The Formation of the First Massive Black Holes

Supermassive black holes (SMBHs) are common in local galactic nuclei, and SMBHs as massive as several billion solar masses already exist at redshift z=6. These earliest SMBHs may grow by the combination of radiation-pressure-limited accretion and mergers of stellar-mass seed BHs, left behind by the first generation of metal-free stars, or may be formed by more rapid direct collapse of gas in rare special environments where dense gas can accumulate without first fragmenting into stars. This chapter offers a review of these two competing scenarios, as well as some more exotic alternative ideas. It also briefly discusses how the different models may be distinguished in the future by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First Galaxies - Theoretical Predictions and Observational Clues", Springer Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B. Mobasher, in pres

Reconstructing extreme AMOC events through nudging of the ocean surface: a perfect model approach

While the Atlantic Meridional Overturning Circulation (AMOC) is thought to be a crucial component of the North Atlantic climate, past changes in its strength are challenging to quantify, and only limited information is available. In this study, we use a perfect model approach with the IPSL-CM5A-LR model to assess the performance of several surface nudging techniques in reconstructing the variability of the AMOC. Special attention is given to the reproducibility of an extreme positive AMOC peak from a preindustrial control simulation. Nudging includes standard relaxation techniques towards the sea surface temperature and salinity anomalies of this target control simulation, and/or the prescription of the wind-stress fields. Surface nudging approaches using standard fixed restoring terms succeed in reproducing most of the target AMOC variability, including the timing of the extreme event, but systematically underestimate its amplitude. A detailed analysis of the AMOC variability mechanisms reveals that the underestimation of the extreme AMOC maximum comes from a deficit in the formation of the dense water masses in the main convection region, located south of Iceland in the model. This issue is largely corrected after introducing a novel surface nudging approach, which uses a varying restoring coefficient that is proportional to the simulated mixed layer depth, which, in essence, keeps the restoring time scale constant. This new technique substantially improves water mass transformation in the regions of convection, and in particular, the formation of the densest waters, which are key for the representation of the AMOC extreme. It is therefore a promising strategy that may help to better constrain the AMOC variability and other ocean features in the models. As this restoring technique only uses surface data, for which better and longer observations are available, it opens up opportunities for improved reconstructions of the AMOC over the last few decades

In vitro epithelial-to-mesenchymal transformation in human adult epicardial cells is regulated by TGFβ-signaling and WT1

Adult epicardial cells are required for endogenous cardiac repair. After myocardial injury, they are reactivated, undergo epithelial-to-mesenchymal transformation (EMT) and migrate into the injured myocardium where they generate various cell types, including coronary smooth muscle cells and cardiac interstitial fibroblasts, which contribute to cardiac repair. To understand what drives epicardial EMT, we used an in vitro model for human adult epicardial cells. These cells have an epithelium-like morphology and markedly express the cell surface marker vascular cell adhesion marker (VCAM-1). In culture, epicardial cells spontaneously undergo EMT after which the spindle-shaped cells now express endoglin. Both epicardial cells before and after EMT express the epicardial marker, Wilms tumor 1 (WT1). Adding transforming growth factor beta (TGFβ) induces loss of epithelial character and initiates the onset of mesenchymal differentiation in human adult epicardial cells. In this study, we show that TGFβ-induced EMT is dependent on type-1 TGFβ receptor activity and can be inhibited by soluble VCAM-1. We also show that epicardial-specific knockdown of Wilms tumor-1 (WT1) induces the process of EMT in human adult epicardial cells, through transcriptional regulation of platelet-derived growth factor receptor alpha (Pdgfrα), Snai1 and VCAM-1. These data provide new insights into the process of EMT in human adult epicardial cells, which might provide opportunities to develop new strategies for endogenous cell-based cardiac repair

The impact of ENSO on Southern African rainfall in CMIP5 ocean atmosphere coupled climate models

We study the ability of 24 ocean atmosphere global coupled models from the Coupled Model Intercomparison Project 5 (CMIP5) to reproduce the teleconnections between El Niño Southern Oscillation (ENSO) and Southern African rainfall in austral summer using historical forced simulations, with a focus on the atmospheric dynamic associated with El Niño. Overestimations of summer rainfall occur over Southern Africa in all CMIP5 models. Abnormal westward extensions of ENSO patterns are a common feature of all CMIP5 models, while the warming of the Indian Ocean that happens during El Niño is not correctly reproduced. This could impact the teleconnection between ENSO and Southern African rainfall which is represented with mixed success in CMIP5 models. Large-scale anomalies of suppressed deep-convection over the tropical maritime continent and enhanced convection from the central to eastern Pacific are correctly simulated. However, regional biases occur above Africa and the Indian Ocean, particularly in the position of the deep convection anomalies associated with El Niño, which can lead to the wrong sign in rainfall anomalies in the northwest part of South Africa. From the near-surface to mid-troposphere, CMIP5 models underestimate the observed anomalous pattern of pressure occurring over Southern Africa that leads to dry conditions during El Niño years

Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy

In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an important cause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, the public health benefits of IPTp are declining due to SP resistance. The combination of azithromycin and chloroquine is a potential alternative to SP for IPTp. This review summarizes key in vitro and in vivo evidence of azithromycin and chloroquine activity against Plasmodium falciparum and Plasmodium vivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp, including the cure and prevention of many sexually transmitted diseases. Drug costs and the necessity for external financing are discussed along with a range of issues related to drug resistance and surveillance. Several scientific and programmatic questions of interest to policymakers and programme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp

SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis

Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM. Further scrutiny of these data identified a panel of highly expressed ECM proteins, including Osteopontin (OPN), Osteoactivin (GPNMB), Fibronectin (FN1), Osteonectin (SPARC) and Vimentin (VIM) as SOX9 targets amenable to assay in patient serum. In vivo all SOX-regulated targets were increased in human disease and mouse models of fibrosis and decreased following Sox9-loss in mice with parenchymal and biliary fibrosis. In patient serum samples, SOX9-regulated ECM proteins were altered in response to fibrosis severity, whereas comparison with established clinical biomarkers demonstrated superiority for OPN and VIM at detecting early stages of fibrosis. These data support SOX9 in the mechanisms underlying fibrosis and highlight SOX9 and its downstream targets as new measures to stratify patients with liver fibrosis

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe