Mapping and validating predictions of soil bacterial biodiversity using European and national scale datasets

Recent research has highlighted strong correlations between soil edaphic parameters and bacterial biodiversity. Here we seek to explore these relationships across the European Union member states with respect to mapping bacterial biodiversity at the continental scale. As part of the EU FP7 EcoFINDERs project, bacterial communities from 76 soil samples taken across Europe were assessed from eleven countries encompassing Arctic to Southern Mediterranean climes, representing a diverse range of soil types and land uses (grassland, forest and arable land). We found predictable relationships between community biodiversity (ordination site scores) and land use factors as well as soil properties such as pH. Based on the modelled relationship between soil pH and bacterial biodiversity found for the surveyed soils, we were able to predict biodiversity in ∼1000 soils for which soil pH data had been collected as part of national scale monitoring. We then performed interpolative mapping utilising existing EU wide soil pH data to present the first map of bacterial biodiversity across the EU member states. The predictive accuracy of the map was assessed again using the national scale data, but this time contrasting the EU wide spatial predictions with point data on bacterial communities. Generally the maps were useful at predicting broad extremes of biodiversity reflective of low or high pH soils, though predictive accuracy was limited for Britain particularly for organic/acidic soil communities. Spatial accuracy could however be increased by utilising published maps of soil pH calculated using geostatistical approaches at both global and national scales. These findings will contribute to wider efforts to predict and understand the spatial distribution of soil biodiversity at global scales. Further work should focus on enhancing the predictive power of such maps, by harmonising global datasets on soil conditioning parameters, soil properties and biodiversity; and the continued efforts to advance the geostatistical modelling of specific components of soil biodiversity at local to global scales

A Tale of Two Disks: Mapping the Milky Way with the Final Data Release of APOGEE

We present new maps of the Milky Way disk showing the distribution of metallicity ([Fe/H]), $\alpha$-element abundances ([Mg/Fe]), and stellar age, using a sample of 66,496 red giant stars from the final data release (DR17) of the Apache Point Observatory Galactic Evolution Experiment (APOGEE) survey. We measure radial and vertical gradients, quantify the distribution functions for age and metallicity, and explore chemical clock relations across the Milky Way for the low-$\alpha$ disk, high-$\alpha$ disk, and total population independently. The low-$\alpha$ disk exhibits a negative radial metallicity gradient of $-0.06 \pm 0.001$ dex kpc$^{-1}$, which flattens with distance from the midplane. The high-$\alpha$ disk shows a flat radial gradient in metallicity and age across nearly all locations of the disk. The age and metallicity distribution functions shift from negatively skewed in the inner Galaxy to positively skewed at large radius. Significant bimodality in the [Mg/Fe]-[Fe/H] plane and in the [Mg/Fe]-age relation persist across the entire disk. The age estimates have typical uncertainties of $\sim0.15$ in $\log$(age) and may be subject to additional systematic errors, which impose limitations on conclusions drawn from this sample. Nevertheless, these results act as critical constraints on galactic evolution models, constraining which physical processes played a dominant role in the formation of the Milky Way disk. We discuss how radial migration predicts many of the observed trends near the solar neighborhood and in the outer disk, but an additional more dramatic evolution history, such as the multi-infall model or a merger event, is needed to explain the chemical and age bimodality elsewhere in the Galaxy.Comment: 41 pages, 32 figures, accepted to Ap

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The establishment, maintenance, and adaptation of high- and low-impact chronic pain: a framework for biopsychosocial pain research

We present a framework for the study of states of chronic pain and transitions between those states. We capture in the framework the dynamic nature of pain: people live with pain that changes over time. First, we offer definitions of both acute and chronic pain and explore the contextual considerations related to the common use of this temporal dichotomy. Second, we promote the importance of incorporating the impact pain has on a person's life. Finally, we discuss the challenges and opportunities inherent in implementing this common approach. Our goal is to produce a framework for the study of the development, maintenance, and resolution of chronic pain. Whether a single brief event or a constant feature of life, pain interrupts to prioritise protection, interferes with activity, reduces quality of life, and can alter identity.44 Protection is achieved by escape from harm, avoidance of perceived danger, withdrawal for respite and repair, and communication of incapacity and environmental risk; longer-term protection is achieved by learning the cues for pain and injury.53 From this perspective, pain is most usefully considered a need state, fundamentally a motivational drive to protect.49 This approach centres our attention on the consequences of pain for the person in their context, on its duration and its impact

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD

Proceedings of Abstracts, School of Physics, Engineering and Computer Science Research Conference 2022

© 2022 The Author(s). This is an open-access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. For further details please see https://creativecommons.org/licenses/by/4.0/. Plenary by Prof. Timothy Foat, ‘Indoor dispersion at Dstl and its recent application to COVID-19 transmission’ is © Crown copyright (2022), Dstl. This material is licensed under the terms of the Open Government Licence except where otherwise stated. To view this licence, visit http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: [email protected] present proceedings record the abstracts submitted and accepted for presentation at SPECS 2022, the second edition of the School of Physics, Engineering and Computer Science Research Conference that took place online, the 12th April 2022

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

The Public Repository of Xenografts enables discovery and randomized phase II-like trials in mice

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease