Abnormal Calcium Handling and Exaggerated Cardiac Dysfunction in Mice with Defective Vitamin D Signaling

Aim Altered vitamin D signaling is associated with cardiac dysfunction, but the pathogenic mechanism is not clearly understood. We examine the mechanism and the role of vitamin D signaling in the development of cardiac dysfunction. Methods and Results: We analyzed 1α-hydroxylase (1α-OHase) knockout (1α-OHase−/−) mice, which lack 1α-OH enzymes that convert the inactive form to hormonally active form of vitamin D. 1α-OHase−/− mice showed modest cardiac hypertrophy at baseline. Induction of pressure overload by transverse aortic constriction (TAC) demonstrated exaggerated cardiac dysfunction in 1α-OHase−/− mice compared to their WT littermates with a significant increase in fibrosis and expression of inflammatory cytokines. Analysis of calcium (Ca2+) transient demonstrated profound Ca2+ handling abnormalities in 1α-OHase−/− mouse cardiomyocytes (CMs), and treatment with paricalcitol (PC), an activated vitamin D3 analog, significantly attenuated defective Ca2+ handling in 1α-OHase−/− CMs. We further delineated the effect of vitamin D deficiency condition to TAC by first correcting the vitamin D deficiency in 1α-OHase−/− mice, followed then by either a daily maintenance dose of vitamin D or vehicle (to achieve vitamin D deficiency) at the time of sham or TAC. In mice treated with vitamin D, there was a significant attenuation of TAC-induced cardiac hypertrophy, interstitial fibrosis, inflammatory markers, Ca2+ handling abnormalities and cardiac function compared to the vehicle treated animals. Conclusions: Our results provide insight into the mechanism of cardiac dysfunction, which is associated with severely defective Ca2+ handling and defective vitamin D signaling in 1α-OHase−/− mice

Cost-effective opportunities for climate change mitigation in Indian agriculture

This work was jointly carried out by International Maize and Wheat Improvement Center (CIMMYT) and University of Aberdeen and funded by the CGIAR research program on Climate Change, Agriculture and Food Security (CCAFS). CCAFS’ work is supported by CGIAR Fund Donors and through bilateral funding agreements. For details please visit https://ccafs.cgiar.org/donors. The views expressed in this paper cannot be taken to reflect the official opinions of these organizations. We sincerely acknowledge the input and support provided by various stakeholders in India during stakeholder meetings. We are thankful to Gokul Prasad for graphics assistance.Peer reviewedPublisher PD

Towards successful coordination of electronic health record based-referrals: a qualitative analysis

<p>Abstract</p> <p>Background</p> <p>Successful subspecialty referrals require considerable coordination and interactive communication among the primary care provider (PCP), the subspecialist, and the patient, which may be challenging in the outpatient setting. Even when referrals are facilitated by electronic health records (EHRs) (<it>i.e</it>., e-referrals), lapses in patient follow-up might occur. Although compelling reasons exist why referral coordination <it>should </it>be improved, little is known about which elements of the complex referral coordination process should be targeted for improvement. Using Okhuysen & Bechky's coordination framework, this paper aims to understand the barriers, facilitators, and suggestions for improving communication and coordination of EHR-based referrals in an integrated healthcare system.</p> <p>Methods</p> <p>We conducted a qualitative study to understand coordination breakdowns related to e-referrals in an integrated healthcare system and examined work-system factors that affect the timely receipt of subspecialty care. We conducted interviews with seven subject matter experts and six focus groups with a total of 30 PCPs and subspecialists at two tertiary care Department of Veterans Affairs (VA) medical centers. Using techniques from grounded theory and content analysis, we identified organizational themes that affected the referral process.</p> <p>Results</p> <p>Four themes emerged: lack of an institutional referral policy, lack of standardization in certain referral procedures, ambiguity in roles and responsibilities, and inadequate resources to adapt and respond to referral requests effectively. Marked differences in PCPs' and subspecialists' communication styles and individual mental models of the referral processes likely precluded the development of a <it>shared </it>mental model to facilitate coordination and successful referral completion. Notably, very few barriers related to the EHR were reported.</p> <p>Conclusions</p> <p>Despite facilitating information transfer between PCPs and subspecialists, e-referrals remain prone to coordination breakdowns. Clear referral policies, well-defined roles and responsibilities for key personnel, standardized procedures and communication protocols, and adequate human resources must be in place before implementing an EHR to facilitate referrals.</p

'Pregnancy comes accidentally - like it did with me': reproductive decisions among women on ART and their partners in rural Uganda

