Transcriptome Analysis of CD4+ T Cells in Coeliac Disease Reveals Imprint of BACH2 and IFNγ Regulation

peer-reviewedData Availability: The raw sequencing reads (FASTQ files) and sequence read counts mapped to UCSC hg19 for each of the 74 transcriptomes sequenced in this study have been deposited at Gene Expression Omnibus (GEO) accession GSE69549.This project was funded by Science Foundation Ireland Grant number 09/IN.1/B2640 to RM.Genetic studies have to date identified 43 genome wide significant coeliac disease susceptibility (CD) loci comprising over 70 candidate genes. However, how altered regulation of such disease associated genes contributes to CD pathogenesis remains to be elucidated. Recently there has been considerable emphasis on characterising cell type specific and stimulus dependent genetic variants. Therefore in this study we used RNA sequencing to profile over 70 transcriptomes of CD4+ T cells, a cell type crucial for CD pathogenesis, in both stimulated and resting samples from individuals with CD and unaffected controls. We identified extensive transcriptional changes across all conditions, with the previously established CD gene IFNy the most strongly up-regulated gene (log2 fold change 4.6; Padjusted = 2.40x10-11) in CD4+ T cells from CD patients compared to controls. We show a significant correlation of differentially expressed genes with genetic studies of the disease to date (Padjusted = 0.002), and 21 CD candidate susceptibility genes are differentially expressed under one or more of the conditions used in this study. Pathway analysis revealed significant enrichment of immune related processes. Co-expression network analysis identified several modules of coordinately expressed CD genes. Two modules were particularly highly enriched for differentially expressed genes (P</iframe

The Use of a Pressure-Indicating Sensor Film to Provide Feedback upon Hydrogel-Forming Microneedle Array Self-Application In Vivo

PURPOSE: To evaluate the combination of a pressure-indicating sensor film with hydrogel-forming microneedle arrays, as a method of feedback to confirm MN insertion in vivo. METHODS: Pilot in vitro insertion studies were conducted using a Texture Analyser to insert MN arrays, coupled with a pressure-indicating sensor film, at varying forces into excised neonatal porcine skin. In vivo studies involved twenty human volunteers, who self-applied two hydrogel-forming MN arrays, one with a pressure-indicating sensor film incorporated and one without. Optical coherence tomography was employed to measure the resulting penetration depth and colorimetric analysis to investigate the associated colour change of the pressure-indicating sensor film. RESULTS: Microneedle insertion was achieved in vitro at three different forces, demonstrating the colour change of the pressure-indicating sensor film upon application of increasing pressure. When self-applied in vivo, there was no significant difference in the microneedle penetration depth resulting from each type of array, with a mean depth of 237 μm recorded. When the pressure-indicating sensor film was present, a colour change occurred upon each application, providing evidence of insertion. CONCLUSIONS: For the first time, this study shows how the incorporation of a simple, low-cost pressure-indicating sensor film can indicate microneedle insertion in vitro and in vivo, providing visual feedback to assure the user of correct application. Such a strategy may enhance usability of a microneedle device and, hence, assist in the future translation of the technology to widespread clinical use

Pho4 mediates phosphate acquisition in Candida albicans and is vital for stress resistance and metal homeostasis

ACKNOWLEDGMENTS We thank Karl Kuchler for the C. albicans superoxide dismutase mutants used in this study. This work was funded by a Medical Research Council Doctoral Training Program studentship to M.A.C.I.; Wellcome Trust Grants 089930 to J.Q., 080088 to A.J.P.B., and 097377 to J.Q., A.J.P.B., and L.P.E.; Biotechnology and Biological Sciences Research Council Grants BB/K016393/1 to J.Q. and BB/F00513X/1 and BB/K017365/1 to A.J.P.B.; European Research Council STRIFE Advanced Grant ERC-2009-AdG-249793 to A.J.P.B.; and Wellcome Trust and Royal Society Sir Henry Dale Fellowship 098375/Z/12/Z to K.J.W. and E.T. The funders had no role in study design, data collection, or interpretation or the decision to submit the work for publication.Peer reviewedPublisher PD

