Calcium Dependent CAMTA1 in Adult Stem Cell Commitment to a Myocardial Lineage

The phenotype of somatic cells has recently been found to be reversible. Direct reprogramming of one cell type into another has been achieved with transduction and over expression of exogenous defined transcription factors emphasizing their role in specifying cell fate. To discover early and novel endogenous transcription factors that may have a role in adult-derived stem cell acquisition of a cardiomyocyte phenotype, mesenchymal stem cells from human and mouse bone marrow and rat liver were co-cultured with neonatal cardiomyocytes as an in vitro cardiogenic microenvironment. Cell-cell communications develop between the two cell types as early as 24 hrs in co-culture and are required for elaboration of a myocardial phenotype in the stem cells 8-16 days later. These intercellular communications are associated with novel Ca(2+) oscillations in the stem cells that are synchronous with the Ca(2+) transients in adjacent cardiomyocytes and are detected in the stem cells as early as 24-48 hrs in co-culture. Early and significant up-regulation of Ca(2+)-dependent effectors, CAMTA1 and RCAN1 ensues before a myocardial program is activated. CAMTA1 loss-of-function minimizes the activation of the cardiac gene program in the stem cells. While the expression of RCAN1 suggests involvement of the well-characterized calcineurin-NFAT pathway as a response to a Ca(2+) signal, the CAMTA1 up-regulated expression as a response to such a signal in the stem cells was unknown. Cell-cell communications between the stem cells and adjacent cardiomyocytes induce Ca(2+) signals that activate a myocardial gene program in the stem cells via a novel and early Ca(2+)-dependent intermediate, up-regulation of CAMTA1

Post radiation chylous ascites: a case report

We report a 64 years old gentleman with unresectable right-sided retroperitoneal liposarcoma, who underwent radiotherapy & subsequently developed chylous ascites. He failed conservative management of chylous ascites and this was successfully managed with a peritoneovenous shunt. The pathophysiology and management of post radiational chylous ascites is discussed

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

A student-initiated and student-facilitated international health elective for preclinical medical students

Introduction: Global health education is becoming more important for developing well-rounded physicians and may encourage students toward a career in primary care. Many medical schools, however, lack adequate and structured opportunities for students beginning the curriculum. Methods: Second-year medical students initiated, designed, and facilitated a pass–fail international health elective, providing a curricular framework for preclinical medical students wishing to gain exposure to the clinical and cultural practices of a developing country. Results: All course participants (N=30) completed a post-travel questionnaire within one week of sharing their experiences. Screening reflection essays for common themes that fulfill university core competencies yielded specific global health learning outcomes, including analysis of health care determinants. Conclusion: Medical students successfully implemented a sustainable global health curriculum for preclinical student peers. Financial constraints, language, and organizational burdens limit student participation. In future, long-term studies should analyze career impact and benefits to the host country

Deoxyribonucleic Acid Encoded and Size-Defined π-Stacking of Perylene Diimides.

Funder: University of CambridgeNatural photosystems use protein scaffolds to control intermolecular interactions that enable exciton flow, charge generation, and long-range charge separation. In contrast, there is limited structural control in current organic electronic devices such as OLEDs and solar cells. We report here the DNA-encoded assembly of π-conjugated perylene diimides (PDIs) with deterministic control over the number of electronically coupled molecules. The PDIs are integrated within DNA chains using phosphoramidite coupling chemistry, allowing selection of the DNA sequence to either side, and specification of intermolecular DNA hybridization. In this way, we have developed a "toolbox" for construction of any stacking sequence of these semiconducting molecules. We have discovered that we need to use a full hierarchy of interactions: DNA guides the semiconductors into specified close proximity, hydrophobic-hydrophilic differentiation drives aggregation of the semiconductor moieties, and local geometry and electrostatic interactions define intermolecular positioning. As a result, the PDIs pack to give substantial intermolecular π wave function overlap, leading to an evolution of singlet excited states from localized excitons in the PDI monomer to excimers with wave functions delocalized over all five PDIs in the pentamer. This is accompanied by a change in the dominant triplet forming mechanism from localized spin-orbit charge transfer mediated intersystem crossing for the monomer toward a delocalized excimer process for the pentamer. Our modular DNA-based assembly reveals real opportunities for the rapid development of bespoke semiconductor architectures with molecule-by-molecule precision.ERC Horizon 2020 (grant agreement No 670405 and No 803326) EPSRC Tier-2 capital grant EP/P020259/1. Winton Advanced Research Programme for the Physics of Sustainability. Simons Foundation (Grant 601946). Swedish research council, Vetenskapsrådet 2018-0023

Predictors of Hospitalized Exacerbations and Mortality in Chronic Obstructive Pulmonary Disease

