Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a ...substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.
Context. One of the key questions of the star formation problem is whether brown dwarfs (BDs) form in the manner of stars directly from the gravitational collapse of a molecular cloud core ...(star-like) or whether BDs and some very low-mass stars (VLMSs) constitute a separate population that forms alongside stars comparable to the population of planets, for example through circumstellar disk (peripheral) fragmentation. Aims. For young stars in Taurus-Auriga the binary fraction has been shown to be large with little dependence on primary mass above ≈ 0.2 M⊙, while for BDs the binary fraction is < 10%. Here we investigate a case in which BDs in Taurus formed dominantly, but not exclusively, through peripheral fragmentation, which naturally results in small binary fractions. The decline of the binary frequency in the transition region between star-like formation and peripheral formation is modelled. Methods. We employed a dynamical population synthesis model in which stellar binary formation is universal with a large binary fraction close to unity. Peripheral objects form separately in circumstellar disks with a distinctive initial mass function (IMF), their own orbital parameter distributions for binaries, and small binary fractions, according to observations and expectations from smoothed particle hydrodynamics (SPH) and grid-based computations. A small amount of dynamical processing of the stellar component was accounted for as appropriate for the low-density Taurus-Auriga embedded clusters. Results. The binary fraction declines strongly in the transition region between star-like and peripheral formation, exhibiting characteristic features. The location of these features and the steepness of this trend depend on the mass limits for star-like and peripheral formation. Such a trend might be unique to low density regions, such as Taurus, which host binary populations that are largely unprocessed dynamically in which the binary fraction is large for stars down to M-dwarfs and small for BDs. Conclusions. The existence of a strong decline in the binary fraction – primary mass diagram will become verifiable in future surveys on BD and VLMS binarity in the Taurus-Auriga star-forming region. The binary fraction – primary mass diagram is a diagnostic of the (non-)continuity of star formation along the mass scale, the separateness of the stellar and BD populations, and the dominant formation channel for BDs and BD binaries in regions of low stellar density hosting dynamically unprocessed populations.
Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ ...significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.
To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA).
Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour ...necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy).
During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001).
Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.
The Majorana Demonstrator neutrinoless double-beta decay experiment comprises a 44 kg (30 kg enriched in ^{76}Ge) array of p-type, point-contact germanium detectors. With its unprecedented energy ...resolution and ultralow backgrounds, Majorana also searches for rare event signatures from beyond standard model physics in the low energy region below 100 keV. In this Letter, we test the continuous spontaneous localization (CSL) model, one of the mathematically well-motivated wave function collapse models aimed at solving the long-standing unresolved quantum mechanical measurement problem. While the CSL predicts the existence of a detectable radiation signature in the x-ray domain, we find no evidence of such radiation in the 19-100 keV range in a 37.5 kg-y enriched germanium exposure collected between December 31, 2015, and November 27, 2019, with the Demonstrator. We explored both the non-mass-proportional (n-m-p) and the mass-proportional (m-p) versions of the CSL with two different assumptions: that only the quasifree electrons can emit the x-ray radiation and that the nucleus can coherently emit an amplified radiation. In all cases, we set the most stringent upper limit to date for the white CSL model on the collapse rate, λ, providing a factor of 40-100 improvement in sensitivity over comparable searches. Our limit is the most stringent for large parts of the allowed parameter space. If the result is interpreted in terms of the Diòsi-Penrose gravitational wave function collapse model, the lower bound with a 95% confidence level is almost an order of magnitude improvement over the previous best limit.
The Balloon-borne Large Aperture Submillimeter Telescope (BLAST) is a suborbital surveying experiment designed to study the evolutionary history and processes of star formation in local galaxies ...(including the Milky Way) and galaxies at cosmological distances. The BLAST continuum camera, which consists of 270 detectors distributed between three arrays, observes simultaneously in broadband (30%) spectral windows at 250, 350, and 500 mum. The optical design is based on a 2 m diameter telescope, providing a diffraction-limited resolution of 30 super(image ) at 250 mum. The gondola pointing system enables raster mapping of arbitrary geometry, with a repeatable positional accuracy of image30 super(image ); postflight pointing reconstruction to image5 super(image ) rms is achieved. The onboard telescope control software permits autonomous execution of a preselected set of maps, with the option of manual override. In this paper we describe the primary characteristics and measured in-flight performance of BLAST. BLAST performed a test flight in 2003 and has since made two scientifically productive long- duration balloon flights: a 100 hr flight from ESRANGE (Kiruna), Sweden to Victoria Island, northern Canada in 2005 June; and a 250 hr, circumpolar flight from McMurdo Station, Antarctica, in 2006 December.
In many parts of the world the damaging potato late blight pathogen, Phytophthora infestans, is spread as a succession of clonal lineages. The discrimination of genetic diversity within such evolving ...populations provides insights into the processes generating novel lineages and the pathways and drivers of pathogen evolution and dissemination at local and global scales. This knowledge, in turn, helps optimise management practices. Here we combine two key methods for dissecting mitochondrial and nuclear diversity and resolve intra and inter-lineage diversity of over 100 P. infestans isolates representative of key clonal lineages found globally. A novel set of PCR primers that amplify five target regions are provided for mitochondrial DNA sequence analysis. These five loci increased the number of mtDNA haplotypes resolved from four with the PCR RFLP method to 37 (17, 6, 8 and 4 for Ia, Ib, IIa, and IIb haplotypes, respectively, plus 2 Herb-1 haplotypes). As with the PCR RFLP method, two main lineages, I and II were defined. Group I contained 25 mtDNA haplotypes that grouped broadly according to the Ia and Ib types and resolved several sub-clades amongst the global sample. Group II comprised two distinct clusters with four haplotypes corresponding to the RFLP type IIb and eight haplotypes resolved within type IIa. The 12-plex SSR assay revealed 90 multilocus genotypes providing accurate discrimination of dominant clonal lineages and other genetically diverse isolates. Some association of genetic diversity and geographic region of contemporary isolates was observed; US and Mexican isolates formed a loose grouping, distinct from isolates from Europe, South America and other regions. Diversity within clonal lineages was observed that varied according to the age of the clone. In combination, these fine-scale nuclear and maternally inherited mitochondrial markers enabled a greater level of discrimination among isolates than previously available and provided complementary perspectives on evolutionary questions relating to the diversity, phylogeography and the origins and spread of clonal lineages of P. infestans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Connecting scientific research and government policy is essential for achieving objectives in sustaining biodiversity in an economic context. Our approach to connecting theoretical ecology, applied ...ecology, and policy was devised using principles of restoration ecology and the requisite methodology to restore biodiverse ecosystems. Using a threatened ecological community (TEC) with >120 plant species, we posit our approach as a guide for interpreting and achieving regulatory compliance (i.e., government conditions) enacted to manage or offset environmental impacts of development. We inform the scientific approach necessary to delivering outcomes appropriate to policy intent and biodiverse restoration through theoretical and applied research into the ecological restoration of the highly endemic flora of banded ironstone formations of the Mid West of Western Australia. Our approach (1) defines scale‐appropriate restoration targets that meet regulatory compliance (e.g., Government of Western Australia Ministerial Conditions); (2) determines the optimal method to return individual plant species to the restoration landscape; (3) develops a conceptual model for our system, based on existing restoration frameworks, to optimize and facilitate the pathway to the restoration of a vegetation community (e.g., TEC) using diverse research approaches; and (4) develops an assessment protocol to compare restoration achievements against the expected regulatory outcomes using our experimental restoration trials as a test example. Our approach systematically addressed the complex challenges in setting and achieving restoration targets for an entire vegetation community, a first for a semiarid environment. We interpret our approach as an industry application relevant to policy‐ or regulator‐mediated mine restoration programs that seek to return biodiverse species assemblages at landscape scales.
We report on the light sterile neutrino search from the first four-week science run of the KATRIN experiment in 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are ...analyzed by a high-resolution MAC-E filter down to 40 eV below the endpoint at 18.57 keV. We consider the framework with three active neutrinos and one sterile neutrino. The analysis is sensitive to the mass, m_{4}, of the fourth mass state for m_{4}^{2}≲1000 eV^{2} and to active-to-sterile neutrino mixing down to |U_{e4}|^{2}≳2×10^{-2}. No significant spectral distortion is observed and exclusion bounds on the sterile mass and mixing are reported. These new limits supersede the Mainz results for m_{4}^{2}≲1000 eV^{2} and improve the Troitsk bound for m_{4}^{2}<30 eV^{2}. The reactor and gallium anomalies are constrained for 100<Δm_{41}^{2}<1000 eV^{2}.
El presente artículo propone un sucinto recorrido por algunos de los principales tópicos historiográficos sobre la fiscalidad del Río de la Plata durante un período de cambios y transiciones: 1760 a ...1820. Con ello, se intenta ofrecer un breve panorama sobre el estado de distintas cuestiones que resultan relevantes para consolidar una renovada agenda de investigación en curso.