We present the results of a search for galaxy clusters in the Subaru–XMM Deep Field (SXDF). We reach a depth for a total cluster flux in the 0.5–2 keV band of 2 × 10−15 erg cm−2 s−1 over one of the ...widest XMM–Newton contiguous raster surveys, covering an area of 1.3 deg2. Cluster candidates are identified through a wavelet detection of extended X-ray emission. The red-sequence technique allows us to identify 57 cluster candidates. We report on the progress with the cluster spectroscopic follow-up and derive their properties based on the X-ray luminosity and cluster scaling relations. In addition, three sources are identified as X-ray counterparts of radio lobes, and in three further sources, an X-ray counterpart of the radio lobes provides a significant fraction of the total flux of the source. In the area covered by near-infrared data, our identification success rate achieves 86 per cent. We detect a number of radio galaxies within our groups, and for a luminosity-limited sample of radio galaxies we compute halo occupation statistics using a marked cluster mass function. We compare the cluster detection statistics in the SXDF with that in the literature and provide the modelling using the concordance cosmology combined with current knowledge of the X-ray cluster properties. The joint cluster log(N) − log(S) is overpredicted by the model, and an agreement can be achieved through a reduction of the concordance σ8 value by 5 per cent. Having considered the dn/dz and the X-ray luminosity function of clusters, we conclude that to pin down the origin of disagreement a much wider (50 deg2) survey is needed.
Involving peer volunteers in intervention delivery can provide social support and improve adherence. Whilst such interventions have the potential to reduce physical activity (PA) intervention costs, ...little is known about the process of delivering them in practice. This qualitative study explored the facilitators and challenges of delivering a peer-support PA intervention for older adults, with a view to making recommendations for the delivery of future interventions.
Data were collected via (7) semi-structured interviews and a focus group with stakeholders involved in a peer-support PA intervention for older adults in a large city in the North-West of England. Participants included local authority staff (n = 3), peer volunteers (n = 2) and service users (n = 7). Audio data were transcribed verbatim and thematically coded to identify perceived facilitators and challenges.
Facilitators to delivery included social interaction, community referral pathways, suitable facilities, peer volunteers and high-quality instructors. Challenges surrounded inconsistent practice, staff capacity, safety and accountability, and awareness raising.
Peer volunteers can provide an additional support mechanism alongside qualified instructors for increasing social interaction within PA interventions. For optimal intervention delivery, consideration needs to be given to equipment and space, safety and accountability and consistency of practice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Knowing how species respond to fire regimes is essential for ecologically sustainable management. This axiom raises two important questions: (1) what knowledge is the most important to develop and ...(2) to what extent can current research methods deliver that knowledge? We identify three areas of required knowledge: (i) a mechanistic understanding of species’ responses to fire regimes; (ii) knowledge of how the spatial and temporal arrangement of fires influences the biota; and (iii) an understanding of interactions of fire regimes with other processes. We review the capacity of empirical research to address these knowledge gaps, and reveal many limitations. Manipulative experiments are limited by the number and scope of treatments that can be applied, natural experiments are limited by treatment availability and confounding factors, and longitudinal studies are difficult to maintain, particularly due to unplanned disturbance events. Simulation modelling is limited by the quality of the underlying empirical data and by uncertainty in how well model structure represents reality. Due to the constraints on large-scale, long-term research, the potential for management experiments to inform adaptive management is limited. Rather than simply recommending adaptive management, we define a research agenda to maximise the rate of learning in this difficult field. This includes measuring responses at a species level, building capacity to implement natural experiments, undertaking simulation modelling, and judicious application of experimental approaches. Developing ecologically sustainable fire management practices will require sustained research effort and a sophisticated research agenda based on carefully targeting appropriate methods to address critical management questions.
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and ...antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of
and
that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
A search for nonresonant Higgs boson pair production in the <img src="http://www.diva-portal.org/cgi-bin/mimetex.cgi?%5Cmathit%7Bb%5Cbar%7Bb%7Db%5Cbar%7Bb%7D%7D" data-classname="equation" ...data-title="" /> final state is presented. The analysis uses 126 fb −1 of pp collision data at √ s =13 TeV collected with the ATLAS detector at the Large Hadron Collider, and targets both the gluon-gluon fusion and vector-boson fusion production modes. No evidence of the signal is found and the observed (expected) upper limit on the cross section for nonresonant Higgs boson pair production is determined to be 5.4 (8.1) times the Standard Model predicted cross section at 95% confidence level. Constraints are placed on modifiers to the HHH and HHVV couplings. The observed (expected) 2σ constraints on the HHH coupling modifier, κ λ , are determined to be −3.5,11.3 (−5.4,11.4), while the corresponding constraints for the HHVV coupling modifier, κ 2V , are −0.0,2.1 (−0.1,2.1). In addition, constraints on relevant coefficients are derived in the context of the Standard Model effective field theory and Higgs effective field theory, and upper limits on the HH production cross section are placed in seven Higgs effective field theory benchmark scenarios.
Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors ...aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified 60 (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.
CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against genetic invaders, such as bacteriophages. The systems integrate short sequences from the phage genome into the bacterial ...CRISPR array. These 'spacers' provide sequence-specific immunity but drive natural selection of evolved phage mutants that escape the CRISPR-Cas defence. Spacer acquisition occurs by either naive or primed adaptation. Naive adaptation typically results in the incorporation of a single spacer. By contrast, priming is a positive feedback loop that often results in acquisition of multiple spacers, which occurs when a pre-existing spacer matches the invading phage. We predicted that single and multiple spacers, representative of naive and primed adaptation, respectively, would cause differing outcomes after phage infection. We investigated the response of two phages, ϕTE and ϕM1, to the Pectobacterium atrosepticum type I-F CRISPR-Cas system and observed that escape from single spacers typically occurred via point mutations. Alternatively, phages escaped multiple spacers through deletions, which can occur in genes encoding structural proteins. Cryo-EM analysis of the ϕTE structure revealed shortened tails in escape mutants with tape measure protein deletions. We conclude that CRISPR-Cas systems can drive phage genetic diversity, altering morphology and fitness, through selective pressures arising from naive and primed acquisition events. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.
Lynds dark cloud LDN1622 represents one of the best examples of anomalous dust emission, possibly originating from small spinning dust grains. We present Cosmic Background Imager (CBI) 31-GHz data of ...LDN1621, a diffuse dark cloud to the north of LDN1622 in a region known as Orion East. A broken ring-like structure with diameter ≈20 arcmin of diffuse emission is detected at 31 GHz, at ≈20–30 mJy beam−1 with an angular resolution of ≈5 arcmin. The ring-like structure is highly correlated with far-infrared (FIR) emission at 12–100 μm with correlation coefficients of r≈ 0.7–0.8, significant at ∼10σ. The FIR-correlated emission at 31 GHz therefore appears to be mostly due to radiation associated with dust. Multifrequency data are used to place constraints on other components of emission that could be contributing to the 31-GHz flux. An analysis of the GB6 survey maps at 4.85 GHz yields a 3σ upper limit on free–free emission of 7.2 mJy beam−1 (≲30 per cent of the observed flux) at the CBI resolution. The bulk of the 31-GHz flux therefore appears to be mostly due to dust radiation. Aperture photometry, at an angular resolution of 13 arcmin and with an aperture of diameter 30 arcmin, allowed the use of IRAS maps and the Wilkinson Microwave Anisotropy Probe 5-yr W-band map at 93.5 GHz. A single modified blackbody model was fitted to the data to estimate the contribution from thermal dust, which amounts to ∼10 per cent at 31 GHz. In this model, an excess of 1.52 ± 0.66 Jy (2.3σ) is seen at 31 GHz. Correlations with the IRAS 100 μm gave a coupling coefficient of 18.1 ± 4.4 μK (MJy sr−1)−1, consistent with the values found for LDN1622.
Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro ...phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.
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