Abstract
The ultraluminous X-ray source (ULX) population is known to contain neutron stars (NS), but the relative number of these compared to black hole (BH) primaries is unknown. Assuming classical ...supercritical accretion and resultant geometrical beaming, we show that the observed population ratio can be predicted from the mean masses of each family of compact objects and the relative spatial density of NSs to BHs. Conversely – and perhaps more importantly – given even a crude estimate for the spatial densities, an estimate of the fraction of the population containing NSs will begin to constrain the mean mass of BHs in ultraluminous X-ray sources.
The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, ...we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: 'immune hot' and 'immune cold', which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy.
Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that ...supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntington's disease, reducing messenger RNA and protein throughout the brain. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders.
The brightness of an active galactic nucleus is set by the gas falling onto it from the galaxy, and the gas infall rate is regulated by the brightness of the active galactic nucleus; this feedback ...loop is the process by which supermassive black holes in the centres of galaxies may moderate the growth of their hosts. Gas outflows (in the form of disk winds) release huge quantities of energy into the interstellar medium, potentially clearing the surrounding gas. The most extreme (in terms of speed and energy) of these-the ultrafast outflows-are the subset of X-ray-detected outflows with velocities higher than 10,000 kilometres per second, believed to originate in relativistic (that is, near the speed of light) disk winds a few hundred gravitational radii from the black hole. The absorption features produced by these outflows are variable, but no clear link has been found between the behaviour of the X-ray continuum and the velocity or optical depth of the outflows, owing to the long timescales of quasar variability. Here we report the observation of multiple absorption lines from an extreme ultrafast gas flow in the X-ray spectrum of the active galactic nucleus IRAS 13224-3809, at 0.236 ± 0.006 times the speed of light (71,000 kilometres per second), where the absorption is strongly anti-correlated with the emission of X-rays from the inner regions of the accretion disk. If the gas flow is identified as a genuine outflow then it is in the fastest five per cent of such winds, and its variability is hundreds of times faster than in other variable winds, allowing us to observe in hours what would take months in a quasar. We find X-ray spectral signatures of the wind simultaneously in both low- and high-energy detectors, suggesting a single ionized outflow, linking the low- and high-energy absorption lines. That this disk wind is responding to the emission from the inner accretion disk demonstrates a connection between accretion processes occurring on very different scales: the X-ray emission from within a few gravitational radii of the black hole ionizing the disk wind hundreds of gravitational radii further away as the X-ray flux rises.
Prenatal maternal stress (PNMS) predicts a wide variety of behavioral and physical outcomes in the offspring. Although epigenetic processes may be responsible for PNMS effects, human research is ...hampered by the lack of experimental methods that parallel controlled animal studies. Disasters, however, provide natural experiments that can provide models of prenatal stress.
Five months after the 1998 Quebec ice storm we recruited women who had been pregnant during the disaster and assessed their degrees of objective hardship and subjective distress. Thirteen years later, we investigated DNA methylation profiling in T cells obtained from 36 of the children, and compared selected results with those from saliva samples obtained from the same children at age 8.
Prenatal maternal objective hardship was correlated with DNA methylation levels in 1675 CGs affiliated with 957 genes predominantly related to immune function; maternal subjective distress was uncorrelated. DNA methylation changes in SCG5 and LTA, both highly correlated with maternal objective stress, were comparable in T cells, peripheral blood mononuclear cells (PBMCs) and saliva cells.
These data provide first evidence in humans supporting the conclusion that PNMS results in a lasting, broad, and functionally organized DNA methylation signature in several tissues in offspring. By using a natural disaster model, we can infer that the epigenetic effects found in Project Ice Storm are due to objective levels of hardship experienced by the pregnant woman rather than to her level of sustained distress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Data sharing, research ethics, and incentives must improve
The field of computational social science (CSS) has exploded in prominence over the past decade, with thousands of papers published using ...observational data, experimental designs, and large-scale simulations that were once unfeasible or unavailable to researchers. These studies have greatly improved our understanding of important phenomena, ranging from social inequality to the spread of infectious diseases. The institutions supporting CSS in the academy have also grown substantially, as evidenced by the proliferation of conferences, workshops, and summer schools across the globe, across disciplines, and across sources of data. But the field has also fallen short in important ways. Many institutional structures around the field—including research ethics, pedagogy, and data infrastructure—are still nascent. We suggest opportunities to address these issues, especially in improving the alignment between the organization of the 20th-century university and the intellectual requirements of the field.
