Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Perceived Barriers to Weight Management in Primary Care—Perspectives of Patients and Providers

BACKGROUND: Despite the consequences of overweight and obesity, effective weight management is not occurring in primary care. OBJECTIVE: To identify beliefs about obesity that act as barriers to weight management in primary care by surveying both patients and providers and comparing their responses. DESIGN: Anonymous, cross-sectional, self-administered survey of patients and providers of a Veteran’s Administration Primary Care Clinic, distributed at the clinic site. SUBJECTS: Forty-eight Internal Medicine providers and 488 patients. MEASUREMENTS: Beliefs, attitudes, and experiences with weight management as well as demographic characteristics were collected through a questionnaire. RESULTS: Providers and patients differed significantly on many beliefs about weight. Providers were more likely than patients to perceive that patients lack self-control to stay on a diet and that fattening food in society and lack of time for exercise were prime factors in weight gain. They also expressed more interest in helping patients with weight management than patients desiring this. Patients were more likely to state that weight problems should be managed on one’s own, talking to a provider is not helpful, providers blame them for their weight problem, and that appointments contain sufficient time for weight discussion. CONCLUSION: Providers and patients emphasize different barriers to weight management. Providers need to be aware of the beliefs that their patients hold to improve weight management discussions and interventions in primary care

Shallow water marine sediment bacterial community shifts along a natural CO2 gradient in the Mediterranean Sea off Vulcano, Italy.

The effects of increasing atmospheric CO(2) on ocean ecosystems are a major environmental concern, as rapid shoaling of the carbonate saturation horizon is exposing vast areas of marine sediments to corrosive waters worldwide. Natural CO(2) gradients off Vulcano, Italy, have revealed profound ecosystem changes along rocky shore habitats as carbonate saturation levels decrease, but no investigations have yet been made of the sedimentary habitat. Here, we sampled the upper 2 cm of volcanic sand in three zones, ambient (median pCO(2) 419 μatm, minimum Ω(arag) 3.77), moderately CO(2)-enriched (median pCO(2) 592 μatm, minimum Ω(arag) 2.96), and highly CO(2)-enriched (median pCO(2) 1611 μatm, minimum Ω(arag) 0.35). We tested the hypothesis that increasing levels of seawater pCO(2) would cause significant shifts in sediment bacterial community composition, as shown recently in epilithic biofilms at the study site. In this study, 454 pyrosequencing of the V1 to V3 region of the 16S rRNA gene revealed a shift in community composition with increasing pCO(2). The relative abundances of most of the dominant genera were unaffected by the pCO(2) gradient, although there were significant differences for some 5 % of the genera present (viz. Georgenia, Lutibacter, Photobacterium, Acinetobacter, and Paenibacillus), and Shannon Diversity was greatest in sediments subject to long-term acidification (>100 years). Overall, this supports the view that globally increased ocean pCO(2) will be associated with changes in sediment bacterial community composition but that most of these organisms are resilient. However, further work is required to assess whether these results apply to other types of coastal sediments and whether the changes in relative abundance of bacterial taxa that we observed can significantly alter the biogeochemical functions of marine sediments

Mario Bunge and the Current Revival of Causal Realism

Mario Bunge’s Causality and Modern Science is arguably one of the best treatments of the causal realist tradition ever to have been written, one that defends the place of causality as a category in the conceptual framework of modern science. And yet in the current revival of causal realism in contemporary metaphysics, there is very little awareness of Bunge’s work. This paper seeks to remedy this, by highlighting one particular criticism Bunge levels at the Aristotelian view of causation and illustrating its relevance for contemporary powers-based accounts. Roughly, the Aristotelian view depicts interactions between objects as involving a unidirectional exertion of influence of one object upon another. This idea of unidirectional action is central to the Aristotelian distinction between active and passive powers, and its corresponding distinction between active and passive objects. As Bunge points out, modern physics does not recognise the existence of any unidirectional actions at all; all influence comes in the form of reciprocal action, or interaction. If this is right, all notions deriving from or influenced by the idea of unidirectional actions—such as the concept of mutual manifestation and reciprocal disposition partners—risk being false by the same measure. Bunge drew the conclusion that the Aristotelian view is ontologically inadequate, but still advocated its use as the most useful approximation available in science. He considered, but ultimately rejected the possibility of a modified view of causation built on reciprocal action, because, in his view, it couldn’t account for the productivity of causation. Bunge’s critique of this particular aspect of the Aristotelian view cannot be overlooked in contemporary metaphysics, but it is possible to construe a modified view of causation that takes the reciprocity of interactions seriously without loss of productivity.Peer reviewe

