Bone Morphogenetic Protein‐2 Decreases MicroRNA‐30b and MicroRNA‐30c to Promote Vascular Smooth Muscle Cell Calcification

Background: Vascular calcification resembles bone formation and involves vascular smooth muscle cell (SMC) transition to an osteoblast‐like phenotype to express Runx2, a master osteoblast transcription factor. One possible mechanism by which Runx2 protein expression is induced is downregulation of inhibitory microRNAs (miR). Methods and Results: Human coronary artery SMCs (CASMCs) treated with bone morphogenetic protein‐2 (BMP‐2; 100 ng/mL) demonstrated a 1.7‐fold (P<0.02) increase in Runx2 protein expression at 24 hours. A miR microarray and target prediction database analysis independently identified miR‐30b and miR‐30c (miR‐30b‐c) as miRs that regulate Runx2 expression. Real‐time–polymerase chain reaction confirmed that BMP‐2 decreased miR‐30b and miR‐30c expression. A luciferase reporter assay verified that both miR‐30b and miR‐30c bind to the 3′‐untranslated region of Runx2 mRNA to regulate its expression. CASMCs transfected with antagomirs to downregulate miR‐30b‐c demonstrated significantly increased Runx2, intracellular calcium deposition, and mineralization. Conversely, forced expression of miR‐30b‐c by transfection with pre–miR‐30b‐c prevented the increase in Runx2 expression and mineralization of SMCs. Calcified human coronary arteries demonstrated higher levels of BMP‐2 and lower levels of miR‐30b than did noncalcified donor coronary arteries. Conclusions: BMP‐2 downregulates miR‐30b and miR‐30c to increase Runx2 expression in CASMCs and promote mineralization. Strategies that modulate expression of miR‐30b and miR‐30c may influence vascular calcification

Real-time single-molecule observation of rolling-circle DNA replication

We present a simple technique for visualizing replication of individual DNA molecules in real time. By attaching a rolling-circle substrate to a TIRF microscope-mounted flow chamber, we are able to monitor the progression of single-DNA synthesis events and accurately measure rates and processivities of single T7 and Escherichia coli replisomes as they replicate DNA. This method allows for rapid and precise characterization of the kinetics of DNA synthesis and the effects of replication inhibitors

Detection of the Power Spectrum of Cosmic Microwave Background Lensing by the Atacama Cosmology Telescope

We report the first detection of the gravitational lensing of the cosmic microwave background through a measurement of the four-point correlation function in the temperature maps made by the Atacama Cosmology Telescope. We verify our detection by calculating the levels of potential contaminants and performing a number of null tests. The resulting convergence power spectrum at 2-degree angular scales measures the amplitude of matter density fluctuations on comoving length scales of around 100 Mpc at redshifts around 0.5 to 3. The measured amplitude of the signal agrees with Lambda Cold Dark Matter cosmology predictions. Since the amplitude of the convergence power spectrum scales as the square of the amplitude of the density fluctuations, the 4-sigma detection of the lensing signal measures the amplitude of density fluctuations to 12%.Comment: 4 pages, 4 figures, replaced title and author list with version accepted by Physical Review Letters. Likelihood code can be downloaded from http://bccp.lbl.gov/~sudeep/ACTLensLike.htm

Contributions Made by CDC25 Phosphatases to Proliferation of Intestinal Epithelial Stem and Progenitor Cells

