Epigenetic Factors Impacting Type 2 Diabetes in American Indians

American Indians have been found to be at higher risk of type 2 diabetes (T2D) than any other ethnic or racial groups in the United States, with an estimated prevalence rate of 33%. Given that T2D prevalence rates amongst the American Indian population are so high, studying the complex factors that contribute to T2D is crucial. Of particular importance to this study is identifying heritable effects involved in development of T2D. Epigenetic effects, heritable changes to DNA that affect gene expression such as DNA methylation (DNAm), have been shown to be associated with T2D phenotypes. Studies in other subpopulations have previously identified differential DNAm at the ABCG1 gene as being associated with T2D. ABCG1 plays a significant role in promoting cholesterol efflux, and it has been associated with T2D and related traits. As such, we sought to determine whether those results generalized to American Indians by assaying DNAm at ABCG1 within a sample population of 285 American Indian participants in the Strong Heart Study (SHS). In verifying whether there is a significant association between DNAm levels and T2D, we hypothesize that individuals diagnosed with T2D will have higher rates of DNAm at loci in ABCG1 than individuals who do not have T2D. Ultimately, we hope the results of this experiment can provide more insight on the role that differential DNAm has to play in the risk and development of T2D

Checklist for One Health Epidemiological Reporting of Evidence (COHERE).

One Health is defined as the intersection and integration of knowledge regarding humans, animals, and the environment, yet as the One Health scientific literature expands, there is considerable heterogeneity of approach and quality of reporting in One Health studies. In addition, many researchers who publish such studies do not include or integrate data from all three domains of human, animal, and environmental health. This points to a critical need to unify guidelines for One Health studies. This report details the Checklist for One Health Epidemiological Reporting of Evidence (COHERE) to guide the design and publication format of future One Health studies. COHERE was developed by a core writing team and international expert review group that represents multiple disciplines, including human medicine, veterinary medicine, public health, allied professionals, clinical laboratory science, epidemiology, the social sciences, ecohealth and environmental health. The twin aims of the COHERE standards are to 1) improve the quality of reporting of observational or interventional epidemiological studies that collect and integrate data from humans, animals and/or vectors, and their environments; and 2) promote the concept that One Health studies should integrate knowledge from these three domains. The 19 standards in the COHERE checklist address descriptions of human populations, animal populations, environmental assessment, spatial and temporal relationships of data from the three domains, integration of analyses and interpretation, and inclusion of expertise in the research team from disciplines related to human health, animal health, and environmental health

Yeast Integral Membrane Proteins Apq12, Brl1, and Brr6 Form a Complex Important for Regulation of Membrane Homeostasis and Nuclear Pore Complex Biogenesis

Proper functioning of intracellular membranes is critical for many cellular processes. A key feature of membranes is their ability to adapt to changes in environmental conditions by adjusting their composition so as to maintain constant biophysical proper- ties, including fluidity and flexibility. Similar changes in the biophysical properties of membranes likely occur when intracellular processes, such as vesicle formation and fusion, require dramatic changes in membrane curvature. Similar modifications must also be made when nuclear pore complexes (NPCs) are constructed within the existing nuclear membrane, as occurs during in- terphase in all eukaryotes. Here we report on the role of the essential nuclear envelope/endoplasmic reticulum (NE/ER) protein Brl1 in regulating the membrane composition of the NE/ER. We show that Brl1 and two other proteins characterized previous- ly—Brr6, which is closely related to Brl1, and Apq12—function together and are required for lipid homeostasis. All three trans- membrane proteins are localized to the NE and can be coprecipitated. As has been shown for mutations affecting Brr6 and Apq12, mutations in Brl1 lead to defects in lipid metabolism, increased sensitivity to drugs that inhibit enzymes involved in lipid synthesis, and strong genetic interactions with mutations affecting lipid metabolism. Mutations affecting Brl1 or Brr6 or the absence of Apq12 leads to hyperfluid membranes, because mutant cells are hypersensitive to agents that increase membrane flu- idity. We suggest that the defects in nuclear pore complex biogenesis and mRNA export seen in these mutants are consequences of defects in maintaining the biophysical properties of the NE