Optimizing substitution matrix choice and gap parameters for sequence alignment

<p>Abstract</p> <p>Background</p> <p>While substitution matrices can readily be computed from reference alignments, it is challenging to compute optimal or approximately optimal gap penalties. It is also not well understood which substitution matrices are the most effective when alignment accuracy is the goal rather than homolog recognition. Here a new parameter optimization procedure, POP, is described and applied to the problems of optimizing gap penalties and selecting substitution matrices for pair-wise global protein alignments.</p> <p>Results</p> <p>POP is compared to a recent method due to Kim and Kececioglu and found to achieve from 0.2% to 1.3% higher accuracies on pair-wise benchmarks extracted from BALIBASE. The VTML matrix series is shown to be the most accurate on several global pair-wise alignment benchmarks, with VTML200 giving best or close to the best performance in all tests. BLOSUM matrices are found to be slightly inferior, even with the marginal improvements in the bug-fixed RBLOSUM series. The PAM series is significantly worse, giving accuracies typically 2% less than VTML. Integer rounding is found to cause slight degradations in accuracy. No evidence is found that selecting a matrix based on sequence divergence improves accuracy, suggesting that the use of this heuristic in CLUSTALW may be ineffective. Using VTML200 is found to improve the accuracy of CLUSTALW by 8% on BALIBASE and 5% on PREFAB.</p> <p>Conclusion</p> <p>The hypothesis that more accurate alignments of distantly related sequences may be achieved using low-identity matrices is shown to be false for commonly used matrix types. Source code and test data is freely available from the author's web site at <url>http://www.drive5.com/pop</url>.</p

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis

Association between footwear use and neglected tropical diseases: a systematic review and meta-analysis

BACKGROUND The control of neglected tropical diseases (NTDs) has primarily focused on preventive chemotherapy and case management. Less attention has been placed on the role of ensuring access to adequate water, sanitation, and hygiene and personal preventive measures in reducing exposure to infection. Our aim was to assess whether footwear use was associated with a lower risk of selected NTDs. METHODOLOGY We conducted a systematic review and meta-analysis to assess the association between footwear use and infection or disease for those NTDs for which the route of transmission or occurrence may be through the feet. We included Buruli ulcer, cutaneous larva migrans (CLM), leptospirosis, mycetoma, myiasis, podoconiosis, snakebite, tungiasis, and soil-transmitted helminth (STH) infections, particularly hookworm infection and strongyloidiasis. We searched Medline, Embase, Cochrane, Web of Science, CINAHL Plus, and Popline databases, contacted experts, and hand-searched reference lists for eligible studies. The search was conducted in English without language, publication status, or date restrictions up to January 2014. Studies were eligible for inclusion if they reported a measure of the association between footwear use and the risk of each NTD. Publication bias was assessed using funnel plots. Descriptive study characteristics and methodological quality of the included studies were summarized. For each study outcome, both outcome and exposure data were abstracted and crude and adjusted effect estimates presented. Individual and summary odds ratio (OR) estimates and corresponding 95% confidence intervals (CIs) were calculated as a measure of intervention effect, using random effects meta-analyses. PRINCIPAL FINDINGS Among the 427 studies screened, 53 met our inclusion criteria. Footwear use was significantly associated with a lower odds of infection of Buruli ulcer (OR=0.15; 95% CI: 0.08-0.29), CLM (OR=0.24; 95% CI: 0.06-0.96), tungiasis (OR=0.42; 95% CI: 0.26-0.70), hookworm infection (OR=0.48; 95% CI: 0.37-0.61), any STH infection (OR=0.57; 95% CI: 0.39-0.84), strongyloidiasis (OR=0.56; 95% CI: 0.38-0.83), and leptospirosis (OR=0.59; 95% CI: 0.37-0.94). No significant association between footwear use and podoconiosis (OR=0.63; 95% CI: 0.38-1.05) was found and no data were available for mycetoma, myiasis, and snakebite. The main limitations were evidence of heterogeneity and poor study quality inherent to the observational studies included. CONCLUSIONS/SIGNIFICANCE Our results show that footwear use was associated with a lower odds of several different NTDs. Access to footwear should be prioritized alongside existing NTD interventions to ensure a lasting reduction of multiple NTDs and to accelerate their control and elimination. PROTOCOL REGISTRATION PROSPERO International prospective register of systematic reviews CRD42012003338

The Genomic Signature of Crop-Wild Introgression in Maize

The evolutionary significance of hybridization and subsequent introgression has long been appreciated, but evaluation of the genome-wide effects of these phenomena has only recently become possible. Crop-wild study systems represent ideal opportunities to examine evolution through hybridization. For example, maize and the conspecific wild teosinte Zea mays ssp. mexicana, (hereafter, mexicana) are known to hybridize in the fields of highland Mexico. Despite widespread evidence of gene flow, maize and mexicana maintain distinct morphologies and have done so in sympatry for thousands of years. Neither the genomic extent nor the evolutionary importance of introgression between these taxa is understood. In this study we assessed patterns of genome-wide introgression based on 39,029 single nucleotide polymorphisms genotyped in 189 individuals from nine sympatric maize-mexicana populations and reference allopatric populations. While portions of the maize and mexicana genomes were particularly resistant to introgression (notably near known cross-incompatibility and domestication loci), we detected widespread evidence for introgression in both directions of gene flow. Through further characterization of these regions and preliminary growth chamber experiments, we found evidence suggestive of the incorporation of adaptive mexicana alleles into maize during its expansion to the highlands of central Mexico. In contrast, very little evidence was found for adaptive introgression from maize to mexicana. The methods we have applied here can be replicated widely, and such analyses have the potential to greatly informing our understanding of evolution through introgressive hybridization. Crop species, due to their exceptional genomic resources and frequent histories of spread into sympatry with relatives, should be particularly influential in these studies