The CDC25 protein phosphatases drive cell cycle advancement by activating cyclin-dependent protein kinases (CDKs). Humans and mice encode three family members denoted CDC25A, -B and -C and genes encoding these family members can be disrupted individually with minimal phenotypic consequences in adult mice. However, adult mice globally deleted for all three phosphatases die within one week after Cdc25 disruption. A severe loss of absorptive villi due to a failure of crypt epithelial cells to proliferate was observed in the small intestines of these mice. Because the Cdc25s were globally deleted, the small intestinal phenotype and loss of animal viability could not be solely attributed to an intrinsic defect in the inability of small intestinal stem and progenitor cells to divide. Here, we report the consequences of deleting different combinations of Cdc25s specifically in intestinal epithelial cells. The phenotypes arising in these mice were then compared with those arising in mice globally deleted for the Cdc25s and in mice treated with irinotecan, a chemotherapeutic agent commonly used to treat colorectal cancer. We report that the phenotypes arising in mice globally deleted for the Cdc25s are due to the failure of small intestinal stem and progenitor cells to proliferate and that blocking cell division by inhibiting the cell cycle engine (through Cdc25 loss) versus by inducing DNA damage (via irinotecan) provokes a markedly different response of small intestinal epithelial cells. Finally, we demonstrate that CDC25A and CDC25B but not CDC25C compensate for each other to maintain the proliferative capacity of intestinal epithelial stem and progenitor cells

Differences in relative and absolute effectiveness of oral P2Y12 inhibition in men and women: a meta-analysis and modelling study

ObjectiveTo estimate the absolute treatment effects of newer P2Y12 inhibitors (ticagrelor and prasugrel) compared to clopidogrel in men and women with acute coronary syndrome (ACS).MethodsWe searched Ovid MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for randomised controlled trials of oral P2Y12 inhibitors for acute stroke or ACS. Age and sex-specific mortality was obtained for all patients admitted to hospital with myocardial infarction in Scotland from 2006 to 2010 (prior to introduction of prasugrel or ticagrelor).ResultsFrom 9,277 articles, 9 fulfilled our inclusion criteria. Three trials compared newer P2Y12 inhibitors to clopidogrel in ACS, in which the treatment rate ratio (RR) for major adverse cardiovascular events in men was 0.80 (95% CI 0.69 to 0.93). For the same outcome, across all 9 trials the sex-treatment interaction RR was 1.08 (95% CI 0.98 to 1.19). Combining these estimates yielded a treatment RR in women of 0.86 (95% CI 0.72 to 1.04). 17,842 women and 27,818 men were admitted to hospital with myocardial infarction. Mortality was higher for women than men for all-cause (5708, 32.0% versus 5891,21.2%), cardiovascular(4032, 22.6% versus 4117, 14.8%) and bleeding (193, 1.1% versus 228, 0.8%) deaths. On applying the sex-specific RRs to this population, the absolute risk reduction for mortality at 1- year was similar for women and men for all-cause (2.30% (95% CI -0.92 to 5.22) versus 2.47% (95% CI 0.62 to 4.10)), cardiovascular (2.70% (95% CI -0.63 to 5.74)) versus 2.72% (95% CI 0.92 to 4.35)) and bleeding (-0.27% (95% CI -1.06 to 0.30) versus -0.18% (95% CI -0.71 to 0.24)) deaths.ConclusionNewer P2Y12 inhibitors may be slightly less efficacious in women than men, but the absolute risk reduction is similar in both sexes

Chemistry in Cosmic-Ray Dominated Regions (CRDRs)

Molecular line observations may serve as diagnostics of the degree to which the number density of cosmic ray protons, having energies of 10s to 100s of MeVs each, is enhanced in starburst galaxies and galaxies with active nuclei. Results, obtained with the UCL\_PDR code, for the fractional abundances of molecules as functions of the cosmic-ray induced ionisation rate, $\zeta$, are presented. The aim is not to model any particular external galaxies. Rather, it is to identify characteristics of the dependencies of molecular abundances on $\zeta$, in part to enable the development of suitable observational programmes for cosmic ray dominated regions (CRDRs) which will then stimulate detailed modelling. For a number density of hydrogen nuclei of of $10^4$ cm$^{-3}$, and high visual extinction, the fractional abundances of some species increase as $\zeta$ increases to $10^{-14}$ s$^{-1}$, but for much higher values of $\zeta$ the fractional abundances of all molecular species are significantly below their peak values. We show in particular that OH, H$_{2}$O, H$_{3}^{+}$, H$_{3}$O$^{+}$ and OH$^{+}$ attain large fractional abundances ($\geqslant 10^{-8}$) for $\zeta$ as large as $10^{-12}$ s$^{-1}$. HCO$^{+}$ is a poor tracer of CRDRs when $\zeta > 10^{-13}$ s$^{-1}$. Sulphur-bearing species may be useful tracers of CRDRs gas in which $\zeta \sim 10^{-16}$ s$^{-1}$. Ammonia has a large fractional abundance for $\zeta \leqslant 10^{-16}$ s$^{-1}$ and nitrogen appears in CN-bearing species at significant levels as $\zeta$ increases, even up to $\sim 10^{-14}$ s$^{-1}$. In this paper, we also discuss our model predictions, comparing them to recent detections in both galactic and extragalactic sources. We show that they agree well, to a first approximation, with the observational constraints.Comment: 11 pages, 4 figures, 2 tables, Accepted to MNRAS publicatio

How are gender equality and human rights interventions included in sexual and reproductive health programmes and policies: A systematic review of existing research foci and gaps

The importance of promoting gender equality and human rights in sexual and reproductive health (SRH) programmes and policies has been affirmed in numerous international and regional agreements, most recently the 2030 Agenda for Sustainable Development. Given the critical role of research to determine what works, we aimed to identify research gaps as part of a broader priority setting exercise on integrating gender equality and human rights approaches in SRH programmes and policies. A systematic literature review of reviews was conducted to examine the question: what do we know about how research in the context of SRH programmes and policies has addressed gender equality and human rights and what are the current gaps in research. We searched three databases for reviews that addressed the research question, were published between 1994-2014, and met methodological standards for systematic reviews, qualitative meta-syntheses and other reviews of relevance to the research question. Additional grey literature was identified based on expert input. Articles were appraised by the primary author and examined by an expert panel. An abstraction and thematic analysis process was used to synthesize findings. Of the 3,073 abstracts identified, 56 articles were reviewed in full and 23 were included along with 10 from the grey literature. The majority focused on interventions addressing gender inequalities; very few reviews explicitly included human rights based interventions. Across both topics, weak study designs and use of intermediate outcome measures limited evidence quality. Further, there was limited evidence on interventions that addressed marginalized groups. Better quality studies, longer-term indicators, and measurement of unintended consequences are needed to better understand the impact of these types of interventions on SRH outcomes. Further efforts are needed to cover research on gender equality and human rights issues as they pertain to a broader set of SRH topics and populations.Scopu

Day and night surgery: is there any influence in the patient postoperative period of urgent colorectal intervention?

Background Medical activity performed outside regular work hours may increase risk for patients and professionals. There is few data with respect to urgent colorectal surgery. The aim of this work was to evaluate the impact of daytime versus nighttime surgery on postoperative period of patients with acute colorectal disease. Methods A retrospective study was conducted in a sample of patients with acute colorectal disease who underwent urgent surgery at the General Surgery Unit of Braga Hospital, between January 2005 and March 2013. Patients were stratified by operative time of day into a daytime group (surgery between 8:00 and 20:59) and the nighttime group (21:00–7:59) and compared for clinical and surgical parameters. A questionnaire was distributed to surgeons, covering aspects related to the practice of urgent colorectal surgery and fatigue. Results A total of 330 patients were included, with 214 (64.8 %) in the daytime group and 116 (35.2 %) in the nighttime group. Colorectal cancer was the most frequent pathology. Waiting time (p?<?0.001) and total length of hospital stay (p?=?0.008) were significantly longer in the daytime group. There were no significant differences with respect to early or late complications. However, 100 % of surgeons reported that they are less proficient during nighttime. Conclusions Among patients with acute colorectal disease subjected to urgent surgery, there was no significant association between nighttime surgery and the presence of postoperative medical and surgical morbidities. Patients who were subjected to daytime surgery had longer length of stay at the hospital

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types