How partnerships for community-based health professions training were affected by national changes in funding

Background: Area Health Education Centers (AHEC) have contributed to U.S. healthcare workforce training since 1971. National funders recently refocused efforts from K-12 students to matriculated health profession students, which reduced annual funding by $75,000 (25%) per year per Center. Objectives: To describe how community partnership changed due to funding reductions. Methods: Key informant interviews were conducted with all four regional center directors with community partnerships. Lessons learned: Hosted regional centers navigated partnerships in ways that did not significantly change programs because the host institutions supported continuing the partnerships. Independent centers experienced significant changes in partnerships by ending well-established programs and starting new programs with new partners. Both hosted and independent centers took salary cuts, downsized staff, and applied for grants and contracts to fill the funding gap. Improved communication with the Oregon AHEC program office was reported as needed. Conclusions: Navigating partnerships differed according to host status

Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines

BackgroundImatinib mesylate is currently the drug of choice to treat chronic myeloid leukemia. However, patient resistance and cytotoxicity make secondary lines of treatment, such as omacetaxine mepesuccinate, a necessity. Given that drug cytotoxicity represents a major problem during treatment, it is essential to understand the biological pathways affected to better predict poor drug response and prioritize a treatment regime.MethodsWe conducted cell viability and gene expression assays to determine heritability and gene expression changes associated with imatinib and omacetaxine treatment of 55 non-cancerous lymphoblastoid cell lines, derived from 17 pedigrees. In total, 48,803 transcripts derived from Illumina Human WG-6 BeadChips were analyzed for each sample using SOLAR, whilst correcting for kinship structure.ResultsCytotoxicity within cell lines was highly heritable following imatinib treatment (h2&thinsp;=&thinsp;0.60-0.73), but not omacetaxine treatment. Cell lines treated with an IC20 dose of imatinib or omacetaxine showed differential gene expression for 956 (1.96%) and 3,892 transcripts (7.97%), respectively; 395 of these (0.8%) were significantly influenced by both imatinib and omacetaxine treatment. k-means clustering and DAVID functional annotation showed expression changes in genes related to kinase binding and vacuole-related functions following imatinib treatment, whilst expression changes in genes related to cell division and apoptosis were evident following treatment with omacetaxine. The enrichment scores for these ontologies were very high (mostly &gt;10).ConclusionsInduction of gene expression changes related to different pathways following imatinib and omacetaxine treatment suggests that the cytotoxicity of such drugs may be differentially tolerated by individuals based on their genetic background.<br /

Assessing the Use of GEE Methods for Analyzing Continuous Outcomes from Family Studies: Strong Heart Family Study

Background: Because of its convenience and robustness, the generalized estimating equations (GEE) method has been commonly used to fit marginal models of continuous outcomes in family studies. However, unbalanced family sizes and complex pedigree structures within each family may challenge the GEE method, which treats families as clusters with the same correlation structure. The appropriateness of using the GEE method to analyze continuous outcomes in family studies remains unclear. In this paper, we performed simulation studies to evaluate the performance of GEE in the analysis of family study data. Methods: In simulation studies, we generated data from a linear mixed effects model with individual random effects. The random effects covariance matrix is specified as twice that of the pedigree matrix from the Strong Heart Family Study (SHFS) and other hypothetical pedigree structures. A Bayesian approach that utilizes the pedigree matrix was also conducted as a benchmark to compare with GEE methods with either independent or exchangeable correlation structures. Finally, analysis with a real data example was included. Results: Our simulation results showed that GEE with independent correlation structure worked well for family data with continuous outcomes. Real data analysis revealed that all GEE and Bayesian approaches produced similar results. Conclusion: GEE model performs well on continuous outcome in family studies, and it yields estimated coefficients similar to a Bayesian model, which takes genetic relationship into account. Overall, GEE is robust to misspecification of genetic relationships among family members

Analysis of SLC16A11 Variants in 12,811 American Indians: Genotype-Obesity Interaction for Type 2 Diabetes and an Association With RNASEK Expression

