The Relationship between Gene Isoform Multiplicity,Number of Exons and Protein Divergence

At present we know that phenotypic differences between organisms arise from a variety of sources, like protein sequence divergence, regulatory sequence divergence, alternative splicing, etc. However, we do not have yet a complete view of how these sources are related. Here we address this problem, studying the relationship between protein divergence and the ability of genes to express multiple isoforms. We used three genome-wide datasets of human-mouse orthologs to study the relationship between isoform multiplicity co-occurrence between orthologs (the fact that two orthologs have more than one isoform) and protein divergence. In all cases our results showed that there was a monotonic dependence between these two properties. We could explain this relationship in terms of a more fundamental one, between exon number of the largest isoform and protein divergence. We found that this last relationship was present, although with variations, in other species (chimpanzee, cow, rat, chicken, zebrafish and fruit fly). In summary, we have identified a relationship between protein divergence and isoform multiplicity co-occurrence and explained its origin in terms of a simple gene-level property. Finally, we discuss the biological implications of these findings for our understanding of inter-species phenotypic differences.     

The Role of Peroxisome Proliferator-Activated Receptor γ in Immune Responses to Enteroaggregative Escherichia coli Infection

Background

Enteroaggregative Escherichia coli (EAEC) is recognized as an emerging cause of persistent diarrhea and enteric disease worldwide. Mucosal immunity towards EAEC infections is incompletely understood due in part to the lack of appropriate animal models. This study presents a new mouse model and investigates the role of peroxisome proliferator-activated receptor gamma (PPARγ) in the modulation of host responses to EAEC in nourished and malnourished mice.

Methods/Principal Findings

Wild-type and T cell-specific PPARγ null C57BL/6 mice were fed protein-deficient diets at weaning and challenged with 5×10⁹cfu EAEC strain JM221 to measure colonic gene expression and immune responses to EAEC. Antigen-specific responses to E. coli antigens were measured in nourished and malnourished mice following infection and demonstrated the immunosuppressive effects of malnutrition at the cellular level. At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery. The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo.

Conclusions

Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.     

Modeling-Enabled Characterization of Novel NLRX1 Ligands

Nucleotide-binding domain and leucine-rich repeat containing (NLR) family are intracellular sentinels of cytosolic homeostasis that orchestrate immune and inflammatory responses in infectious and immune-mediated diseases. NLRX1 is a mitochondrial-associated NOD-like receptor involved in the modulation of immune and metabolic responses. This study utilizes molecular docking approaches to investigate the structure of NLRX1 and experimentally assesses binding to naturally occurring compounds from several natural product and lipid databases. Screening of compound libraries predicts targeting of NLRX1 by conjugated trienes, polyketides, prenol lipids, sterol lipids, and coenzyme A-containing fatty acids for activating the NLRX1 pathway. The ligands of NLRX1 were identified by docking punicic acid (PUA), eleostearic acid (ESA), and docosahexaenoic acid (DHA) to the C-terminal fragment of the human NLRX1 (cNLRX1). Their binding and that of positive control RNA to cNLRX1 were experimentally determined by surface plasmon resonance (SPR) spectroscopy. In addition, the ligand binding sites of cNLRX1 were predicted in silico and validated experimentally. Target mutagenesis studies demonstrate that mutation of 4 critical residues ASP677, PHE680, PHE681, and GLU684 to alanine resulted in diminished affinity of PUA, ESA, and DHA to NLRX1. Consistent with the regulatory actions of NLRX1 on the NF-κB pathway, treatment of bone marrow derived macrophages (BMDM)s with PUA and DHA suppressed NF-κB activity in a NLRX1 dependent mechanism. In addition, a series of pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the regulatory function of PUA on colitis is NLRX1 dependent. Thus, we identified novel small molecules that bind to NLRX1 and exert anti-inflammatory actions.     

Individual wealth rank, community wealth inequality, and self-reported adult poor health: a test of hypotheses with panel data (2002-2006) from native Amazonians, Bolivia

Growing evidence suggests that economic inequality in a community harms the health of a person. Using panel data from a small-scale, preindustrial rural society, we test whether individual wealth rank and village wealth inequality affects self-reported poor health in a foraging-farming native Amazonian society. A person's wealth rank was negatively but weakly associated with self-reported morbidity. Each step up/year in the village wealth hierarchy reduced total self-reported days ill by 0.4 percent. The Gini coefficient of village wealth inequality bore a positive association with self-reported poor health that was large in size, but not statistically significant. We found small village wealth inequality, and evidence that individual economic rank did not change. The modest effects may have to do with having used subjective rather than objective measures of health, having small village wealth inequality, and with the possibly true modest effect of a person's wealth rank on health in a small-scale, kin-based society. Finally, we also found that an increase in mean individual wealth by village was related to worse self-reported health. As the Tsimane' integrate into the market economy, their possibilities of wealth accumulation rise, which may affect their well-being. Our work contributes to recent efforts in biocultural anthropology to link the study of social inequalities, human biology, and human-environment interactions.     

Ethnobotanical Knowledge and Crop Diversity in Swidden Fields: A Study in a Native Amazonian Society

Crop diversity protects food consumption in poor households within developing nations. Here we estimate the association between crop diversity on swidden fields and ethnobotanical knowledge. We conducted research among 215 male household heads from a native Amazonian society. Using multivariate regressions, we found higher crop diversity among households that depend on agricultural production for household consumption. We also found a statistically significant and positive, but low, association between the ethnobotanical knowledge of the male household head and crop diversity. Doubling the stock of ethnobotanical knowledge of the male household head is associated with a 9% increase in the number of crops sown by a household. The association remained after we controlled for the household level of market exposure, but vanished after we controlled for the social capital of the male household head. Future research should compare the association between ethnobotanical knowledge and crop diversity across different agricultural systems (i.e., home gardens, fallow fields).     

Knowledge and Use Value of Plant Species in a Rarámuri Community: A Gender Perspective for Conservation

We used a quantitative ethnobotanical approach to analyze factors influencing the use value of plant species among men and women of the Rarámuri people in Cuiteco, Chihuahua, Mexico. We constructed a use value index (UV) combining the use frequency (U) and the quality perception (Q) of useful plant species by local people. We identified all plant species used by the Rarámuri and classified them into 14 general use categories. We interviewed 34 households in the village to compare men and women’s knowledge on the five main general use categories (and on their respective subcategories and specific uses), to document how they practice gathering activities and to calculate scores of plants UV. A total of 226 useful plant species were identified, but only 12% of them had high UV scores for the 42 specific uses defined. When the overall knowledge of plant species was examined, no significant differences were detected between men and women, but significant differences were identified in general use categories such as medicinal plants, plants for construction and domestic goods, but not in plants used as food and firewood. We identified a division of labor in gathering activities associated with gender, with women mainly gathering medicinal and edible plants and being involved in preparing medicines and food, whereas men were primarily gathering and using plants for manufacturing domestic goods, firewood, and building materials. Plant species UV associated to gender were significantly different between men and women at the level of specific uses in the general category of domestic goods and building. Frequency of use is highly associated with plant species quality perception.     

Maintenance versus growth: investigating the costs of immune activation among children in lowland Bolivia

Immune function is a central component of maintenance effort, and it provides critical protection against the potentially life threatening effects of pathogens. However, immune defenses are energetically expensive, and the resources they consume are not available to support other activities related to growth and/or reproduction. In our study we use a life history theory framework to investigate tradeoffs between maintenance effort and growth among children in a remote area of Amazonian Bolivia. Baseline concentrations of C-reactive protein (CRP) were measured in 309 2- to 10-year olds as an indicator of immune activation, and height was measured at baseline and three months later. Elevated CRP at baseline predicts smaller gains in height over the subsequent three months, with the costs to growth particularly high for 2- to 4-year olds and for those with low energy reserves (in the form of body fat) at the time of immunostimulation. These results provide evidence for a significant tradeoff between investment in immunity and growth in humans, and highlight an important physiological mechanism through which maintenance effort may have lasting effects on child growth and development.     

L-carnosine as an enhancer to computerized cognitive behaviour therapy in Japanese workers,an unjustified claim

This letter comments on the conclusion drawn by Shirotsuki et al. (2017) in their article entitled “The effect for Japanese workers of a self-help computerized cognitive behaviour therapy program with a supplement soft drink”, recently published in BioPsychoSocial Medicine. The authors concluded that their drink, containing L-carnosine, enhances the effects of a computerized cognitive-behavioural therapy (CCBT) on the psychological well-being of healthy Japanese workers. Yet, we argue that their conclusion is unfounded given their results and the methodological shortcomings of their study. Briefly, while the authors reported improvement on the tension-anxiety subscale of the Profile of Mood States (POMS) in the CCBT only group, they also observed a lack of improvement on this subscale in the CCBT+L-carnosine group suggesting that the drink washes out this beneficial effect of CCBT. Methodological issues include the uncontrolled levels of L-carnosine metabolized by participants jeopardize the study’s internal validity. Also, the clinical meaningfulness of the findings seems dubious as post-treatment scores remained within the range of the general Japanese population. Consequently, we argue that Shirotsuki et al.’s study should be re-conducted before drawing any valid conclusion.