Altered growth-mediated signaling in the hearts of NFATc2 null mice

An abnormality associated with all forms of cardiovascular diseases is cardiac hypertrophy, which is an overall increase in heart mass without improved contractile function. Prolonged cardiac hypertrophy eventually leads to heart failure, in which the heart can no longer supply adequate amounts of blood to meet the body’s hemodynamic demands, resulting in cardiac dilatation, thinning of the myocardial walls, decrease in contractile effectiveness, organ failure and death. The Ca2+- dependent phosphatase, calcineurin (Cn) and its downstream target, nuclear factor of activated T-cells (NFAT), are major intracellular modulators of cardiac hypertrophy. In young 1-2 month old mice, the NFATc2 transcription factor has been identified as the major NFAT isoform responsible for Cn-mediated cardiac hypertrophy. We observed that adult 6-9 month old NFATc2-/- mice were more prone to sudden death, suggesting that the loss of NFATc2 was detrimental at later stages of life. Using histology, we showed that adult NFATc2-/- mice display left ventricular dilatation and thinning of the ventricular walls, characteristic of failure. Western blot and immunofluorescene results showed that NFATc2-/- mice displayed alterations in the signaling of growth pathways, which predisposed these mice to heart failure. Furthermore, angiotensin II-induced cardiac growth revealed that the hearts of NFATc2-/- mice displayed changes in contractile protein gene expression and an inactivation of both transcriptional and translational mechanisms. Our collective findings propose an uncharacterized role of NFATc2 for normal heart function and biochemical signaling in adult mice, providing further evidence that normal Cn-signaling is crucial in the heart

tGBS® genotyping-by-sequencing enables reliable genotyping of heterozygous loci

Conventional genotyping-by-sequencing (cGBS) strategies suffer from high rates of missing data and genotyping errors, particularly at heterozygous sites. tGBS® genotyping-by-sequencing is a novel method of genome reduction that employs two restriction enzymes to generate overhangs in opposite orientations to which (single-strand) oligos rather than (double-stranded) adaptors are ligated. This strategy ensures that only doubledigested fragments are amplified and sequenced. The use of oligos avoids the necessity of preparing adaptors and the problems associated with inter-adaptor annealing/ligation. Hence, the tGBS protocol simplifies the preparation of high-quality GBS sequencing libraries. During polymerase chain reaction (PCR) amplification, selective nucleotides included at the 3\u27-end of the PCR primers result in additional genome reduction as compared to cGBS. By adjusting the number of selective bases, different numbers of genomic sites are targeted for sequencing. Therefore, for equivalent amounts of sequencing, more reads per site are available for SNP calling. Hence, as compared to cGBS, tGBS delivers higher SNP calling accuracy (\u3e97–99%), even at heterozygous sites, less missing data per marker across a population of samples, and an enhanced ability to genotype rare alleles. tGBS is particularly well suited for genomic selection, which often requires the ability to genotype populations of individuals that are heterozygous at many loci

The Long-term Burden of COPD Exacerbations during Maintenance Therapy and Lung Function Decline

Data Sharing Statement The dataset supporting the conclusions of this article was derived from the Clinical Practice Research Datalink (www.cprd.com) and the Optimum Patient Care Research Database (www.opcrd.co.uk). The CPRD has broad National Research Ethics Service Committee (NRES) ethics approval for purely observational research using the primary care data and established data linkages. The OPCRD has ethical approval from the National Health Service (NHS) Research Authority to hold and process anonymized research data (Research Ethics Committee reference: 15/EM/0150). This study was approved by the Anonymized Data Ethics Protocols and Transparency (ADEPT) committee – the independent scientific advisory committee for the OPCRD, and the Independent Scientific Advisory Committee (ISAC) for the CPRD. The authors do not have permission to give public access to the study dataset; researchers may request access to CPRD or OPCRD data for their own purposes. Access to CPRD can be made via the CPRD website (https://www.cprd.com/researcher/) or via the inquiries email [email protected]. Access to OCPRD can be made via the OCPRD website (https://opcrd.co.uk/our-database/data-requests/) or via the inquiries email [email protected]. Funding This study is funded by AstraZeneca. AstraZeneca participated in the study design and reporting.Peer reviewedPublisher PD

Sustainable Sourcing of Global Agricultural Raw Materials: Assessing Gaps in Key Impact and Vulnerability Issues and Indicators.

Understanding how to source agricultural raw materials sustainably is challenging in today's globalized food system given the variety of issues to be considered and the multitude of suggested indicators for representing these issues. Furthermore, stakeholders in the global food system both impact these issues and are themselves vulnerable to these issues, an important duality that is often implied but not explicitly described. The attention given to these issues and conceptual frameworks varies greatly--depending largely on the stakeholder perspective--as does the set of indicators developed to measure them. To better structure these complex relationships and assess any gaps, we collate a comprehensive list of sustainability issues and a database of sustainability indicators to represent them. To assure a breadth of inclusion, the issues are pulled from the following three perspectives: major global sustainability assessments, sustainability communications from global food companies, and conceptual frameworks of sustainable livelihoods from academic publications. These terms are integrated across perspectives using a common vocabulary, classified by their relevance to impacts and vulnerabilities, and categorized into groups by economic, environmental, physical, human, social, and political characteristics. These issues are then associated with over 2,000 sustainability indicators gathered from existing sources. A gap analysis is then performed to determine if particular issues and issue groups are over or underrepresented. This process results in 44 "integrated" issues--24 impact issues and 36 vulnerability issues--that are composed of 318 "component" issues. The gap analysis shows that although every integrated issue is mentioned at least 40% of the time across perspectives, no issue is mentioned more than 70% of the time. A few issues infrequently mentioned across perspectives also have relatively few indicators available to fully represent them. Issues in the impact framework generally have fewer gaps than those in the vulnerability framework

Association between COPD exacerbations and lung function decline during maintenance therapy

Acknowledgements: Writing and editorial support was provided by Dr Julia Granerod, supported by the Observational and Pragmatic Research Institute Pte. Ltd (OPRI). Funding: This study was funded by AstraZeneca.Data availability statement: Data may be obtained from a third party and are not publicly available. The dataset supporting the conclusions of this article was derived from the Clinical Practice Research Datalink (www.cprd.com) and the Optimum Patient Care Research Database (www.opcrd.co.uk). The CPRD has broad National Research Ethics Service Committee (NRES) ethics approval for purely observational research using the primary care data and established data linkages. The OPCRD has ethical approval from the National Health Service (NHS) Research Authority to hold and process anonymised research data (Research Ethics Committee reference: 5/EM/0150). This study was approved by the Anonymised Data Ethics Protocols and Transparency (ADEPT) committee – the independent scientific advisory committee for the OPCRD, and the Independent Scientific Advisory Committee (ISAC) for the CPRD. The authors do not have permission to give public access to the study dataset; researchers may request access to CPRD or OPCRD data for their own purposes. Access to CPRD can be made via the CPRD website (https://www.cprd.com/researcher/) or via the enquiries email enquiries@cprd. com. Access to OCPRD can be made via the OCPRD website(https://opcrd.co.uk/our-database/data-requests/) or via the enquiries email [email protected]. The study was designed, implemented, and registered in accordance with the criteria of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS19879).Peer reviewedPublisher PD

The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in the Era of MDM2 and CDK4 Testing

Introduction. Extremity lipomas and well-differentiated liposarcomas (WDLs) are difficult to distinguish on MR imaging. We sought to evaluate the accuracy of MRI interpretation using MDM2 amplification, via fluorescence in-situ hybridization (FISH), as the gold standard for pathologic diagnosis. Furthermore, we aimed to investigate the utility of a diagnostic formula proposed in the literature. Methods. We retrospectively collected 49 patients with lipomas or WDLs utilizing MDM2 for pathologic diagnosis. Four expert readers interpreted each patient\u27s MRI independently and provided a diagnosis. Additionally, a formula based on imaging characteristics (i.e. tumor depth, diameter, presence of septa, and internal cystic change) was used to predict the pathologic diagnosis. The accuracy and reliability of imaging-based diagnoses were then analyzed in comparison to the MDM2 pathologic diagnoses. Results. The accuracy of MRI readers was 73.5% (95% CI 61-86%) with substantial interobserver agreement (κ = 0.7022). The formula had an accuracy of 71%, which was not significantly different from the readers (p = 0.71). The formula and expert observers had similar sensitivity (83% versus 83%) and specificity (64.5% versus 67.7%; p = 0.659) for detecting WDLs. Conclusion. The accuracy of both our readers and the formula suggests that MRI remains unreliable for distinguishing between lipoma and WDLs

Supermassive black holes at high redshifts

MeV blazars are the most luminous persistent sources in the Universe and emit most of their energy in the MeV band. These objects display very large jet powers and accretion luminosities and are known to host black holes with a mass often exceeding $10^9 M_{\odot}$. An MeV survey, performed by a new generation MeV telescope which will bridge the entire energy and sensitivity gap between the current generation of hard X-ray and gamma-ray instruments, will detect $>$1000 MeV blazars up to a redshift of $z=5-6$. Here we show that this would allow us: 1) to probe the formation and growth mechanisms of supermassive black holes at high redshifts, 2) to pinpoint the location of the emission region in powerful blazars, 3) to determine how accretion and black hole spin interplay to power the jet.Comment: 7 pages, 4 figure. Submitted to the Astro2020 call for Science White Paper

Role of Pentraxin 3 in Shaping Arthritogenic Alphaviral Disease: From Enhanced Viral Replication to Immunomodulation

10.1371/journal.ppat.1004649PLoS Pathogens11

Prioritization of candidate causal genes for asthma in susceptibility loci derived from UK Biobank

Kim Valette et al. perform a genomic study on asthma integrating genome-wide association study, functional mapping using lung and blood transcriptome-wide profiles, as well as Mendelian randomization. They show candidate causal genes expressed in lung and blood tissues that are putative therapeutic targets for asthma