Aims/hypothesis
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the ...aim of identifying novel variants for type 2 diabetes in Asians.
Methods
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
Results
We identified
CDKN2A/B
and four novel type 2 diabetes association signals with
p
< 1 × 10
−5
from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (
p
meta
= 2.6 × 10
−8
; OR 95% CI 1.18 1.11, 1.25). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (
p
meta
= 2.3 × 10
−10
) and a population of European descent (
p
= 8.6 × 10
−3
). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Conclusions/interpretation
Our study identifies rs10229583 near
PAX4
as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is ...currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.
Bacteria within family S24-7 (phylum Bacteroidetes) are dominant in the mouse gut microbiota and detected in the intestine of other animals. Because they had not been cultured until recently and the ...family classification is still ambiguous, interaction with their host was difficult to study and confusion still exists regarding sequence data annotation.
We investigated family S24-7 by combining data from large-scale 16S rRNA gene analysis and from functional and taxonomic studies of metagenomic and cultured species.
A total of 685 species was inferred by full-length 16S rRNA gene sequence clustering. While many species could not be assigned ecological habitats (93,045 samples analyzed), the mouse was the most commonly identified host (average of 20% relative abundance and nine co-occurring species). Shotgun metagenomics allowed reconstruction of 59 molecular species, of which 34 were representative of the 16S rRNA gene-derived species clusters. In addition, cultivation efforts allowed isolating five strains representing three species, including two novel taxa. Genome analysis revealed that S24-7 spp. are functionally distinct from neighboring families and versatile with respect to complex carbohydrate degradation.
We provide novel data on the diversity, ecology, and description of bacterial family S24-7, for which the name Muribaculaceae is proposed.
We report on a novel compact laser-driven neutron source with an unprecedented short pulse duration (<50 ps) and high peak flux (>10(18) n/cm(2)/s), an order of magnitude higher than any existing ...source. In our experiments, high-energy electron jets are generated from thin (<3 μm) plastic targets irradiated by a petawatt laser. These intense electron beams are employed to generate neutrons from a metal converter. Our method opens venues for enhancing neutron radiography contrast and for creating astrophysical conditions of heavy element synthesis in the laboratory.
Abstract Biobanks provide an important repository of samples for research purposes. However, for those samples to reflect the in vivo state, and for experimental reliability and reproducibility, ...careful attention to collection, processing and storage is essential. This is particularly true for the placenta, which is potentially subjected to stressful conditions during delivery, and sample collection may be delayed owing to routine postpartum inspection by clinical staff. In addition, standardisation of the collection procedure enables samples to be shared among research groups, allowing larger datasets to be established. Here, we provide an evidence-based and experts' review of the factors surrounding collection that may influence data obtained from the human placenta. We outline particular requirements for specific techniques, and propose a protocol for optimal sample collection. We recognise that the relevance of these factors, and of the sample types collected to a particular study will depend on the research questions being addressed. We therefore anticipate that researchers will select from the protocol to meet their needs and resources available. Wherever possible, we encourage researchers to extend their collection to include additional samples that can be shared on an international collaborative basis, with appropriate informed consent, to raise the quality, as well as quantity, of placental research.
Most supermassive black holes (SMBHs) are accreting at very low levels and are difficult to distinguish from the galaxy centers where they reside. Our own Galaxy's SMBH provides an instructive ...exception, and we present a close-up view of its quiescent x-ray emission based on 3 megaseconds of Chandra observations. Although the x-ray emission is elongated and aligns well with a surrounding disk of massive stars, we can rule out a concentration of low-mass coronally active stars as the origin of the emission on the basis of the lack of predicted iron (Fe) Kα emission. The extremely weak hydrogen (H)—like Fe Kα line further suggests the presence of an outflow from the accretion flow onto the SMBH. These results provide important constraints for models of the prevalent radiatively inefficient accretion state.
High-sensitivity radio-frequency observations of millisecond pulsars usually show stochastic, broad-band, pulse-shape variations intrinsic to the pulsar emission process. These variations induce ...jitter noise in pulsar timing observations; understanding the properties of this noise is of particular importance for the effort to detect gravitational waves with pulsar timing arrays. We assess the short-term profile and timing stability of 22 millisecond pulsars that are part of the Parkes Pulsar Timing Array sample by examining intraobservation arrival time variability and single-pulse phenomenology. In 7 of the 22 pulsars, in the band centred at approximately 1400 MHz, we find that the brightest observations are limited by intrinsic jitter. We find consistent results, either detections or upper limits, for jitter noise in other frequency bands. PSR J1909−3744 shows the lowest levels of jitter noise, which we estimate to contribute ∼10 ns root mean square error to the arrival times for hour-duration observations. Larger levels of jitter noise are found in pulsars with wider pulses and distributions of pulse intensities. The jitter noise in PSR J0437−4715 decorrelates over a bandwidth of ∼2 GHz. We show that the uncertainties associated with timing pulsar models can be improved by including physically motivated jitter uncertainties. Pulse-shape variations will limit the timing precision at future, more sensitive, telescopes; it is imperative to account for this noise when designing instrumentation and timing campaigns for these facilities.
United airways disease (UAD) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower ...airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma‐allergic rhinitis is the archetypal UAD, but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a “treatable traits” approach for the classification and management of UAD, wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD.
Context.
The recent gravitational wave measurements have demonstrated the existence of stellar mass black hole binaries. It is essential for our understanding of massive star evolution to identify ...the contribution of binary evolution to the formation of double black holes.
Aims.
A promising way to progress is investigating the progenitors of double black hole systems and comparing predictions with local massive star samples, such as the population in 30 Doradus in the Large Magellanic Cloud (LMC).
Methods.
With this purpose in mind, we analysed a large grid of detailed binary evolution models at LMC metallicity with initial primary masses between 10 and 40
M
⊙
, and identified the model systems that potentially evolve into a binary consisting of a black hole and a massive main-sequence star. We then derived the observable properties of such systems, as well as peculiarities of the OB star component.
Results.
We find that ∼3% of the LMC late-O and early-B stars in binaries are expected to possess a black hole companion when stars with a final helium core mass above 6.6
M
⊙
are assumed to form black holes. While the vast majority of them may be X-ray quiet, our models suggest that these black holes may be identified in spectroscopic binaries, either by large amplitude radial velocity variations (≳50 km s
−1
) and simultaneous nitrogen surface enrichment, or through a moderate radial velocity (≳10 km s
−1
) and simultaneous rapid rotation of the OB star. The predicted mass ratios are such that main-sequence companions can be excluded in most cases. A comparison to the observed OB+WR binaries in the LMC, Be and X-ray binaries, and known massive black hole binaries supports our conclusion.
Conclusions.
We expect spectroscopic observations to be able to test key assumptions in our models, with important implications for massive star evolution in general and for the formation of double black hole mergers in particular.
Chimeric antigen receptor (CAR) T cells directed against the B-cell marker CD19 are currently changing the landscape for treatment of patients with refractory and/or relapsed B-cell malignancies. Due ...to the nature of CAR T cells as living drugs, they display a unique toxicity profile. As CAR T-cell therapy is extending towards other diseases and being more broadly employed in hematology and oncology, optimal management strategies of side-effects associated with CAR T-cell therapy are of high relevance. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias constitute challenges in the treatment of patients with CAR T cells. This review summarizes the current understanding of CAR T-cell toxicity and its management.
•CAR T cells are associated with unique side-effects.•Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and cytopenias are common.•Understanding the presentation, pathophysiology, grading and management of side-effects is crucial for CAR T-cell safety.
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