Individual-based multiple-unit dissimilarity: novel indices and null model for assessing temporal variability in community composition Beta-diversity was originally defined spatially, i.e., as variation in community composition among sites in a region. However, the concept of beta-diversity has since been expanded to temporal contexts. This is referred to as "temporal beta-diversity", and most approaches are simply an extension of spatial beta-diversity. The persistence and turnover of individuals over time is a unique feature of temporal beta-diversity. Nakadai (2020) introduced the "individual-based beta-diversity" concept, and provided novel indices to evaluate individual turnover and compositional shift by comparing individual turnover between two periods at a given site. However, the proposed individual-based indices are applicable only to pairwise dissimilarity, not to multiple-temporal (or more generally, multiple-unit) dissimilarity. Here, individual-based beta-diversity indices are extended to multiple-unit cases. In addition, a novel type of random permutation criterion related to these multiple-unit indices for detecting patterns of individual persistence is introduced in the present study. To demonstrate the usage the properties of these indices compared to average pairwise measures, I applied them to a dataset for a permanent 50-ha forest dynamics plot on Barro Colorado Island in Panama. Information regarding "individuals" is generally missing from community ecology and biodiversity studies of temporal dynamics. In this context, the methods proposed here are expected to be useful for addressing a wide range of research questions regarding temporal changes in biodiversity, especially studies using traditional individual-tracked forest monitoring data.
Missing the forest for the trees: Do seaweed ecosystems mitigate atmospheric CO2 emissions? Global seaweed carbon sequestration estimates are currently taken as the fraction of the net primary production (NPP) exported to the deep ocean. However, this perspective does not account for CO2 from the consumption of external subsidies. Here we clarify: i) the role of export relative to seaweed net ecosystem production (NEP) for a closed system and one more likely open to subsidies; ii) the importance of subsidies by compiling published estimates of NEP from seaweed-dominated ecosystems; and iii) discuss their impact on the global seaweed net carbon balance and other sequestration constraints as a mitigation service. Examples of seaweed NEP (n = 18) were sparse and variable. Nevertheless, the average NEP (-9.2mmol C m-2 day-1 SE {+/-} 11.6) suggested that seaweed ecosystems are a C source, becoming increasingly heterotrophic as their export is consumed. Critically, mitigation of greenhouse gas emissions was mixed relative to their replacement or baseline states, and where CO2 is supplied independently of organic metabolism and atmospheric exchange we caution a sole reliance on NEP or NPP. This will ensure a more accurate seaweed mitigation assessment, one that does exceed their capacity and is effective within a compliance and carbon trading scheme.
Phytoene synthase 2 in tomato fruits remains functional and contributes to abscisic acid formation In ripening tomato fruits, the leaf-specific carotenoids biosynthesis mediated by phytoene synthase 2 (PSY2) is replaced by a fruit-specific pathway by the expression of two chromoplast-specific genes: phytoene synthase 1 (PSY1) and lycopene-{beta}-cyclase (CYCB). Though both PSY1 and PSY2 genes express in tomato fruits, the functional role of PSY2 is not known. To decipher whether PSY2-mediated carotenogenesis operates in ripening fruits, we blocked the in vivo activity of lycopene-{beta}-cyclases in fruits of several carotenoids and ripening mutants by CPTA (2-(4-Chlorophenylthio)triethylamine hydrochloride), an inhibitor of lycopene-{beta}-cyclases. The CPTA-treatment induced accumulation of lycopene in leaves, immature-green and ripening fruits. Even, in psy1 mutants V7 and r that are deficient in fruit-specific carotenoid biosynthesis, CPTA triggered lycopene accumulation but lowered the abscisic acid level. Differing from fruit-specific carotenogenesis, CPTA-treated V7 and r mutant fruits accumulated lycopene but not phytoene and phytofluene. The lack of phytoene and phytofluene accumulation was reminiscent of PSY2-mediated leaf-like carotenogenesis, where phytoene and phytofluene accumulation is never seen. The lycopene accumulation was associated with the partial transformation of chloroplasts to chromoplasts bearing thread-like crystalline structures. Our study uncovers the operation of a parallel carotenogenesis pathway mediated by PSY2 that provides precursors for abscisic acid biosynthesis in ripening tomato fruits.

Significance statementIt is believed that in ripening tomato fruits phytoene synthase 2 that drives carotenoid biosynthesis in leaves is redundant. Contrary to this, we show that in phytoene synthase 1 mutant fruit that is bereft of lycopene, the chemical inhibition of lycopene {beta}-cyclases triggers lycopene accumulation. Our results uncover that phytoene synthase 2 remains functional in ripening fruits and provides precursors for abscisic acid formation in fruits. Hematopoietic-SLC37A2 deficiency accelerates atherosclerosis in LDL receptor-deficient mice Macrophages play a central role in the pathogenesis of atherosclerosis. Our previous study demonstrated that solute carrier family 37 member 2 (SLC37A2), an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter, negatively regulates macrophage Toll-like receptor activation by fine-tuning glycolytic reprogramming in vitro. Whether macrophage SLC37A2 impacts in vivo macrophage inflammation and atherosclerosis under hyperlipidemic conditions is unknown. We generated hematopoietic cell-specific SLC37A2 knockout and control mice in C57Bl/6 Ldlr-/- mice by bone marrow transplantation. Hematopoietic-specific SLC37A2 deletion in Ldlr-/- mice increased plasma lipid concentrations 12-16 wks of Western diet induction, attenuated macrophage anti-inflammatory responses, and resulted in more atherosclerosis compared to Ldlr-/- mice transplanted with wild type bone marrow. Aortic root intimal area was inversely correlated with plasma IL-10 levels, but not total cholesterol concentrations, suggesting inflammation but not plasma cholesterol was responsible for increased atherosclerosis in bone marrow SLC37A2-deficient mice. Our in vitro study demonstrated that SLC37A2 deficiency impaired IL-4-induced macrophage activation, independently of glycolysis or mitochondrial respiration. Importantly, SLC37A2 deficiency impaired apoptotic cell-induced glycolysis, subsequently attenuating IL-10 production. Our study suggests that SLC37A2 expression is required to support alternative macrophage activation in vitro and in vivo. In vivo disruption of hematopoietic SLC37A2 accelerates atherosclerosis under hyperlipidemic pro-atherogenic conditions. Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching  acanthodian-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckels cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth of Acanthodopsis are borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly. Topographic projection of retinal ganglion cell axons at single-cell precision underlies retinotopy in the mouse superior colliculus Retinotopy, like all long-range projections, can arise from the axons themselves or their targets, but details of the connectivity remain unknown. Using two-photon axonal imaging, we functionally mapped the mouse retinocollicular projection at single-cell resolution. We found a near-perfect match between the spatial patterns of retinal ganglion cell axon terminals in the superior colliculus and their corresponding receptive fields, indicating that retinotopy arises from topographic axonal organizations at single-cell precision. A Hierarchy of Biomolecular Proportional-Integral-Derivative Feedback Controllers for Robust Perfect Adaptation and Dynamic Performance Proportional-Integral-Derivative (PID) feedback controllers have been the most widely used controllers in industry for almost a century due to their good performance, simplicity, and ease of tuning. Motivated by their success in various engineering disciplines, PID controllers recently found their way into synthetic biology, where the design of feedback molecular control systems has been identified as an important goal. In this paper, we consider the mathematical realization of PID controllers via biomolecular interactions. We propose an array of topologies that offer a compromise between simplicity and high performance. We first demonstrate that different Proportional-Integral (PI) controllers exhibit different capabilities for enhancing the dynamics and reducing variance (cell-to-cell variability). Next, we introduce several derivative controllers that are realized based on incoherent feedforward loops acting in a feedback configuration. Alternatively, we show that differentiators can be realized by placing molecular integrators in a negative feedback loop--an arrangement that can then be augmented by PI components to yield PID feedback controllers. We demonstrate that the derivative component can be exploited for enhancing system stability, dramatically increasing the molecular control systems dynamic performance, and for reducing the noise effect on the output of interest. The PID controller features are established through various deterministic and stochastic analyses as well as numerical simulations. Finally, we provide an experimental demonstration using a recently developed hybrid setup, the cyberloop, where the controller is implemented in silico to control a biological genetic circuit in vivo. The large array of novel biomolecular PID controllers introduced here forms a basis for the design and construction of advanced high-performance biomolecular control systems that robustly regulate the dynamics of living systems. Diet effects on mouse meiotic recombination: a warning for recombination studies Meiotic recombination is a critical process for sexually reproducing organisms. This exchange of genetic information between homologous chromosomes during meiosis is important not only because it generates genetic diversity, but also because it is often required for proper chromosome segregation. Consequently, the frequency and distribution of crossovers are tightly controlled to ensure fertility and offspring viability. However, in many systems it has been shown that environmental factors can alter the frequency of crossover events. Two studies in flies and yeast point to nutritional status affecting the frequency of crossing over. However, this question remains unexplored in mammals. Here we test how crossover frequency varies in response to diet in Mus musculus males. We use immunohistochemistry to estimate crossover frequency in multiple genotypes under two diet treatments. Our results indicate that while crossover frequency was unaffected by diet in some strains, other strains were sensitive even to small composition changes between two common laboratory chows. Therefore, recombination is both resistant and sensitive to certain dietary changes in a strain-dependent manner and, hence, this response is genetically determined. Our study is the first to report a nutrition effect on genome-wide levels of recombination. Moreover, our work highlights the importance of controlling diet in recombination studies and may point to diet as a potential source of variability among studies, which is relevant for reproducibility. TeamTree analysis: a new approach to evaluate scientific production Advances in science and technology depend on the work of research teams and the publication of results through peer-reviewed articles representing a growing socio-economic resource. Current methods to mine the scientific literature regarding a field of interest focus on content, but the workforce credited by authorship remains largely unexplored, and appropriate measures of scientific production are debated. Here, a new bibliometric approach named TeamTree analysis is introduced that visualizes the development and composition of the workforce driving a field. A new citation-independent measure that scales with the H index estimates impact based on publication record, genealogical ties and collaborative connections. This author-centered approach complements existing tools to mine the scientific literature and to evaluate research across disciplines. In vitro synthesis and reconstitution using mammalian cell-free lysates enables the systematic study of the regulation of LINC complex assembly Membrane proteins perform numerous important functions in cells and tissues. Approximately 20% of the human genome encodes for membrane proteins, which represent the majority of targets for clinically relevant small molecules. Consequently, understanding their structure and structure-function relationships is a fundamental problem in biomedical research. Given the difficulties inherent to performing mechanistic biochemical and biophysical studies of membrane proteins in vitro, we previously developed a facile HeLa cell-based cell-free expression (CFE) system that enables the efficient reconstitution of full-length (FL) functional membrane proteins in supported lipid bilayers. Despite having shown the directional reconstitution of CFE-synthesized FL inner nuclear membrane SUN proteins (i.e. SUN1 and SUN2), which directly interact with outer nuclear membrane KASH proteins within the nuclear envelope lumen to form linker of nucleoskeleton and cytoskeleton (LINC) complexes that mechanically couple the cytoskeleton and nucleus, the mechanism underlying regulated LINC complex assembly remains unclear. Here, we provide evidence that suggests that the reconstitution of CFE-synthesized FL membrane proteins in supported lipid bilayers occurs primarily through the fusion of endoplasmic reticulum-derived microsomes present within our CFE reactions with our supported lipid bilayers. In addition, we demonstrate the ease with which our synthetic biology platform can be used to investigate the impact of the chemical environment (e.g. calcium ions and redox state) on the ability of CFE-synthesized FL SUN proteins reconstituted in supported lipid bilayers to interact with the luminal domain of the KASH protein nesprin-2. Moreover, we use our platform to study the molecular requirements for the homo- and hetero-typic interactions that can occur between SUN1 and SUN2. Finally, we show that our platform can be used to simultaneously reconstitute three different CFE-synthesized FL membrane proteins in a single supported lipid bilayer. Overall, these results establish our HeLa cell-based CFE and supported lipid bilayer reconstitution platform as a powerful tool for performing mechanistic dissections of the oligomerization and function of FL membrane proteins in vitro. While our platform is not a substitute for cell-based studies of membrane protein biochemistry and function, it does provide important mechanistic insights into the biology of difficult-to-study membrane proteins.

ABSTRACT GRAPHIC O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significant PIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found allelic imbalances in the expression of PIK3CA in normal breast tissue and mapped a germline candidate regulatory variant. An imbalance was also frequently observed in the expression of the missense mutant and wild-type PIK3CA alleles in breast tumors from METABRIC and TCGA projects. Moreover, although 60% of tumors preferentially expressed the mutant allele, 10% did preferentially express the wild-type allele. Mechanistically, we show that these imbalances are more frequently due to regulatory variants in cis than altered copy-number and predict that somatic variants have a more significant role than germline ones. We further found that imbalanced allelic expression between mutant and wild-type alleles due to cis-regulatory variants associated with poor prognosis (p=0.0081).

Interestingly, ER+, PR+, and Her2- tumors expressing very low levels of the mutant allele had the poorest prognosis (DSS <7.5yrs for ER+ and PR+ tumors and <5yrs for Her2- tumors). Hence, our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying this cohort of low mutant allele expressing patients of poorer prognosis, who will unlikely benefit from PI3K inhibitors. Furthermore, our work establishes a new model of differential regulation of critical cancer-promoting genes. Genome editing excisase origins illuminated by somatic genome of Blepharisma Massive DNA excision occurs regularly in ciliates, ubiquitous microbial eukaryotes with somatic and germline nuclei in the same cell. Tens of thousands of internally eliminated sequences (IESs) scattered throughout a copy of the ciliate germline genome are deleted during development of the streamlined somatic genome. Blepharisma represents one of the two earliest diverging ciliate classes, and, unusually, has dual pathways of somatic nuclear development, making it ideal for investigating the functioning and evolution of these processes. Here, we report the somatic genome assembly of Blepharisma stoltei strain ATCC 30299 (41 Mb), arranged as numerous alternative telomere-capped minichromosomes. This genome encodes eight PiggyBac transposase homologs liberated from transposons. All are subject to purifying selection, but just one, the putative IES excisase, has a complete catalytic triad. We propose PiggyBac homologs were ancestral excisases that enabled evolution of extensive, natural genome editing. Phenotypic plasticity is aligned with phenological adaptation on both micro- and macroevolutionary timescales In seasonally-variable environments, phenotypic plasticity in phenology may be critical for adaptation to fluctuating environmental (temperature) conditions. Using an 18-generation longitudinal dataset from natural insect (damselfly) populations, we show that phenology has strongly advanced. Individual fitness data suggest this is likely an adaptive response towards a thermally-dependent fitness optimum. A laboratory experiment revealed that developmental plasticity qualitatively matches environmental-dependence of selection, partially explaining observed phenological advance. Expanding our analysis to the macroevolutionary level, we use a database of over 1-million occurrence records and spatiotemporally-matched temperature data from 49 Swedish Odonate species to infer macroevolutionary dynamics of phenology. Phenological plasticity was more closely aligned with adaptation for species that have recently colonized northern latitudes, with more phenological mismatch at lower latitudes. Our results show that phenological plasticity plays a key role in microevolutionary dynamics within a single species, and such plasticity may have facilitated post-Pleistocene range expansion in this insect clade. Embedded 3D printing in self-healing annealable composites for precise patterning of functionally mature human neural constructs Human in vitro models of neural tissue with controllable cellular identity, tunable microenvironment, and defined spatial arrangement are needed to facilitate studies of brain development and disease. Towards this end, embedded printing in jammed microgel supports (i.e., granular gels) holds great promise as it allows precise and programmable patterning of extremely soft and compliant tissue constructs. However, in contrast to the vast material landscape available for bulk hydrogels, granular printing support formulations are restricted to a handful of materials without the ability for facile adjustment of biofunctional properties of the cellular microenvironment. Therefore, there has been a need for novel materials that take advantage of versatile biomimicry of bulk hydrogels while providing high-fidelity support for embedded printing akin to granular gels. To address this need, we present a modular platform for bioengineering of neuronal networks via direct embedded 3D printing of human stem cells inside Self-Healing Annealable Particle-Extracellular matrix (SHAPE) composites. SHAPE composites consist of soft microgels immersed in viscous extracellular-matrix solution to enable precise freeform patterning of human stem cells and consequent generation and long-term maintenance of mature subtype-specific neurons that extend projections within the volume of the annealed support. The developed approach further allows multi-ink deposition, live spatial and temporal monitoring of oxygen levels, as well as creation of vascular channels. Due to its modularity, SHAPE biomanufacturing toolbox not only offers a solution for functional modeling of mechanically sensitive neural constructs, but also has potential to be applied to a wide range of biomaterials with different crosslinking mechanisms to model tissues and diseases where recapitulation of complex architectural features and topological cues is essential. Nuclear Progestin Receptor Mediated Linkage of Blood Coagulation and Ovulation Ovulation is a dramatic remodeling process that includes rupture of blood capillaries and clotting, but coagulation is not thought to directly regulate this process. Herein, we report remarkable increases of coagulation factors V (f5, [~]3145-fold) and tissue factor (f3a, [~]120-fold) in zebrafish ovarian follicle cells during ovulation. This increase was mediated through the nuclear progestin receptor (Pgr), which is essential for ovulation in zebrafish, and was totally abolished in ovarian follicular cells from pgr-/- mutants. In addition, promoter activities of f5 and f3a were significantly enhanced by progestin (DHP) via Pgr. Similar regulation of human F5 promoter activity was induced via human PGRB, suggesting a conserved mechanism. Site-directed mutagenesis of the zebrafish f5 promoter further demonstrated a direct regulation of coagulation factors via progestin response elements. Moreover, a stark increase of erythrocytes occurred in capillaries meshed in wildtype preovulatory follicles but was absent in pgr-/- mutants. Interestingly, anticoagulants significantly inhibited ovulation both in vitro and in vivo, respectively. Furthermore, reduced fecundity was observed in f5+/- female zebrafish. Taken together, our study provides plausible evidence for steroid regulation of coagulation factors, and a new hypothesis for blood clotting triggered ovulation in vertebrates. The influence of saccades on insect flight control In a way analogous to human vision, the fruit fly Drosophila melanogaster and many other flying insects generate smooth and saccadic movements to stabilize and shift their gaze in flight, respectively. It has been hypothesized that this combination of continuous and discrete movements benefits both flight stability and performance, particularly at high frequencies or speeds. Here we develop a hybrid control system model to explore the effects of saccades on the yaw stabilization reflex of D. melanogaster. Inspired from experimental data, the model includes a first order plant, a Proportional-Integral (PI) continuous controller, and a saccadic reset system that fires based on the integrated error of the continuous controller. We explore the gain, delay and switching threshold parameter space to quantify the optimum regions for stability and performance. We show that the addition of saccades to a continuous controller provides benefits to both stability and performance across a range of frequencies. Our model suggests that Drosophila operate near its optimal switching threshold for its experimental gain set. We also show that based on experimental data, D. melanogaster operates in a region that trades off performance and stability. This trade-off increases flight robustness to compensate for environmental uncertainties such as wing damage. Towards a mathematical understanding of colonization resistance in multispecies microbial communities Microbial community composition and dynamics are key to health and disease. Explaining the forces generating and shaping diversity in the microbial consortia making up our bodys defenses is a major aim of current research in microbiology. For this, tractable models are needed, that bridge the gap between observations of patterns and underlying mechanisms. While most microbial dynamics models are based on the Lotka-Volterra framework, we still do not have an analytic quantity for colonization resistance, by which a microbial systems fitness as a whole can be understood. Here, inspired by an epidemiological perspective, we propose a rather general modeling framework whereby colonization resistance can be clearly mathematically defined and studied. In our model, N similar species interact with each other through a co-colonization interaction network encompassing pairwise competition and cooperation, abstractly mirroring how organisms effectively modify their micro-scale environment in relation to others. This formulation relies on a generic notion of shared resources between members of a consortium, yielding explicit frequency-dependent dynamics among N species, in the form of a replicator equation, and offering a precise definition of colonization resistance. We demonstrate that colonization resistance arises and evolves naturally in a multispecies system as a collective quadratic term in a replicator equation, describing dynamic mean invasion fitness. Each pairwise invasion growth rate between two ecological partners, [Formula], is derived explicitly from species asymmetries and mean traits. This makes the systemic colonization resistance [Formula] also an emergent function of global mean-field parameters and trait variation architecture, weighted by the evolving relative abundances among species. In particular, if the underlying invasion fitness matrix {Lambda} displays species-specific  invasiveness or  invasibility structure, colonization resistance will be insensitive to mean micro-scale cooperation or competition. However, in general, colonization resistance depends on and may undergo critical transitions with changes in mean  environment, e.g. cooperation and growth level in a community. We illustrate several key links between our proposed measure of colonization resistance and invader success, including sensitivity to timing, and to the intrinsic pairwise invasion architecture of the resident community. Our simulations reveal that symmetric and invader-driven mutual invasion among resident species tend to maximize systemic colonization resistance to outsiders, when compared to resident-driven, anti-symmetric, almost anti-symmetric and random {Lambda} structures. We contend this modeling approach is a powerful new avenue to study, test and validate interaction networks and invasion topologies in diverse microbial consortia, and quantify analytically their role in colonization resistance, system function, and invasibility. First detection of herpesvirus and prevalence of mycoplasma infection in free-ranging Hermann s tortoises (Testudo hermanni), and in potential pet vectors AO_SCPLOWBSTRACTC_SCPLOWTwo types of pathogens cause highly contagious upper respiratory tract diseases (URTD) in Chelonians: testudinid herpesviruses (TeHV) and a mycoplasma (Mycoplasma agassizii). In captivity, these infections are frequent and can provoke outbreaks. Pet trade generates international flow of tortoises, often without sanitary checking; individuals intentionally or accidentally released in the wild may spread pathogens. A better understanding of the transmission of infectious agents from captivity to wild tortoises is needed. Many exotic individuals have been introduced in populations of the endangered western Hermanns tortoise (Testudo hermanni hermanni), notably spur-thighed tortoises (Testudo graeca). We assessed the presence of TeHV and mycoplasma in native western Hermanns tortoises and in potential pet vectors in south-eastern France. Using a large sample (N=572 tortoises), this study revealed, by PCR, the worrying presence of herpesvirus in 7 free-ranging individuals (3 sub-populations). Additionally, Mycoplasma agassizii was detected, by PCR, in 15 of the 18 populations sampled with a frequency ranging from 3.4% (1 of 29 tortoises) to 25% (3 of 12 tortoises). Exotic spur-thighed tortoises showed high frequency of mycoplasma infection in captivity (18.2%) and in individuals (50%) found in native Hermanns tortoise sub-populations, suggesting that this species could be a significant vector. The paucity of information of TeHV on European tortoise URTD in natural settings, especially in combination with mycoplasma, prompts for further studies. Indeed, sick tortoises remain concealed and may not be easily detected in the field. Our results indicate a good health for most infected tortoise but it should be screened in the field as well as in captivity. GPI-anchored FGF directs cytoneme-mediated bidirectional signaling to self-regulate tissue-specific dispersion How signaling proteins generate a multitude of information to organize tissue patterns is critical to understanding morphogenesis. In Drosophila, FGF produced in wing-disc cells regulates the development of the disc-associated air-sac-primordium (ASP). Here, we show that FGF is Glycosylphosphatidylinositol-anchored to the producing cell surface and that this modification both inhibits free FGF secretion and activates target-specific bidirectional FGF-FGFR signaling through cytonemes. FGF-source and recipient ASP cells extend cytonemes that present FGF and FGFR on their surfaces and reciprocally recognize each other over distance by contacting through CAM-like FGF-FGFR binding. Contact-mediated FGF-FGFR binding induces bidirectional signaling, which, in turn, promotes ASP and source cells to polarize cytonemes toward each other and reinforce signaling contacts. Subsequent un-anchoring of FGFR-bound-FGF from the source cell membrane dissociates cytoneme contacts and delivers FGF target-specifically to ASP cytonemes for paracrine functions. Thus, GPI-anchored FGF organizes both source and recipient cells and self-regulates its cytoneme-mediated tissue-specific dispersion and signaling. Cellular feedback to organotelluranes displays modulation of antioxidant proteins gene expression Organotelluranes RT3 and RT4 are thiol reagents that induce mitochondrial transition pore (MTP) opening in a sensitive and insensitive manner to cyclosporin A. Although RT3 and RT4 promote glutathione depletion, paradoxically, they are also an efficient antioxidant for membrane lipids. These compounds antagonistic effects elicited the challenging question of how the gene expression of antioxidant enzymes would respond to treatment with these compounds. The influence of RT3 and RT4 on antioxidant enzyme expression was investigated in cultured aortic smooth muscle cells (ASMC). RT3 and RT4 promoted disruption of ionic calcium homeostasis, mitochondrial transmembrane potential ({Delta}{Psi}), and cell death in a dose-dependent manner. The cell death mechanisms responded qualitatively to the increase of the organotellurane concentration and changed from apoptosis to necrosis. RT3 and RT4 increased the expression of thioredoxin significantly. RT3 also increased the expression of glutaredoxin and glutathione peroxidase, slightly the catalase expression without significant effects on SOD expression. The results are consistent with GSH and protein thiol depletion and discussed based on the cell toxicity mechanism exhibited by these compounds.



O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/425411v4_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@52bb82org.highwire.dtl.DTLVardef@19476d9org.highwire.dtl.DTLVardef@6aa99org.highwire.dtl.DTLVardef@1aa605e_HPS_FORMAT_FIGEXP  M_FIG C_FIG Structural effects driven by rare point mutations in amylin hormone, the type II diabetes-associated peptide BackgroundAmylin is a 37-amino-acid peptide hormone co-secreted with insulin, which participates in glucose homeostasis. This hormone is able to aggregate in a {beta}-sheet conformation and deposit in islet amyloids, a hallmark in type II diabetes. Since amylin is a gene-encoded hormone, this peptide has variants caused by point mutations that can impact its functions.

MethodsHere, we analyzed the structural effects caused by S20G and G33R point mutations which, according to the 1000 Genomes Project, have frequency in East Asian and European populations, respectively. The analyses were performed by means of aggrescan server, SNP functional effect predictors, and molecular dynamics.

ResultsWe found that both mutations have aggregation potential and cause changes in the monomeric forms when compared with wild-type amylin. Furthermore, comparative analyses with pramlintide, an amylin drug analogue, allowed us to infer that second -helix maintenance may be related to the aggregation potential.

ConclusionsThe S20G mutation has been described as pathologically related, which is in agreement with our findings. In addition, our data suggest that the G33R mutation might have a deleterious effect. The data presented here also provide new therapy opportunities, whether for creating more effective drugs for diabetes or implementing specific treatment for patients with these mutations.

General SignificanceOur data could help to better understand the impact of mutations on the wild-type amylin sequence, as a starting point for the evaluation and characterization of other variations. Moreover, these findings could improve the health of patients with type II diabetes. Reduced glutathione decreases cell adhesion and increases cell volume. Glutathione is the most abundant thiol in animal cells. Reduced glutathione (GSH) is a major intracellular antioxidant neutralizing free radicals and detoxifying electrophiles. It plays important roles in many cellular processes, including cell differentiation, proliferation, and apoptosis. In the present study we demonstrate that extracellular concentration of reduced glutathione markedly increases cell volume within few hours, in a dose-response manner. Pre-incubation of cells with BSO, the inhibitor of {gamma}-glutamylcysteine synthetase, responsible for the first step in intracellular glutathione synthesis did not change the effect of reduced glutathione on cell volume suggesting a mechanism limited to the interaction of extracellular reduced glutathione on cell membrane. Similarly, inhibition of {gamma}-glutamylcyclotransferase involved in intracellular glutamate production had no effect on the action of reduced glutathione. Oxidized glutathione exerted no effect on cell volume. Results show that reduced GSH decreases cell adhesion resulting in an increased cell volume. Since many cell types are able to export GSH, the present results suggest that this could be a fundamental self-regulation of cell volume, giving the cells a self-control on their adhesion proteins. Game of theories: an agent-based model of how variation in contest cost-benefits determines the evolution of contest resolution rules Game-theory based models are used to understand rules that animals use to settle contests over indivisible resources. However, the empirical literature of contests indicates controversial support to models, with some species supporting different models and other species showing no support to any model. Since strategies used to resolve contests may have different associated costs, it is possible that different conditions have determined the evolution of distinct assessment strategies used by animals. We used an agent-based model to explore the importance of the following conditions: resource availability, probability of reproduction with resource, and damage costs on evolution of assessment strategies. We used self- and mutual-assessment models as a heurist framework to build agents with different assessment strategies. In our model, agents competed for resources in scenarios with different combinations of resource availability, probability of reproduction with resource, and damage costs. We found that agents following the self-assessment with damage strategy were prevalent in scenarios with no probability of reproduction without the resource, independently of other variables. We also found that agents following the non-aggressive strategy occurred in all scenarios. However, agents using the non-aggressive strategy were prevalent only in scenarios with probability of reproduction with the resource. Finally, we observed that agents using mutual-assessment occurred only in a scenario with high risk of damage, low availability of resources, and with probability of reproduction without the resource. These results indicate that agents following the self-assessment with damage and non-aggressive strategies may be able to stay at most scenarios. Fatal COVID-19 ARDS associated with incomplete AEC1 differentiation from the transitional state without senescence or fibrosis ARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis. A computational modeling approach for predicting multicell patterns based on signaling-induced differential adhesion Differential adhesion within cell populations enables the emergence of unique patterns in heterogeneous multicellular systems. This process has been previously explored using synthetically engineered heterogenous multicell spheroid systems, in which cell subpopulations engage in bidirectional intercellular signaling to regulate the expression of different cadherins. While engineered cell systems provide excellent experimental tools to observe pattern formation in cell populations, computational models may be leveraged to more systematically explore the key parameters that drive the emergence of different patterns. We developed and validated two- and three-dimensional agent-based models (ABMs) of spheroid patterning for cells engineered with a bidirectional signaling circuit that regulates N- and P-cadherin expression. The model was used to predict how varying initial cell seedings, cadherin induction probabilities, or homotypic adhesion strengths between cells impact spheroid patterning, and unsupervised machine learning techniques were used to map system parameters to unique spheroid patterns. The model was then deployed to design new synthetic cell signaling circuits based on a desired final multicell pattern. Identification and characterization of the WYL BrxR protein and its gene asseparable regulatory elements of a BREX phage restriction system Bacteriophage exclusion ( BREX) phage restriction systems are found in a wide range of bacteria. Various BREX systems encode unique combinations of proteins that usually include a site-specific methyltransferase; none appear to contain a nuclease. Here we describe the identification and characterization of a Type I BREX system from Acinetobacter and the effect of deleting each BREX ORF on growth, methylation, and restriction. We identified a previously uncharacterized gene in the BREX operon that is dispensable for methylation but involved in restriction. Biochemical and crystallographic analyses of this factor, which we term BrxR ( BREX Regulator), demonstrate that it forms a homodimer and specifically binds a DNA target site upstream of its transcription start site. Deletion of the BrxR gene causes cell toxicity, reduces restriction, and significantly increases the expression of BrxC. In contrast, the introduction of a premature stop codon into the BrxR gene, or a point mutation blocking its DNA binding ability, has little effect on restriction, implying that the BrxR coding sequence and BrxR protein play independent functional roles. We speculate that the BrxR coding sequence is involved in cis regulation of anti-phage activity, while the BrxR protein plays an additional regulatory role, perhaps during horizontal transfer.