Systematic Investigation of the Permeability of Androgen Receptor PROTACs

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed

Galaxy and Mass Assembly (GAMA): Panchromatic data release (far-UV–far-IR) and the low-z energy budget

We present the Galaxy And Mass Assembly (GAMA) Panchromatic Data Release (PDR) constituting over 230 deg2 of imaging with photometry in 21 bands extending from the farUV to the far-IR. These data complement our spectroscopic campaign of over 300k galaxies, and are compiled from observations with a variety of facilities including: GALaxy Evolution eXplorer, Sloan Digital Sky Survey, Visible and Infrared Telescope for Astronomy (VISTA), Wide-field Infrared Survey Explorer, and Herschel, with the GAMA regions currently being surveyedbyVLTSurveyTelescope(VST)andscheduledforobservationsbyAustralianSquare Kilometer Array Pathfinder (ASKAP). These data are processed to a common astrometric solution, from which photometry is derived for ∼221373 galaxies with r < 19.8 mag. Online tools are provided to access and download data cutouts, or the full mosaics of the GAMA regions in each band. We focus, in particular, on the reduction and analysis of the VISTA VIsta Kilo-degree INfrared Galaxy data, and compare to earlier data sets (i.e. 2MASS and UKIDSS) before combining the data and examining its integrity. Having derived the 21-band photometric catalogue, we proceed to fit the data using the energy balance code MAGPHYS. These measurements are then used to obtain the first fully empirical measurement of the 0.1–500 μm energy output of the Universe. Exploring the cosmic spectral energy distribution across three time-intervals (0.3–1.1, 1.1–1.8, and 1.8–2.4 Gyr), we find that the Universe is currently generating (1.5 ± 0.3) × 1035 h70 W Mpc−3, down from (2.5 ± 0.2) × 1035 h70 W Mpc−3 2.3 Gyr ago. More importantly, we identify significant and smooth evolution in the integrated photon escape fraction at all wavelengths, with the UV escape fraction increasing from 27(18) per cent at z= 0.18 in NUV(FUV) to 34(23) per cent at z= 0.06. The GAMA PDR can be found at: http://gama-psi.icrar.org/

Healthcare Utilization Patterns for Acute Febrile Illness in Bangladesh, Nepal, and Pakistan: Results from the Surveillance for Enteric Fever in Asia Project

Background: Characterizing healthcare-seeking patterns for acute febrile illness is critical for generating population-based enteric fever incidence estimates from facility-based surveillance data. Methods: We used a hybrid model in the Surveillance for Enteric Fever in Asia Project (SEAP) to assess incidence of enteric fever at 6 study hospitals in 3 countries. We recruited individuals presenting to the hospitals and obtained blood cultures to evaluate for enteric fever. For this analysis, we undertook cluster random household surveys in Dhaka, Bangladesh (2 sites); Karachi, Pakistan; Kathmandu, Nepal; and Kavrepalanchok, Nepal between January 2017 and February 2019, to ascertain care-seeking behavior for individuals with 1) fever for ≥3 consecutive days within the past 8 weeks; or 2) fever resulting in hospitalization within the past year. We also collected data about disease severity and household demographics and assets. We used mixed-effect multivariable logistic regression models to identify determinants of healthcare seeking at study hospitals and determinants of culture-confirmed enteric fever. Results: We enrolled 31 841 households (53926 children) in Bangladesh, 25510 households (84196 children and adults) in Nepal, and 21310 households (108031 children and adults) in Pakistan. Children <5 years were most likely to be taken to the study hospitals for febrile illness at all sites. Household wealth was positively correlated with healthcare seeking in 4 of 5 study sites, and at least one marker of disease severity was positively associated with healthcare seeking in 3 of 5 catchment areas. Wealth and disease severity were variably predictive of blood culture-confirmed enteric fever. Conclusions: Age, household wealth, and disease severity are important determinants of healthcare seeking for acute febrile illness and enteric fever risk in these communities, and should be incorporated into estimation models for enteric fever incidence

Susceptibility of hamsters to clostridium difficile isolates of differing toxinotype

Clostridium difficile is the most commonly associated cause of antibiotic associated disease (AAD), which caused ~21,000 cases of AAD in 2011 in the U.K. alone. The golden Syrian hamster model of CDI is an acute model displaying many of the clinical features of C. difficile disease. Using this model we characterised three clinical strains of C. difficile, all differing in toxinotype; CD1342 (PaLoc negative), M68 (toxinotype VIII) and BI-7 (toxinotype III). The naturally occurring non-toxic strain colonised all hamsters within 1-day post challenge (d.p.c.) with high-levels of spores being shed in the faeces of animals that appeared well throughout the entire experiment. However, some changes including increased neutrophil influx and unclotted red blood cells were observed at early time points despite the fact that the known C. difficile toxins (TcdA, TcdB and CDT) are absent from the genome. In contrast, hamsters challenged with strain M68 resulted in a 45% mortality rate, with those that survived challenge remaining highly colonised. It is currently unclear why some hamsters survive infection, as bacterial and toxin levels and histology scores were similar to those culled at a similar time-point. Hamsters challenged with strain BI-7 resulted in a rapid fatal infection in 100% of the hamsters approximately 26 hr post challenge. Severe caecal pathology, including transmural neutrophil infiltrates and extensive submucosal damage correlated with high levels of toxin measured in gut filtrates ex vivo. These data describes the infection kinetics and disease outcomes of 3 clinical C. difficile isolates differing in toxin carriage and provides additional insights to the role of each toxin in disease progression

Integration across time determines path deviation discrimination for moving objects.

YesBackground: Human vision is vital in determining our interaction with the outside world. In this study we characterize our ability to judge changes in the direction of motion of objects-a common task which can allow us either to intercept moving objects, or else avoid them if they pose a threat. Methodology/Principal Findings: Observers were presented with objects which moved across a computer monitor on a linear path until the midline, at which point they changed their direction of motion, and observers were required to judge the direction of change. In keeping with the variety of objects we encounter in the real world, we varied characteristics of the moving stimuli such as velocity, extent of motion path and the object size. Furthermore, we compared performance for moving objects with the ability of observers to detect a deviation in a line which formed the static trace of the motion path, since it has been suggested that a form of static memory trace may form the basis for these types of judgment. The static line judgments were well described by a 'scale invariant' model in which any two stimuli which possess the same two-dimensional geometry (length/width) result in the same level of performance. Performance for the moving objects was entirely different. Irrespective of the path length, object size or velocity of motion, path deviation thresholds depended simply upon the duration of the motion path in seconds. Conclusions/Significance: Human vision has long been known to integrate information across space in order to solve spatial tasks such as judgment of orientation or position. Here we demonstrate an intriguing mechanism which integrates direction information across time in order to optimize the judgment of path deviation for moving objects.Wellcome Trust, Leverhulme Trust, NI

Galaxy And Mass Assembly (GAMA): The absence of stellar mass segregation in galaxy groups and consistent predictions from GALFORM and EAGLE simulations

We investigate the contentious issue of the presence, or lack thereof, of satellites mass segregation in galaxy groups using the Galaxy And Mass Assembly (GAMA) survey, the GALFORM semi-analytic and the EAGLE cosmological hydrodynamical simulation catalogues of galaxy groups. We select groups with halo mass $12 \leqslant \log(M_{\text{halo}}/h^{-1}M_\odot) <14.5$ and redshift $z \leqslant 0.32$ and probe the radial distribution of stellar mass out to twice the group virial radius. All the samples are carefully constructed to be complete in stellar mass at each redshift range and efforts are made to regularise the analysis for all the data. Our study shows negligible mass segregation in galaxy group environments with absolute gradients of $\lesssim0.08$ dex and also shows a lack of any redshift evolution. Moreover, we find that our results at least for the GAMA data are robust to different halo mass and group centre estimates. Furthermore, the EAGLE data allows us to probe much fainter luminosities ($r$-band magnitude of 22) as well as investigate the three-dimensional spatial distribution with intrinsic halo properties, beyond what the current observational data can offer. In both cases we find that the fainter EAGLE data show a very mild spatial mass segregation at $z \leqslant 0.22$, which is again not apparent at higher redshift. Interestingly, our results are in contrast to some earlier findings using the Sloan Digital Sky Survey. We investigate the source of the disagreement and suggest that subtle differences between the group finding algorithms could be the root cause