<p>Abstract</p> <p>Background</p> <p>As highly active antiretroviral therapy (ART) restores health, fertility and sexual activity among HIV-infected adults, understanding how ART influences reproductive desires and decisions could inform interventions to reduce sexual and vertical HIV transmission risk.</p> <p>Methods</p> <p>We performed a qualitative sub-study among a Ugandan cohort of 1,000 adults on ART with four purposively selected categories of participants: pregnant, not pregnant, delivered, and aborted. In-depth interviews examined relationships between HIV, ART and pregnancy, desire for children, perceived risks and benefits of pregnancy, decision-making regarding reproduction and family planning (FP) among 29 women and 16 male partners. Analysis focused on dominant explanations for emerging themes across and within participant groups.</p> <p>Results</p> <p>Among those who had conceived, most couples stated that their pregnancy was unintentional, and often occurred because they believed that they were infertile due to HIV. Perceived reasons for women not getting pregnant included: ill health (included HIV infection and ART), having enough children, financial constraints, fear of mother-to-child HIV transmission or transmission to partner, death of a child, and health education. Most women reported FP experiences with condoms and hormonal injections only. Men had limited FP information apart from condoms.</p> <p>Conclusions</p> <p>Counselling at ART initiation may not be sufficient to enable women who do not desire children to adopt relevant family planning practices. On-going reproductive health education and FP services, with emphasis on the restoration of fertility after ART initiation, should be integrated into ART programs for men and women.</p

Identification of Novel Avian Influenza Virus Derived CD8+ T-Cell Epitopes

Avian influenza virus (AIV) infection is a continuing threat to both humans and poultry. Influenza virus specific CD8+ T cells are associated with protection against homologous and heterologous influenza strains. In contrast to what has been described for humans and mice, knowledge on epitope-specific CD8+ T cells in chickens is limited. Therefore, we set out to identify AIV-specific CD8+ T-cell epitopes. Epitope predictions based on anchor residues resulted in 33 candidate epitopes. MHC I inbred chickens were infected with a low pathogenic AIV strain and sacrificed at 5, 7, 10 and 14 days post infection (dpi). Lymphocytes isolated from lung, spleen and blood were stimulated ex vivo with AIV-specific pooled or individual peptides and the production of IFNγ was determined by ELIspot. This resulted in the identification of 12 MHC B12-restricted, 3 B4-restricted and 1 B19-restricted AIV- specific CD8+ T-cell epitopes. In conclusion, we have identified novel AIV-derived CD8+ T-cell epitopes for several inbred chicken strains. This knowledge can be used to study the role of CD8+ T cells against AIV infection in a natural host for influenza, and may be important for vaccine development

Rhizosphere activity and atmospheric methane concentrations drive variations of methane fluxes in a temperate forest soil

Aerated soils represent an important sink for atmospheric methane (CH⁠4), due to the effect of methanotrophic bacteria, thus mitigating current atmospheric CH⁠4 increases. Whilst rates of CH⁠4 oxidation have been linked to types of vegetation cover, there has been no systematic investigation of the interaction between plants and soil in relation to the strength of the soil CH⁠4 sink. We used quasi-continuous automated chamber measurements of soil CH⁠4 and CO⁠2 flux from soil collar treatments that selectively include root and ectomycorrhizal (ECM) mycelium to investigate the role of rhizosphere activity as well as the effects of other environmental drivers on CH⁠4 uptake in a temperate coniferous forest soil. We also assessed the potential impact of measurement bias from sporadic chamber measurements in altering estimates of soil CO⁠2 efflux and CH⁠4 uptake. Results show a clear effect of the presence of live roots and ECM mycelium on soil CO⁠2 efflux and CH⁠4 uptake. The presence of ECM hyphae alone (without plant roots) showed intermediate fluxes of both CO⁠2 and CH⁠4 relative to soils that either contained roots and ECM mycelium, or soil lacking root- and ECM mycelium. Regression analysis confirmed a significant influence of soil moisture as well as temperature on flux dynamics of both CH⁠4 and CO⁠2 flux. We further found a surprising increase in soil CH⁠4 uptake during the night, and discuss diurnal fluctuations in atmospheric CH⁠4 (with higher concentrations during stable atmospheric conditions at night) as a potential driver of CH⁠4 oxidation rates. Using the high temporal resolution of our data set, we show that low-frequency sampling results in systematic bias of up-scaled flux estimates, resulting in under-estimates of up to 20% at our study site, due to fluctuations in flux dynamics on diurnal as well as longer time scales

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment