Defining mechanisms that generate intratumour heterogeneity and branched evolution may inspire novel therapeutic approaches to limit tumour diversity and adaptation. SETD2 (Su(var), Enhancer of ...zeste, Trithorax-domain containing 2) trimethylates histone-3 lysine-36 (H3K36me3) at sites of active transcription and is mutated in diverse tumour types, including clear cell renal carcinomas (ccRCCs). Distinct SETD2 mutations have been identified in spatially separated regions in ccRCC, indicative of intratumour heterogeneity. In this study, we have addressed the consequences of SETD2 loss-of-function through an integrated bioinformatics and functional genomics approach. We find that bi-allelic SETD2 aberrations are not associated with microsatellite instability in ccRCC. SETD2 depletion in ccRCC cells revealed aberrant and reduced nucleosome compaction and chromatin association of the key replication proteins minichromosome maintenance complex component (MCM7) and DNA polymerase δ hindering replication fork progression, and failure to load lens epithelium-derived growth factor and the Rad51 homologous recombination repair factor at DNA breaks. Consistent with these data, we observe chromosomal breakpoint locations are biased away from H3K36me3 sites in SETD2 wild-type ccRCCs relative to tumours with bi-allelic SETD2 aberrations and that H3K36me3-negative ccRCCs display elevated DNA damage in vivo. These data suggest a role for SETD2 in maintaining genome integrity through nucleosome stabilization, suppression of replication stress and the coordination of DNA repair.
The purpose of this study was to examine global epidemiological trends in human norovirus (NoV) outbreaks by transmission route and setting, and describe relationships between these characteristics, ...viral attack rates, and the occurrence of genogroup I (GI) or genogroup II (GII) strains in outbreaks. We analysed data from 902 reverse transcriptase–polymerase chain reaction-confirmed, human NoV outbreaks abstracted from a systematic review of articles published from 1993 to 2011 and indexed under the terms ‘norovirus’ and ‘outbreak’. Multivariate regression analyses demonstrated that foodservice and winter outbreaks were significantly associated with higher attack rates. Foodborne and waterborne outbreaks were associated with multiple strains (GI+GII). Waterborne outbreaks were significantly associated with GI strains, while healthcare-related and winter outbreaks were associated with GII strains. These results identify important trends for epidemic NoV detection, prevention, and control.
Causal mechanisms of norovirus outbreaks are often not revealed. Understanding the transmission route (e.g. foodborne, waterborne, or environmental) and vehicle (e.g. shellfish or recreational water) ...of a norovirus outbreak, however, is of great public health importance; this information can facilitate interventions for an ongoing outbreak and regulatory action to limit future outbreaks. Towards this goal, we conducted a systematic review to examine whether published outbreak information was associated with the implicated transmission route or vehicle. Genogroup distribution was associated with transmission route and food vehicle, but attack rate and the presence of GII.4 strain were not associated with transmission route, food vehicle, or water vehicle. Attack rate, genogroup distribution, and GII.4 strain distribution also varied by other outbreak characteristics (e.g. setting, season, hemisphere). These relationships suggest that different genogroups exploit different environmental conditions and thereby can be used to predict the likelihood of various transmission routes or vehicles.
Results from the Telescope Array Matthews, J.N.
Journal of physics. Conference series,
02/2023, Volume:
2429, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
The Telescope Array is a hybrid cosmic ray detector consisting both of fluorescence telescopes and an array of scintillator surface detectors. It is the largest cosmic ray detector in the ...Northern hemisphere. It is presently expanding from 700 km
2
to 2800 km
2
. The status of spectral, composition, and source search measurements are be presented in addition to an update on the deployment of the TAx4 detector.
We have measured the cosmic ray spectrum above 10(17.2) eV using the two air-fluorescence detectors of the High Resolution Fly's Eye observatory operating in monocular mode. We describe the detector, ...phototube, and atmospheric calibrations, as well as the analysis techniques for the two detectors. We fit the spectrum to a model consisting of galactic and extragalactic sources.
We report the discovery and characterization of two transiting planets around the bright M1 V star LP 961-53 (TOI-776,
J
= 8.5 mag,
M
= 0.54 ± 0.03
M
⊙
) detected during Sector 10 observations of the ...Transiting Exoplanet Survey Satellite (TESS). Combining the TESS photometry with HARPS radial velocities, as well as ground-based follow-up transit observations from the MEarth and LCOGT telescopes, for the inner planet, TOI-776 b, we measured a period of
P
b
= 8.25 d, a radius of
R
b
= 1.85 ± 0.13
R
⊕
, and a mass of
M
b
= 4.0 ± 0.9
M
⊕
; and for the outer planet, TOI-776 c, a period of
P
c
= 15.66 d, a radius of
R
c
= 2.02 ± 0.14
R
⊕
, and a mass of
M
c
= 5.3 ± 1.8
M
⊕
. The Doppler data shows one additional signal, with a period of ~34 d, associated with the rotational period of the star. The analysis of fifteen years of ground-based photometric monitoring data and the inspection of different spectral line indicators confirm this assumption. The bulk densities of TOI-776 b and c allow for a wide range of possible interior and atmospheric compositions. However, both planets have retained a significant atmosphere, with slightly different envelope mass fractions. Thanks to their location near the radius gap for M dwarfs, we can start to explore the mechanism(s) responsible for the radius valley emergence around low-mass stars as compared to solar-like stars. While a larger sample of well-characterized planets in this parameter space is still needed to draw firm conclusions, we tentatively estimate that the stellar mass below which thermally-driven mass loss is no longer the main formation pathway for sculpting the radius valley is between 0.63 and 0.54
M
⊙
. Due to the brightness of the star, the TOI-776 system is also an excellent target for the
James Webb
Space Telescope, providing a remarkable laboratory in which to break the degeneracy in planetary interior models and to test formation and evolution theories of small planets around low-mass stars.
Stepped wedge designs (SWDs) have received considerable attention recently, as they are potentially a useful way to assess new treatments in areas such as health services implementation. Because ...allocation is usually by cluster, SWDs are often viewed as a form of cluster‐randomized trial. However, since the treatment within a cluster changes during the course of the study, they can also be viewed as a form of crossover design. This article explores SWDs from the perspective of crossover trials and designed experiments more generally. We show that the treatment effect estimator in a linear mixed effects model can be decomposed into a weighted mean of the estimators obtained from (1) regarding an SWD as a conventional row‐column design and (2) a so‐called vertical analysis, which is a row‐column design with row effects omitted. This provides a precise representation of “horizontal” and “vertical” comparisons, respectively, which to date have appeared without formal description in the literature. This decomposition displays a sometimes surprising way the analysis corrects for the partial confounding between time and treatment effects. The approach also permits the quantification of the loss of efficiency caused by mis‐specifying the correlation parameter in the mixed‐effects model. Optimal extensions of the vertical analysis are obtained, and these are shown to be highly inefficient for values of the within‐cluster dependence that are likely to be encountered in practice. Some recently described extensions to the classic SWD incorporating multiple treatments are also compared using the experimental design framework.
Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain. Design Randomised, double ...blind, crossover trial of 14 weeks’ duration comparing dihydrocodeine and nabilone.Setting Outpatient units of three hospitals in the United Kingdom.Participants 96 patients with chronic neuropathic pain, aged 23-84 years. Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain, as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period. Secondary outcomes were changes in mood, quality of life, sleep, and psychometric function. Side effects were measured by a questionnaire.Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks. Treatment periods were separated by a 2 week washout period.Results Mean baseline visual analogue score was 69.6 mm (range 29.4-95.2) on a 0-100 mm scale. 73 patients were included in the available case analysis and 64 patients in the per protocol analysis. The mean score was 6.0 mm longer for nabilone than for dihydrocodeine (95% confidence interval 1.4 to 10.5) in the available case analysis and 5.6 mm (10.3 to 0.8) in the per protocol analysis. Side effects were more frequent with nabilone.Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects, although no major adverse events occurred for either drug. Trial registration Current Controlled Trials ISRCTN15330757.
The Telescope Array (TA) observatory utilizes fluorescence detectors and surface detectors (SDs) to observe air showers produced by ultra high energy cosmic rays in Earth's atmosphere. Cosmic-ray ...events observed in this way are termed hybrid data. The depth of air shower maximum is related to the mass of the primary particle that generates the shower. This paper reports on shower maxima data collected over 8.5 yr using the Black Rock Mesa and Long Ridge fluorescence detectors in conjunction with the array of SDs. We compare the means and standard deviations of the observed X max distributions with Monte Carlo X max distributions of unmixed protons, helium, nitrogen, and iron, all generated using the QGSJet II-04 hadronic model. We also perform an unbinned maximum likelihood test of the observed data, which is subjected to variable systematic shifting of the data X max distributions to allow us to test the full distributions, and compare them to the Monte Carlo to see which elements are not compatible with the observed data. For all energy bins, QGSJet II-04 protons are found to be compatible with TA hybrid data at the 95% confidence level after some systematic X max shifting of the data. Three other QGSJet II-04 elements are found to be compatible using the same test procedure in an energy range limited to the highest energies where data statistics are sparse.
ABSTRACT
We study the nature of the faint radio source population detected in the MeerKAT International GHz Tiered Extragalactic Exploration (MIGHTEE) Early Science data in the COSMOS field, focusing ...on the properties of the radio-loud active galactic nuclei (AGNs). Using the extensive multiwavelength data available in the field, we are able to classify 88 per cent of the 5223 radio sources in the field with host galaxy identifications as AGNs (35 per cent) or star-forming galaxies (54 per cent). We select a sample of radio-loud AGNs with redshifts out to z ∼ 6 and radio luminosities 1020 < L1.4 GHz/W Hz−1 < 1027 and classify them as high-excitation and low-excitation radio galaxies (HERGs and LERGs). The classification catalogue is released with this work. We find no significant difference in the host galaxy properties of the HERGs and LERGs in our sample. In contrast to previous work, we find that the HERGs and LERGs have very similar Eddington-scaled accretion rates; in particular we identify a population of very slowly accreting AGNs that are formally classified as HERGs at these low radio luminosities, where separating into HERGs and LERGs possibly becomes redundant. We investigate how black hole mass affects jet power, and find that a black hole mass ≳ 107.8 M⊙ is required to power a jet with mechanical power greater than the radiative luminosity of the AGN (Lmech/Lbol > 1). We discuss that both a high black hole mass and black hole spin may be necessary to launch and sustain a dominant radio jet.
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