Antimicrobial Resistance in Typhoidal Salmonella: Surveillance for Enteric Fever in Asia Project, 2016-2019

Background: Clinicians have limited therapeutic options for enteric as a result of increasing antimicrobial resistance, and therefore typhoid vaccination is recommended as a preventive measure. As a part of the Surveillance for Enteric Fever in Asia Project (SEAP), we investigated the extent measured the burden of antimicrobial resistance (AMR) among confirmed enteric fever cases in Bangladesh, Nepal, and Pakistan. Methods: From September 2016-September 2019, SEAP recruited study participants of all age groups from its outpatient, inpatient, hospital laboratory, laboratory network, and surgical sites who had a diagnosis of febrile illness that was either suspected or blood culture confirmed for enteric fever. Antimicrobial resistance of isolates was determined by disc diffusion using Clinical and Laboratory Standard Institute cut-off points. We reported the frequency of multidrug resistance (MDR)(resistance to ampicillin, cotrimoxazole, and chloramphenicol), extensive drug resistance (XDR) (MDR plus non-susceptible to fluoroquinolone and any 3rd generation cephalosporins), and fluoroquinolone (FQ) and azithromycin non-susceptibility. Results: We enrolled 8,705 blood culture confirmed enteric fever cases: 4,873 (56%) from Bangladesh, 1,602 (18%) from Nepal and 2,230 (26%) from Pakistan. Of these, 7,591 (87%) were Salmonella Typhi and 1114 (13%) were S. Paratyphi. MDR S. Typhi was identified in 17% (701/4065) of isolates in Bangladesh, and 1% (19/1342) in Nepal. In Pakistan, 16 % (331/2084) of S. Typhi isolates were MDR, and 64% (1319/2074) were XDR. FQ nonsusceptibility among S. Typhi isolates was 98% in Bangladesh, 87% in Nepal, and 95% in Pakistan. Azithromycin non-susceptibility was detected in 77 (2%) in Bangladesh, 9 (.67%) in Nepal and 9 (.59%) isolates in Pakistan. In Pakistan, three (2%) S. Paratyphi isolates were MDR; no MDR S. Paratyphi was reported from Bangladesh or Nepal. Conclusions: Although AMR against S. Paratyphi was low across the three countries, there was widespread drug resistance among S. Typhi, including FQ non-susceptibility and the emergence of XDR S. Typhi in Pakistan, limiting treatment options. As typhoid conjugate vaccine (TCV) is rolled out, surveillance should continue to monitor changes in AMR to inform policies and to monitor drug resistance in S. Paratyphi, for which there is no vaccine

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

Nausea is a subjective sensation which is difficult to measure in non-verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations

Green Plants in the Red: A Baseline Global Assessment for the IUCN Sampled Red List Index for Plants

Plants provide fundamental support systems for life on Earth and are the basis for all terrestrial ecosystems; a decline in plant diversity will be detrimental to all other groups of organisms including humans. Decline in plant diversity has been hard to quantify, due to the huge numbers of known and yet to be discovered species and the lack of an adequate baseline assessment of extinction risk against which to track changes. The biodiversity of many remote parts of the world remains poorly known, and the rate of new assessments of extinction risk for individual plant species approximates the rate at which new plant species are described. Thus the question ‘How threatened are plants?’ is still very difficult to answer accurately. While completing assessments for each species of plant remains a distant prospect, by assessing a randomly selected sample of species the Sampled Red List Index for Plants gives, for the first time, an accurate view of how threatened plants are across the world. It represents the first key phase of ongoing efforts to monitor the status of the world’s plants. More than 20% of plant species assessed are threatened with extinction, and the habitat with the most threatened species is overwhelmingly tropical rain forest, where the greatest threat to plants is anthropogenic habitat conversion, for arable and livestock agriculture, and harvesting of natural resources. Gymnosperms (e.g. conifers and cycads) are the most threatened group, while a third of plant species included in this study have yet to receive an assessment or are so poorly known that we cannot yet ascertain whether they are threatened or not. This study provides a baseline assessment from which trends in the status of plant biodiversity can be measured and periodically reassessed