Genomic Basis of Circannual Rhythm in the European Corn Borer Moth

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Media use and obesity in adolescent females

Objective: In the context of growing public health concern with the obesity rates among children and adolescents, much attention has focused on the role of television as a contributor to the problem. Less attention has been devoted to interactive media (internet surfing and video games), despite the fact that these forms of entertainment are fast gaining in popularity among youth. This study investigated the relative associations of TV viewing and interactive media use with body fat and BMI, controlling for both physical activity participation and cardiovascular fitness. Research Methods and Procedures: Female high‐school adolescents (N = 194) were assessed for cardiovascular fitness (cycle ergometer), percent body fat (DXA), and BMI. Time spent in moderate, vigorous, and sedentary activities was assessed with a 3‐day recall. Results: Multivariate regression analysis showed that only interactive media use was associated with percentage body fat and BMI, and the relationship remained strong even after controlling for physical activity participation and cardiovascular fitness. Discussion: It appears that, among this group of adolescent females, the association between interactive media use and obesity is not explained by a reduction in moderate or vigorous activity commensurate with media use.     

Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation

Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome. We firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9, and NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4, and LPL). Conducting mendelian randomisation (MR) provided strong evidence of an effect of drug-based genetic scores on coronary artery disease (CAD) risk with the exception of ANGPTL3. We then systematically estimated the effects of each score on 249 metabolic traits derived using blood samples from an unprecedented sample size of up to 115,082 UK Biobank participants. Genetically predicted effects were generally consistent among drug targets, which were intended to modify the same lipoprotein lipid trait. For example, the linear fit for the MR estimates on all 249 metabolic traits for genetically predicted inhibition of LDL cholesterol lowering targets HMGCR and PCSK9 was r² = 0.91. In contrast, comparisons between drug classes that were designed to modify discrete lipoprotein traits typically had very different effects on metabolic signatures (for instance, HMGCR versus each of the 4 triglyceride targets all had r² < 0.02). Furthermore, we highlight this discrepancy for specific metabolic traits, for example, finding that LDL cholesterol lowering therapies typically had a weak effect on glycoprotein acetyls, a marker of inflammation, whereas triglyceride modifying therapies assessed provided evidence of a strong effect on lowering levels of this inflammatory biomarker. Our findings indicate that genetically predicted perturbations of these drug targets on the blood metabolome can drastically differ, despite largely consistent effects on risk of CAD, with potential implications for biomarkers in clinical development and measuring treatment response.     

Evolutionary insights into primate skeletal gene regulation using a comparative cell culture model

The evolution of complex skeletal traits in primates was likely influenced by both genetic and environmental factors. Because skeletal tissues are notoriously challenging to study using functional genomic approaches, they remain poorly characterized even in humans, let alone across multiple species. The challenges involved in obtaining functional genomic data from the skeleton, combined with the difficulty of obtaining such tissues from nonhuman apes, motivated us to consider an alternative in vitro system with which to comparatively study gene regulation in skeletal cell types. Specifically, we differentiated six human (Homo sapiens) and six chimpanzee (Pan troglodytes) induced pluripotent stem cell lines (iPSCs) into mesenchymal stem cells (MSCs) and subsequently into osteogenic cells (bone cells). We validated differentiation using standard methods and collected single-cell RNA sequencing data from over 100,000 cells across multiple samples and replicates at each stage of differentiation. While most genes that we examined display conserved patterns of expression across species, hundreds of genes are differentially expressed (DE) between humans and chimpanzees within and across stages of osteogenic differentiation. Some of these interspecific DE genes show functional enrichments relevant in skeletal tissue trait development. Moreover, topic modeling indicates that interspecific gene programs become more pronounced as cells mature. Overall, we propose that this in vitro model can be used to identify interspecific regulatory differences that may have contributed to skeletal trait differences between species.     

G protein-dependent CCR5 signaling is not required for efficient infection of primary T lymphocytes and macrophages by R5 human immunodeficiency virus type 1 isolates

The requirement of human immunodeficiency virus (HIV)-induced CCR5 activation for infection by R5 HIV type 1 (HIV-1) strains remains controversial. Ectopic CCR5 expression in CD4(+)-transformed cells or pharmacological inhibition of G(alpha)i proteins coupled to CCR5 left unsolved whether CCR5-dependent cell activation is necessary for the HIV life cycle. In this study, we investigated the role played by HIV-induced CCR5-dependent cell signaling during infection of primary CD4-expressing leukocytes. Using lentiviral vectors, we restored CCR5 expression in T lymphocytes and macrophages from individuals carrying the homozygous 32-bp deletion of the CCR5 gene (ccr5 Delta32/Delta32). Expression of wild-type (wt) CCR5 in ccr5 Delta32/Delta32 cells permitted infection by R5 HIV isolates. We assessed the capacity of a CCR5 derivative carrying a mutated DRY motif (CCR5-R126N) in the second intracellular loop to work as an HIV-1 coreceptor. The R126N mutation is known to disable G protein coupling and agonist-induced signal transduction through CCR5 and other G protein-coupled receptors. Despite its inability to promote either intracellular calcium mobilization or cell chemotaxis, the inactive CCR5-R126N mutant provided full coreceptor function to several R5 HIV-1 isolates in primary cells as efficiently as wt CCR5. We conclude that in a primary, CCR5-reconstituted CD4(+) cell environment, G protein signaling is dispensable for R5 HIV-1 isolates to actively infect primary CD4(+) T lymphocytes or macrophages.     

ISG20, a new interferon-induced RNase specific for single-stranded RNA,defines an alternative antiviral pathway against RNA genomic viruses

Interferons (IFNs) encode a family of secreted proteins that provide the front-line defense against viral infections. Their diverse biological actions are thought to be mediated by the products of specific but usually overlapping sets of cellular genes induced in the target cells. We have recently isolated a new human IFN-induced gene that we have termed ISG20, which codes for a 3' to 5' exonuclease with specificity for single-stranded RNA and, to a lesser extent, for DNA. In this report, we demonstrate that ISG20 is involved in the antiviral functions of IFN. In the absence of IFN treatment, ISG20-overexpressing HeLa cells showed resistance to infections by vesicular stomatitis virus (VSV), influenza virus, and encephalomyocarditis virus (three RNA genomic viruses) but not to the DNA genomic adenovirus. ISG20 specifically interfered with VSV mRNA synthesis and protein production while leaving the expression of cellular control genes unaffected. No antiviral effect was observed in cells overexpressing a mutated ISG20 protein defective in exonuclease activity, demonstrating that the antiviral effects were due to the exonuclease activity of ISG20. In addition, the inactive mutant ISG20 protein, which is able to inhibit ISG20 exonuclease activity in vitro, significantly reduced the ability of IFN to block VSV development. Taken together, these data suggested that the antiviral activity of IFN against VSV is partly mediated by ISG20. We thus show that, besides RNase L, ISG20 has an antiviral activity, supporting the idea that it might represent a novel antiviral pathway in the mechanism of IFN action.     

Cell-intrinsic differences between stem cells from different regions of the peripheral nervous system regulate the generation of neural diversity

Stem cells in different regions of the nervous system give rise to different types of mature cells. This diversity is assumed to arise in response to local environmental differences, but the contribution of cell-intrinsic differences between stem cells has been unclear. At embryonic day (E)14, neural crest stem cells (NCSCs) undergo primarily neurogenesis in the gut but gliogenesis in nerves. Yet gliogenic and neurogenic factors are expressed in both locations. NCSCs isolated by flow-cytometry from E14 sciatic nerve and gut exhibited heritable, cell-intrinsic differences in their responsiveness to lineage determination factors. Gut NCSCs were more responsive to neurogenic factors, while sciatic nerve NCSCs were more responsive to gliogenic factors. Upon transplantation of uncultured NCSCs into developing peripheral nerves in vivo, sciatic nerve NCSCs gave rise only to glia, while gut NCSCs gave rise primarily to neurons. Thus, cell fate in the nerve was stem cell determined.     

Temporally distinct requirements for endothelin receptor B in the generation and migration of gut neural crest stem cells

Loss of Endothelin-3/Endothelin receptor B (EDNRB) signaling leads to aganglionosis of the distal gut (Hirschsprung's disease), but it is unclear whether it is required primarily for neural crest progenitor maintenance or migration. Ednrb-deficient gut neural crest stem cells (NCSCs) were reduced to 40% of wild-type levels by embryonic day 12.5 (E12.5), but no further depletion of NCSCs was subsequently observed. Undifferentiated NCSCs persisted in the proximal guts of Ednrb-deficient rats throughout fetal and postnatal development but exhibited migration defects after E12.5 that prevented distal gut colonization. EDNRB signaling may be required to modulate the response of neural crest progenitors to migratory cues, such as glial cell line-derived neurotrophic factor (GDNF). This migratory defect could be bypassed by transplanting wild-type NCSCs directly into the aganglionic region of the Ednrb(sl/sl) gut, where they engrafted and formed neurons as efficiently as in the wild-type gut.     

A comparison between a new model and current models for estimating trunk segment inertial parameters

Modeling of the body segments to estimate segment inertial parameters is required in the kinetic analysis of human motion. A new geometric model for the trunk has been developed that uses various cross-sectional shapes to estimate segment volume and adopts a non-uniform density function that is gender-specific. The goal of this study was to test the accuracy of the new model for estimating the trunk's inertial parameters by comparing it to the more current models used in biomechanical research. Trunk inertial parameters estimated from dual X-ray absorptiometry (DXA) were used as the standard. Twenty-five female and 24 male college-aged participants were recruited for the study. Comparisons of the new model to the accepted models were accomplished by determining the error between the models’ trunk inertial estimates and that from DXA. Results showed that the new model was more accurate across all inertial estimates than the other models. The new model had errors within 6.0% for both genders, whereas the other models had higher average errors ranging from 10% to over 50% and were much more inconsistent between the genders. In addition, there was little consistency in the level of accuracy for the other models when estimating the different inertial parameters. These results suggest that the new model provides more accurate and consistent trunk inertial estimates than the other models for both female and male college-aged individuals. However, similar studies need to be performed using other populations, such as elderly or individuals from a distinct morphology (e.g. obese). In addition, the effect of using different models on the outcome of kinetic parameters, such as joint moments and forces needs to be assessed.