Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions

Mortality following Stroke, the Weekend Effect and Related Factors: Record Linkage Study

Increased mortality following hospitalisation for stroke has been reported from many but not all studies that have investigated a 'weekend effect' for stroke. However, it is not known whether the weekend effect is affected by factors including hospital size, season and patient distance from hospital.To assess changes over time in mortality following hospitalisation for stroke and how any increased mortality for admissions on weekends is related to factors including the size of the hospital, seasonal factors and distance from hospital.A population study using person linked inpatient, mortality and primary care data for stroke from 2004 to 2012. The outcome measures were, firstly, mortality at seven days and secondly, mortality at 30 days and one year.Overall mortality for 37 888 people hospitalised following stroke was 11.6% at seven days, 21.4% at 30 days and 37.7% at one year. Mortality at seven and 30 days fell significantly by 1.7% and 3.1% per annum respectively from 2004 to 2012. When compared with week days, mortality at seven days was increased significantly by 19% for admissions on weekends, although the admission rate was 21% lower on weekends. Although not significant, there were indications of increased mortality at seven days for weekend admissions during winter months (31%), in community (81%) rather than large hospitals (8%) and for patients resident furthest from hospital (32% for distances of >20 kilometres). The weekend effect was significantly increased (by 39%) for strokes of 'unspecified' subtype.Mortality following stroke has fallen over time. Mortality was increased for admissions at weekends, when compared with normal week days, but may be influenced by a higher stroke severity threshold for admission on weekends. Other than for unspecified strokes, we found no significant variation in the weekend effect for hospital size, season and distance from hospital

Engineered Protein Nano-Compartments for Targeted Enzyme Localization

Compartmentalized co-localization of enzymes and their substrates represents an attractive approach for multi-enzymatic synthesis in engineered cells and biocatalysis. Sequestration of enzymes and substrates would greatly increase reaction efficiency while also protecting engineered host cells from potentially toxic reaction intermediates. Several bacteria form protein-based polyhedral microcompartments which sequester functionally related enzymes and regulate their access to substrates and other small metabolites. Such bacterial microcompartments may be engineered into protein-based nano-bioreactors, provided that they can be assembled in a non-native host cell, and that heterologous enzymes and substrates can be targeted into the engineered compartments. Here, we report that recombinant expression of Salmonella enterica ethanolamine utilization (eut) bacterial microcompartment shell proteins in E. coli results in the formation of polyhedral protein shells. Purified recombinant shells are morphologically similar to the native Eut microcompartments purified from S. enterica. Surprisingly, recombinant expression of only one of the shell proteins (EutS) is sufficient and necessary for creating properly delimited compartments. Co-expression with EutS also facilitates the encapsulation of EGFP fused with a putative Eut shell-targeting signal sequence. We also demonstrate the functional localization of a heterologous enzyme (β-galactosidase) targeted to the recombinant shells. Together our results provide proof-of-concept for the engineering of protein nano-compartments for biosynthesis and biocatalysis

Corals record long-term Leeuwin current variability including Ningaloo Niño/Niña since 1795

Variability of the Leeuwin current (LC) off Western Australia is a footprint of interannual and decadal climate variations in the tropical Indo-Pacific. La Niña events often result in a strengthened LC, high coastal sea levels and unusually warm sea surface temperatures (SSTs), termed Ningaloo Niño. The rarity of such extreme events and the response of the southeastern Indian Ocean to regional and remote climate forcing are poorly understood owing to the lack of long-term records. Here we use well-replicated coral SST records from within the path of the LC, together with a reconstruction of the El Niño-Southern Oscillation to hindcast historical SST and LC strength from 1795 to 2010. We show that interannual and decadal variations in SST and LC strength characterized the past 215 years and that the most extreme sea level and SST anomalies occurred post 1980. These recent events were unprecedented in severity and are likely aided by accelerated global ocean warming and sea-level rise. © 2014 Macmillan Publishers Limited

Incidence and Risk of QTc Interval Prolongation among Cancer Patients Treated with Vandetanib: A Systematic Review and Meta-analysis