PhotoAffinity bits : a photoaffinity-based fragment screening platform for efficient identification of protein ligands

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutic

Demystifying academics to enhance university-business collaborations in environmental science

In countries globally there is intense political interest in fostering effective university-business collaborations, but there has been scant attention devoted to exactly how an individual scientist's workload (i.e. specified tasks) and incentive structures (i.e. assessment criteria) may act as a key barrier to this. To investigate this an original, empirical dataset is derived from UK job specifications and promotion criteria, which distil universities' varied drivers into requirements upon academics. This work reveals the nature of the severe challenge posed by a heavily time-constrained culture; specifically, tension exists between opportunities presented by working with business and non-optional duties (e.g. administration and teaching). Thus, to justify the time to work with business, such work must inspire curiosity and facilitate future novel science in order to mitigate its conflict with the overriding imperative for academics to publish. It must also provide evidence of real-world changes (i.e. impact), and ideally other reportable outcomes (e.g. official status as a business' advisor), to feed back into the scientist's performance appraisals. Indicatively, amid 20-50 key duties, typical full-time scientists may be able to free up to 0.5 day per week for work with business. Thus specific, pragmatic actions, including short-term and time-efficient steps, are proposed in a "user guide"to help initiate and nurture a long-term collaboration between an early- to mid-career environmental scientist and a practitioner in the insurance sector. These actions are mapped back to a tailored typology of impact and a newly created representative set of appraisal criteria to explain how they may be effective, mutually beneficial and overcome barriers. Throughout, the focus is on environmental science, with illustrative detail provided through the example of natural hazard risk modelling in the insurance sector. However, a new conceptual model of academics' behaviour is developed, fusing perspectives from literature on academics' motivations and performance assessment, which we propose is internationally applicable and transferable between sectors. Sector-specific details (e.g. list of relevant impacts and user guide) may serve as templates for how people may act differently to work more effectively together

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis (DEFINE):A Phase Ib/IIa Randomised Controlled Trial

RATIONALE: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. OBJECTIVES: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. METHODS: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. MEASUREMENTS AND MAIN RESULTS: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2–7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. CONCLUSIONS: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020–002230–32)

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

TOI-5126: A hot super-Neptune and warm Neptune pair discovered by TESS\textit{TESS} and CHEOPS\textit{CHEOPS}

We present the confirmation of a hot super-Neptune with an exterior Neptune companion orbiting a bright (V = 10.1 mag) F-dwarf identified by the $\textit{Transiting Exoplanet Survey Satellite}$ ($\textit{TESS}$). The two planets, observed in sectors 45, 46 and 48 of the $\textit{TESS}$ extended mission, are $4.74^{+0.16}_{-0.14}$ $R_{\oplus}$ and $3.86^{+0.17}_{-0.16}$ $R_{\oplus}$ with $5.4588385^{+0.0000070}_{-0.0000072}$ d and $17.8999^{+0.0018}_{-0.0013}$ d orbital periods, respectively. We also obtained precise space based photometric follow-up of the system with ESAs $\textit{CHaracterising ExOplanets Satellite}$ ($\textit{CHEOPS}$) to constrain the radius and ephemeris of TOI-5126 b. TOI 5126 b is located in the "hot Neptune Desert" and is an ideal candidate for follow-up transmission spectroscopy due to its high predicted equilibrium temperature ($T_{eq} = 1442^{+46}_{-40}$ K) implying a cloud-free atmosphere. TOI-5126 c is a warm Neptune ($T_{eq}= 971^{+31}_{-27}$ K) also suitable for follow-up. Tentative transit timing variations (TTVs) have also been identified in analysis, suggesting the presence of at least one additional planet, however this signal may be caused by spot-crossing events, necessitating further precise photometric follow-up to confirm these signals.Comment: Accepted in MNRAS, 18 pages, 14 figure