Two-dimensional materials such as graphene and molybdenum disulfide are often subject to out-of-plane deformation, but its influence on electronic and nanomechanical properties remains poorly ...understood. These physical distortions modulate important properties which can be studied by atomic force microscopy and Raman spectroscopic mapping. Herein, we have identified and investigated different geometries of line defects in graphene and molybdenum disulfide such as standing collapsed wrinkles, folded wrinkles, and grain boundaries that exhibit distinct strain and doping. In addition, we apply nanomechanical atomic force microscopy to determine the influence of these defects on local stiffness. For wrinkles of similar height, the stiffness of graphene was found to be higher than that of molybdenum disulfide by 10–15% due to stronger in-plane covalent bonding. Interestingly, deflated graphene nanobubbles exhibited entirely different characteristics from wrinkles and exhibit the lowest stiffness of all graphene defects. Density functional theory reveals alteration of the bandstructures of graphene and MoS2 due to the wrinkled structure; such modulation is higher in MoS2 compared to graphene. Using this approach, we can ascertain that wrinkles are subject to significant strain but minimal doping, while edges show significant doping and minimal strain. Furthermore, defects in graphene predominantly show compressive strain and increased carrier density. Defects in molybdenum disulfide predominantly show tensile strain and reduced carrier density, with increasing tensile strain minimizing doping across all defects in both materials. The present work provides critical fundamental insights into the electronic and nanomechanical influence of intrinsic structural defects at the nanoscale, which will be valuable in straintronic device engineering.
The vasopressin type 2 receptor (V2R) is a critical G protein-coupled receptor (GPCR) for vertebrate physiology, including the balance of water and sodium ions. It is unclear how its two native ...hormones, vasopressin (VP) and oxytocin (OT), both stimulate the same cAMP/PKA pathway yet produce divergent antinatriuretic and antidiuretic effects that are either strong (VP) or weak (OT). Here, we present a new mechanism that differentiates the action of VP and OT on V2R signaling. We found that vasopressin, as opposed to OT, continued to generate cAMP and promote PKA activation for prolonged periods after ligand washout and receptor internalization in endosomes. Contrary to the classical model of arrestin-mediated GPCR desensitization, arrestins bind the VP-V2R complex yet extend rather than shorten the generation of cAMP. Signaling is instead turned off by the endosomal retromer complex. We propose that this mechanism explains how VP sustains water and Na+ transport in renal collecting duct cells. Together with recent work on the parathyroid hormone receptor, these data support the existence of a novel “noncanonical” regulatory pathway for GPCR activation and response termination, via the sequential action of β-arrestin and the retromer complex.
Background: It remains unclear why vasopressin induces greater antidiuresis through V2R than does oxytocin.
Results: Vasopressin sustains cAMP signaling during V2R internalization, a process promoted by β-arrestins, and is halted by the retromer complex.
Conclusion: This new noncanonical model of GPCR signaling differentiates the actions of vasopressin and oxytocin.
Significance: This emerging model may explain the physiological bias between ligands.
This book provides fully updated coverage of the copper production process encompassing topics as diverse as environmental technology for wind and solar energy transmission, treatment of waste ...byproducts, and recycling of electronic scrap for potential alternative technology implementation. The authors examine industrially-grounded treatments of process fundamentals and the beneficiation of raw materials, smelting and converting, hydrometallurgical processes, and refining technology for a mine-to-market perspective, from primary and secondary raw materials extraction to shipping of rod or billet to customers. The modern coverage of the work includes bath smelting processes such as Ausmelt and Isasmelt which have become state-of-the-art in sulfide concentrate smelting and converting.
Abstract
Ponds are often identified by their small size and shallow depths, but the lack of a universal evidence-based definition hampers science and weakens legal protection. Here, we compile ...existing pond definitions, compare ecosystem metrics (e.g., metabolism, nutrient concentrations, and gas fluxes) among ponds, wetlands, and lakes, and propose an evidence-based pond definition. Compiled definitions often mentioned surface area and depth, but were largely qualitative and variable. Government legislation rarely defined ponds, despite commonly using the term. Ponds, as defined in published studies, varied in origin and hydroperiod and were often distinct from lakes and wetlands in water chemistry. We also compared how ecosystem metrics related to three variables often seen in waterbody definitions: waterbody size, maximum depth, and emergent vegetation cover. Most ecosystem metrics (e.g., water chemistry, gas fluxes, and metabolism) exhibited nonlinear relationships with these variables, with average threshold changes at 3.7 ± 1.8 ha (median: 1.5 ha) in surface area, 5.8 ± 2.5 m (median: 5.2 m) in depth, and 13.4 ± 6.3% (median: 8.2%) emergent vegetation cover. We use this evidence and prior definitions to define ponds as waterbodies that are small (< 5 ha), shallow (< 5 m), with < 30% emergent vegetation and we highlight areas for further study near these boundaries. This definition will inform the science, policy, and management of globally abundant and ecologically significant pond ecosystems.
PDF