Genetic variants in SLC16A11 were recently reported to be associated with type 2 diabetes in Mexican and other Latin American populations. The diabetes risk haplotype had a frequency of 50% in Native Americans from Mexico but was rare in Europeans and Africans. In the current study, we analyzed SLC16A11 in 12,811 North American Indians and found that the diabetes risk haplotype, tagged by the rs75493593 A allele, was nominally associated with type 2 diabetes (P = 0.001, odds ratio 1.11). However, there was a strong interaction with BMI (P = 5.1 × 10(-7)) such that the diabetes association was stronger in leaner individuals. rs75493593 was also strongly associated with BMI in individuals with type 2 diabetes (P = 3.4 × 10(-15)) but not in individuals without diabetes (P = 0.77). Longitudinal analyses suggest that this is due, in part, to an association of the A allele with greater weight loss following diabetes onset (P = 0.02). Analyses of global gene expression data from adipose tissue, skeletal muscle, and whole blood provide evidence that rs75493593 is associated with expression of the nearby RNASEK gene, suggesting that RNASEK expression may mediate the effect of genotype on diabetes

Genetic variants and physical activity interact to affect bone density in Hispanic children

Background: Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study. Methods: Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD. Results: We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD (p \u3c 0.05). Higher PRS was associated with a lower total body BMD (β = − 0.040 ± 0.009, p = 1.1 × 10− 5 ) and lumbar spine BMD (β = − 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (β = − 0.015 ± 0.006, p = 0.02; β = 0.008 ± 0.01, p = 0.4, respectively). Discussion: The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed

Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signaling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here, we show that multinucleate OIS cells originate mostly from failed mitosis. Prior to senescence, mutant H-RasV12 activation in primary human fibroblasts compromised mitosis, concordant with abnormal expression of mitotic genes functionally linked to the observed mitotic spindle and chromatin defects. Simultaneously, H-RasV12 activation enhanced survival of cells with damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional upregulation of Mcl1 was, at least in part, responsible for enhanced survival and slippage of cells with mitotic defects. Importantly, mitotic slippage and oncogene signaling cooperatively induced senescence and key senescence effectors p21 and p16. In summary, activated Ras coordinately triggers mitotic disruption and enhanced cell survival to promote formation of multinucleate senescent cells

Geographically widespread C-13-depletion of grazing caddis larvae:a third way of fuelling stream food webs?

Stream ecosystems are supported by both green (i.e. based on grazing) and brown (i.e. detritus) food webs, whereas methane-derived carbon is not considered generally to be important; here, we add circumstantial evidence for this potential third way. Grazing cased-caddis (Trichoptera) larvae in the family Glossosomatidae can be very abundant in springs and headwaters and frequently have much lower stable carbon isotope ratios (i.e. they are depleted in the heavier C-13 stable isotope) than the biofilm (epilithon) on the upper surfaces of the stones on which they live, and which is their presumed diet. Evidence for similar isotopic depletion in other lotic invertebrates is currently limited, however; even for glossosomatids it has been observed so far only in some streams draining the southern English cretaceous chalk and in a few headwaters in northern California. If this phenomenon proves to be more widespread, among streams or taxa, it could imply a more general underpinning of stream food webs by isotopically light carbon derived from methane and accessed via consumers feeding on methanotrophic bacteria. Here, we sampled 58 stream sites to examine whether caddis larvae are also C-13-depleted in streams draining other geologies. We focused mainly on carboniferous limestone and sandstone, as well as on further chalk streams representative of most of the British chalk aquifer: together, these new sites covered an area of almost 90,000 km(2), around three times greater than that surveyed previously. At all 58 sites methane gas was supersaturated relative to the atmospheric equilibrium, and at 49 of them larvae were conspicuously C-13-depleted (from -17.5 parts per thousand to -3.6 parts per thousand) relative to the bulk epilithon (components of which we know can oxidise methane). Although still most pronounced on chalk, this phenomenon was geographically and geologically much more widespread than shown previously and suggests methane-derived carbon could indeed play a prominent role in stream food webs (i.e. the third way)