Vandetanib is a multikinase inhibitor that is under assessment for the treatment of various cancers. QTc interval prolongation is one of the major adverse effects of this drug, but the reported incidence varies substantially among clinical trials. We performed a systematic review and meta-analysis to obtain a better understanding in the risk of QTc interval prolongation among cancer patients administered vandetanib.Eligible studies were phase II and III prospective clinical trials that involved cancer patients who were prescribed vandetanib 300 mg/d and that included data on QTc interval prolongation. The overall incidence and risk of QTc interval prolongation were calculated using random-effects or fixed-effects models, depending on the heterogeneity of the included studies. Nine trials with 2,188 patients were included for the meta-analysis. The overall incidence of all-grade and high-grade QTc interval prolongation was 16.4% (95% CI, 8.1-30.4%) and 3.7% (8.1-30.4%), respectively, among non-thyroid cancer patients, and 18.0% (10.7-28.6%) and 12.0% (4.5-28.0%), respectively, among thyroid cancer patients. Patients with thyroid cancer who had longer treatment duration also had a higher incidence of high-grade events, with a relative risk of 3.24 (1.57-6.71), than patients who had non-thyroid cancer. Vandetanib was associated with a significantly increased risk of all-grade QTc interval prolongation with overall Peto odds ratios of 7.26 (4.36-12.09) and 5.70 (3.09-10.53) among patients with non-thyroid cancer and thyroid cancer, respectively, compared to the controls.Treatment with vandetanib is associated with a significant increase in the overall incidence and risk of QTc interval prolongation. Different cancer types and treatment durations may affect the risk of developing high-grade QTc interval prolongation

Genetic identification of brain cell types underlying schizophrenia

With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia

Global and local sea level during the Last Interglacial: A probabilistic assessment

The Last Interglacial (LIG) stage, with polar temperatures likely 3-5 C warmer than today, serves as a partial analogue for low-end future warming scenarios. Based upon a small set of local sea level indicators, the Intergovernmental Panel on Climate Change (IPCC) inferred that LIG global sea level (GSL) was about 4-6 m higher than today. However, because local sea levels differ from GSL, accurately reconstructing past GSL requires an integrated analysis of globally distributed data sets. Here we compile an extensive database of sea level indicators and apply a novel statistical approach that couples Gaussian process regression of sea level to Markov Chain Monte Carlo modeling of geochronological errors. Our analysis strongly supports the hypothesis that LIG GSL was higher than today, probably peaking at 6-9 m. Our results highlight the sea level hazard associated with even relatively low levels of sustained global warming.Comment: Preprint version of what has since been published in Natur

Feasibility and diagnostic power of transthoracic coronary Doppler for coronary flow velocity reserve in patients referred for myocardial perfusion imaging

<p>Abstract</p> <p>Background</p> <p>Myocardial perfusion imaging (MPI), using single photon emission computed tomography (SPECT) is a validated method for detecting coronary artery disease. Transthoracic Doppler echocardiography (TTDE) of flow at rest and during adenosine provocation has previously been evaluated in selected patient groups. We therefore wanted to compare the diagnostic ability of TTDE in the left anterior descending coronary artery (LAD) to that of MPI in an unselected population of patients with chest pain referred for MPI. Our hypothesis was that TTDE with high accuracy would identify healthy individuals and exclude them from the need for further studies, enabling invasive investigations to be reserved for patients with a high probability of disease.</p> <p>Methods</p> <p>Sixty-nine patients, 44 men and 25 women, age 61 ± 10 years (range 35–82), with a clinical suspicion of stress induced myocardial ischemia, were investigated. TTDE was performed at rest and during adenosine stress for myocardial scintigraphy.</p> <p>Results</p> <p>We found that coronary flow velocity reserve (CFVR) determined from diastolic measurements separated normal from abnormal MPI findings with statistical significance. TTDE identified coronary artery disease, defined from MPI, as reversible ischemia and/or permanent defect, with a sensitivity of 60% and a specificity of 79%. The positive predictive value was 43% and the negative predictive value was 88%. There was an overlap between groups which could be due to abnormal endothelial function in patients with normal myocardial perfusion having either hypertension or diabetes.</p> <p>Conclusion</p> <p>TTDE is an attractive non-invasive method to evaluate chest pain without the use of isotopes, but the diagnostic power is strongly dependent on the population investigated. Even in our heterogeneous clinical cardiac population, we found that CFVR>2 in the LAD excluded significant coronary artery disease detected by MPI.</p

A Novel Ecdysone Receptor Mediates Steroid-Regulated Developmental Events during the Mid-Third Instar of Drosophila

The larval salivary gland of Drosophila melanogaster synthesizes and secretes glue glycoproteins that cement developing animals to a solid surface during metamorphosis. The steroid hormone 20-hydroxyecdysone (20E) is an essential signaling molecule that modulates most of the physiological functions of the larval gland. At the end of larval development, it is known that 20E—signaling through a nuclear receptor heterodimer consisting of EcR and USP—induces the early and late puffing cascade of the polytene chromosomes and causes the exocytosis of stored glue granules into the lumen of the gland. It has also been reported that an earlier pulse of hormone induces the temporally and spatially specific transcriptional activation of the glue genes; however, the receptor responsible for triggering this response has not been characterized. Here we show that the coordinated expression of the glue genes midway through the third instar is mediated by 20E acting to induce genes of the Broad Complex (BRC) through a receptor that is not an EcR/USP heterodimer. This result is novel because it demonstrates for the first time that at least some 20E-mediated, mid-larval, developmental responses are controlled by an uncharacterized receptor that does not contain an RXR-like component