INSIG1 influences obesity-related hypertriglyceridemia in humans

In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 × 10−3 in 1,560 individuals of the original linkage cohort, P = 8 × 10−4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10−6). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans

Wing scale ultrastructure underlying convergent and divergent iridescent colours in mimetic Heliconius butterflies

Iridescence is an optical phenomenon whereby colour changes with the illumination and viewing angle. It can be produced by thin film interference or diffraction. Iridescent optical structures are fairly common in nature, but relatively little is known about their production or evolution. Here we describe the structures responsible for producing blue-green iridescent colour in Heliconius butterflies. Overall the wing scale structures of iridescent and non-iridescent Heliconius species are very similar, both having longitudinal ridges joined by cross-ribs. However, iridescent scales have ridges composed of layered lamellae, which act as multilayer reflectors. Differences in brightness between species can be explained by the extent of overlap of the lamellae and their curvature as well as the density of ridges on the scale. Heliconius are well known for their Müllerian mimicry. We find that iridescent structural colour is not closely matched between co-mimetic species. Differences appear less pronounced in models of Heliconius vision than models of avian vision, suggesting that they are not driven by selection to avoid heterospecific courtship by co-mimics. Ridge profiles appear to evolve relatively slowly, being similar between closely related taxa, while ridge density evolves faster and is similar between distantly related co-mimics

Catholic Healthcare Organizations and the Articulation of Their Identity

Contains fulltext : 69947.pdf (publisher's version ) (Open Access

The {Mondshein} Sequence

Canonical orderings [STOC'88, FOCS'92] have been used as a key tool in graph drawing, graph encoding and visibility representations for the last decades. We study a far-reaching generalization of canonical orderings to non-planar graphs that was published by Lee Mondshein in a PhD-thesis at M.I.T.\ as early as 1971. Mondshein proposed to order the vertices of a graph in a sequence such that, for any $i$, the vertices from $1$ to $i$ induce essentially a $2$-connected graph while the remaining vertices from $i+1$ to $n$ induce a connected graph. Mondshein's sequence generalizes canonical orderings and became later and independently known under the name \emph{non-separating ear decomposition}. Currently, the best known algorithm for computing this sequence achieves a running time of $O(nm)$; the main open problem in Mondshein's and follow-up work is to improve this running time to a subquadratic time. In this paper, we present the first algorithm that computes a Mondshein sequence in time and space $O(m)$, improving the previous best running time by a factor of $n$. In addition, we illustrate the impact of this result by deducing linear-time algorithms for several other problems, for which the previous best running times have been quadratic. In particular, we show how to compute three independent spanning trees in a $3$-connected graph in linear time, improving a result of Cheriyan and Maheshwari [J. Algorithms 9(4)]. Secondly, we improve the preprocessing time for the output-sensitive data structure by Di Battista, Tamassia and Vismara [Algorithmica 23(4)] that reports three internally disjoint paths between any given vertex pair from $O(n^2)$ to $O(m)$. Finally, we show how a very simple linear-time planarity test can be derived once a Mondshein sequence is computed

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits — The Hispanic/Latino Anthropometry Consortium

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification

Genetic determinants of metabolic biomarkers and their associations with cardiometabolic traits in Hispanic/Latino adolescents

Background: Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers—adiponectin, leptin, ghrelin, and orexin—and their associations with CMD risk factors. Methods: We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling. Results: We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels. Conclusions: The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers. Impact: This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents.Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts.Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels

Global extent and drivers of mammal population declines in protected areas under illegal hunting pressure

Illegal hunting is a persistent problem in many protected areas, but an overview of the extent of this problem and its impact on wildlife is lacking. We reviewed 40 years (1980–2020) of global research to examine the spatial distribution of research and socio-ecological factors influencing population decline within protected areas under illegal hunting pressure. From 81 papers reporting 988 species/site combinations, 294 mammal species were reported to have been illegally hunted from 155 protected areas across 48 countries. Research in illegal hunting has increased substantially during the review period and showed biases towards strictly protected areas and the African continent. Population declines were most frequent in countries with a low human development index, particularly in strict protected areas and for species with a body mass over 100 kg. Our results provide evidence that illegal hunting is most likely to cause declines of large-bodied species in protected areas of resource-poor countries regardless of protected area conservation status. Given the growing pressures of illegal hunting, increased investments in people’s development and additional conservation efforts such as improving anti-poaching strategies and conservation resources in terms of improving funding and personnel directed at this problem are a growing priority

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered