have it, 7 cookies that are going to go stale and end up in the trash if you don't help me out. Do you want to know more about any of them? Anything specific you think I should talk about next week? What do you think is interesting? What do you think is just stupid? Use the comments below, I am eager to hear your ideas.
1 Thanks George for expanding my English vocabulary.
2 By the way, those character drawings are living proof that open development produces better results. Thanks a lot to all the people on Twitter that gave me their opinion when I started posting the first doodles! More soon.


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57. The Three Kingdoms Of Korea (Part 1)
In this episode we talk about Korea's long relationship with China, the fall of the ancient Gojoseon state, and the development of the three kingdoms of Goguryeo, Baekje, and Silla that would dominate the peninsula for centuries. Phil Downey returns as guest.
Podcast: Play in new window | Download
Subscribe: Apple Podcasts | RSS


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Items where Author is "Nguyen, MAI"
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Dao, PHUNG, Nguyen, MAI and NGUYEN, Ngoc Bao Chau (2020) Effect of pronunciation instruction on L2 learners' listening comprehension. Journal of Second Language Pronunciation, 7 (1). pp. 10-37. ISSN 2215-1931


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Unión Cuba-Petróleo (CUPET), in partnership with BGP, will be running a promotional event to include presentations and data viewing relating to the 2019 licensing round, alongside the EAGE conference, 3-6th June 2019. Twenty-four blocks offshore in the Cuban economic exclusive zone of the Gulf of Mexico are being offered.
The Gulf of Mexico is one of the most prolific and prospective offshore areas in the world. Cuba produces around 60000 BOE/day from the western offshore by drilling extended-reach wells through duplex structures in folded and thrusted belts. Reservoirs are composed of fractured and lixiviated carbonates from the Late Jurassic, with seals lithologically composed of Tertiary shale. Source rocks of Jurassic, deep-water clay carbonate facies.
The first well was drilled in 2004. In 2012, three exploration wells were drilled in this area, with targets focused on Cretaceous carbonates and no commercial oil was discovered; however, all wells had oil shows originating in Late Jurassic source rocks.
in 2017, 26,880 km of new, high-definition 2D multiclient seismic was acquired by BGP and has provided valuable information on basement depth and sedimentary thickness. New areas with high potential for petroleum systems have been determined. Through the mapping of several leads in a first interpretation stage, resources are estimated at more than 10 billion barrels of recoverable oil, with expected qualities of 25-35° API.
The Roadshow will take place on Monday 3rd June, at the Institute of Directors, Pall Mall, London. The presentations will provide an opportunity to review and discuss the exploration opportunities, the contractual and fiscal terms, and the legal framework for upstream petroleum activities in Cuba. There will also be the opportunity to meet privately with CUPET, and data viewing will be available at the Aloft Hotel, adjacent to the Excel Centre, on 5th and 6th June.
Offered blocks for the 1st Licensing Round include 24 blocks associated with the highest exploratory potential geological scenarios. Classification criteria is based on available information, mapped leads, sea depths and estimated risks. All existing information and data packages will be available to registered and qualified companies.
To attend the roadshow and data viewing opportunities, contact Tracey Dancy: firstname.lastname@example.com.


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Prof. Dr. Rasha Abdel Rahman
Social and behavioural sciences, Neurocognitive psychology
President of the German Psychological Society (DGPs), since 2014
Social and behavioural sciences
Social psychology, industrial and organisational psychology
Person and self perception, gender research, wellbeing research
Teaching award from the Bavarian State Ministry of Sciences, Research and the Arts, 2012
Wittern-Sterzel Prize, 2010
ancient Greek, English, French, German, Latin, Spanish
Abele, A.E. & Wojciszke, B. (2014). Communal and agentic content. A dual perspective model. Advances in Experimental Social Psychology, 50, 198-255.
Abele, A. E. (2003). The Dynamics of Masculine-Agentic and Feminine-Communal Traits. Findings from a Prospective Study. Journal of Personality and Social Psychology, 85, 768-776.
Abele, A.E. & Wojciszke, B. (2007). Agency and communion from the perspective of self versus. others. Journal of Personality and Social Psychology, 93, 751-763.
Abele, A.E., Bruckmüller, S. (2011). The Bigger one of the "Big Two": Preferential Processing of Communal Information. Journal of Experimental Social Psychology, 47, 935-948.
Abele, A. E., & Spurk, D. (2011). The dual impact of gender and the influence of timing of parenthood on men's and women's career development. Longitudinal findings. International Journal of Behavioral Development, 35, 225-232.
Abele, A.E. & Spurk, D. (2009b). How do objective and subjective career success interrelate over time? Journal of Occupational and Organizational Psychology, 82, 803-824.
Success in one's career and satisfaction with one's life (German Research Foundation (DFG) Individual Grant)
Agency and communion from the perspective of actors and observers (DFG Individual Grant; second phase of the project)
Humboldt Foundation Research Group Linkage Programme with the Academy of Science, Warsaw, Poland
Diversity in an industrial corporation (joint project with a large industrial corporation)
President of the German Psychological Society (DGPs; president elect), since 2014
President of the german federation of psychological associations
Review board in the field of psychology for the German Research Foundation (DFG)
Scientific advisory committee to the Bavarian State Ministry of Labour and Social Welfare
Scientific advisory committees to the Bavarian State Institute for Higher Education Research and Planning
Student liaison for the German National Academic Foundation, until 2002
Editor of the journal Zeitschrift für Sozialpsychologie, 2000 – 2004
Member of several international editorial boards
Trainer in role-playing and psychodrama
Two children
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Social and behavioural sciences, Neurocognitive psychology
Social and behavioural sciences, Social anthropology, ethnology, sociology
Social and behavioural sciences, Languages, Ancient Greek Language and Literature, Translation studies, History of education, History of classical philology
Social and behavioural sciences, Languages, Hispanic Literature
Who is happier - someone who places great importance on social relationships, is friendly and helpful? Or someone who pursues his goals and waits for recognition? The surprising answer is: people need both, according to Prof. Andrea Abele-Brehm from the University of Erlangen.


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We are proud to employ technicians who are NATE Certified, which is the highest certification in the HVAC industry. We seek out these exceptional employees because we always put our clients first, and want to give them the best HVAC service and 100% satisfaction.
We couldn't be happier that our hard work and dedication is paying off. We are Arizona's #1 HVAC Company on Angie's list, an APS Top 10 Contractor, and have an A+ rating from the Better Business Bureau. The recognition feels good, but the driving force has always been creating 100% satisfaction among our clients. This commitment to our clients has helped us become a BBB 2017 Torch Awards for Ethics winner, which recognizes local companies that demonstrate integrity and a strong commitment to ethics in all that they do. You'll recognize our strong ethics, too, any time you hire us for one of our various HVAC services.
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The Technician, Will, was prompt as usual. He did the 16 Point Service which included testing all electrical controls and connections. I always find Will to be personable and professional... an asset to Howard Air!
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Arrived on time and completed the inspection in a timely manner. I'm a happy customer.
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Miguel - Technician was Very professional and explained what he was going to do and what he did at the end of checking the AC unit. Good recommendations to keep the unit clean.
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Very satisfied with Howard Air. Had them install our new system a couple years ago and have great service from them since.
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by Charlotte Wood
(last updated January 3, 2022)
There are those dress jackets that necessitate a specific way of washing and ironing to result in that exact look. One of the things that really can mess up your whole look is when there's a crease in the sleeve of your jacket that shouldn't have a crease. Well, maybe that's not so important to you, but if it is important for your look, here's how you can fix it.
The easiest way to do this is to find a sleeve board. Essentially with sleeve boards you put the sleeve of your jacket onto the sleeve board and iron the sleeve as you move the sleeve around the board. You're basically ironing one small section at a time without creating a crease. The sleeve board is the best because you have the most control. You can iron the sleeve well and make it sharp and crisp and still have it maintain its creaseless look.
One of the problems with jacket sleeves is that you may not have or be able to find a sleeve board. And if you are able to find one, you may not want to invest money in it. There is, however, another solution to the sleeve crease dilemma. You can substitute a rolled-up magazine for a sleeve board. Roll up the magazine, cover it with a cloth, and slip it inside the sleeve. The magazine will then immediately unroll and make a firm ironing pad. You then run your steam iron up and down the sleeve without compressing the rolled up magazine.
The trick with this method, of course, is to choose the right magazine. You want a magazine that's sturdy and thick so you can really iron your sleeve instead of having to lightly brush the sleeve with the iron. You still want your ironing to be effective—you just don't want to have to deal with unwanted creases!
Eliminating creases from your jacket sleeves definitely isn't impossible; you just need to know the right tricks! If you can find a sleeve board or make a good substitute then anything you want to be crease free will be!
Tough Tools for Tough Cleaning Jobs O-Cel-O sponges and Scotch Brite scrubbers are truly a fashion-meets-function success story. The highly absorbent and durable sponges in this handy six-pack make quick work of tough cleaning problems in any kitchen, bathroom, or garage. Check out Scotch-Brite Heavy Duty Scrub Sponges today!
Washing and ironing your clothes is a necessary chore and so you should just accept it and learn how to do it well. ...Discover More
Scorch marks just happen sometimes and you have the power to fix it! Here are a few tips to get those unsightly scorch ...Discover More
Cleaning an ironing board cover may be more involved than you might think. Because of protective coatings applied to some ...Discover More
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The New York Times Releases Application For BlackBerry Smartphones
Initially, the NYTimes BlackBerry application is available for the following BlackBerry smartphone models: the BlackBerry Tour, the BlackBerry Storm, the Blackberry Bold, and the 8900-Curve 2. Readers with other models should use the Times' mobile site, which is accessible at http://www.mobile.nytimes.com .
"Mobile continues to be a very popular way for Times readers to access our content," said Marc Frons, chief technology officer, digital operations, The New York Times Company. "With this new application for BlackBerry smartphones, we are offering BlackBerry users with the latest models a faster, more dynamic and more personalized experience for reading up-to-the-minute news, analysis and opinion from NYTimes.com."
The application is available for free at www.nytimes.com/bbap. Key features include:
- Offline reading – access stored and saved content while airplane mode is activated and in areas without cellular network coverage.
- Simple navigation – view articles and pictures quickly.
- Customization options – specify favorite sections, set synching frequency and adjust font size to customize the experience.
- Save and Share – save articles on the smartphone or share articles via e-mail and SMS text.