Background and Aim Exacerbations of chronic obstructive pulmonary disease (COPD) carry significant consequences for patients and are responsible for considerable health-care costs?particularly if hospitalization is required. Despite the importance of hospitalized exacerbations, relatively little is known about their determinants. This study aimed to analyze predictors of hospitalized exacerbations and mortality in COPD patients. Methods This was a retrospective population-based cohort study.We selected 900 patients with confirmed COPD aged 35 years by simple random sampling among all COPD patients in Cantabria (northern Spain) on December 31, 2011. We defined moderate exacerbations as events that led a care provider to prescribe antibiotics or corticosteroids and severe exacerbations as exacerbations requiring hospital admission.We observed exacerbation frequency over the previous year (2011) and following year (2012). We categorized patients according to COPD severity based on forced expiratory volume in 1 second (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grades 1?4). We estimated the odds ratios (ORs) by logistic regression, adjusting for age, sex, smoking status, COPD severity, and frequent exacerbator phenotype the previous year. Results Of the patients, 16.4%had 1 severe exacerbations, varying from 9.3%in mild GOLD grade 1 to 44%in very severe COPD patients. A history of at least two prior severe exacerbations was positively associated with new severe exacerbations (adjusted OR, 6.73; 95%confidence interval [CI], 3.53?12.83) and mortality (adjusted OR, 7.63; 95%CI, 3.41?17.05). Older age and several comorbidities, such as heart failure and diabetes, were similarly associated. Conclusions Hospitalized exacerbations occurred with all grades of airflow limitation. A history of severe exacerbations was associated with new hospitalized exacerbations and mortality

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.</p> <p>Methods</p> <p>The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.</p> <p>Results</p> <p>Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.</p> <p>Conclusions</p> <p>In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.</p

Creating positive environmental impact through citizen science

Interest in citizen science is growing, including from governments and research funders. This interest is often driven by a desire for positive environmental impact, and the expectation that citizen science can deliver it by engaging the public and simultaneously collecting environmental data. Yet, in practice, there is often a gap between expected and realised impact. To close this gap, we need to better understand pathways to impact and what it takes to realise them. We articulate six key pathways through which citizen science can create positive environmental change: (1) environmental management; (2) evidence for policy; (3) behaviour change; (4) social network championing; (5) political advocacy; and (6) community action. We explore the project attributes likely to create impact through each of these pathways and show that there is an interplay between these project attributes and the needs and motivations of target participant groups. Exploring this interplay, we create a framework that articulates four citizen science approaches that create environmental impact in different ways: place-based community action; interest group investigation; captive learning research; and mass participation census

Performance of the ATLAS forward proton Time-of-Flight detector in Run 2

We present performance studies of the Time-of-Flight (ToF) subdetector of the ATLAS Forward Proton (AFP) detector at the LHC. Efficiencies and resolutions are measured using high-statistics data samples collected at low and moderate pile-up in 2017, the first year when the detectors were installed on both sides of the interaction region. While low efficiencies are observed, of the order of a few percent, the resolutions of the two ToF detectors measured individually are 21 ps and 28 ps, yielding an expected resolution of the longitudinal position of the interaction, z vtx, in the central ATLAS detector of 5.3 ± 0.6 mm. This is in agreement with the observed width of the distribution of the difference between z vtx, measured independently by the central ATLAS tracker and by the ToF detector, of 6.0 ± 2.0 mm

Developing a Citizen Social Science approach to understand urban stress and promote wellbeing in urban communities

This paper sets out the future potential and challenges for developing an interdisciplinary, mixed-method Citizen Social Science approach to researching urban emotions. It focuses on urban stress, which is increasingly noted as a global mental health challenge facing both urbanised and rapidly urbanising societies. The paper reviews the existing use of mobile psychophysiological or biosensing within urban environments—as means of ‘capturing’ the urban geographies of emotions. Methodological reflections are included on primary research using biosensing in a study of workplace and commuter stress for university employees in Birmingham (UK) and Salzburg (Austria) for illustrative purposes. In comparing perspectives on the conceptualisation and measurement of urban stress from psychology, neuroscience and urban planning, the difficulties of defining scientific constructs within Citizen Science are discussed to set out the groundwork for fostering interdisciplinary dialogue. The novel methods, geo-located sensor technologies and data-driven approaches to researching urban stress now available to researchers pose a number of ethical, political and conceptual challenges around defining and measuring emotions, stress, human behaviour and urban space. They also raise issues of rigour, participation and social scientific interpretation. Introducing methods informed by more critical Citizen Social Science perspectives can temper overly individualised forms of data collection to establish more effective ways of addressing urban stress and promoting wellbeing in urban communities