bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minute virus of mice NS1 redirects casein kinase 2 specificity to suppress the ATR DNA damage response pathway during infection
Authors: Etingov Igor , Pintel David J. 
Published: November 2024

ABSTRACT

During infection the autonomous parvovirus minute virus of mice (MVM) generates extensive DNA damage which facilitates virus replication and induces a cellular DNA damage response (DDR) driven by the ataxia telangiectasia mutated (ATM) kinase. Atypically, the ataxia telangiectasia and Rad-3-related (ATR) DDR pathway remains inactive. Upon DNA damage ATR is normally recruited to single-stranded DNA sequences formed at genomic DNA damage sites, and while within a multiprotein complex activates, via phosphorylation, the key DDR regulator checkpoint kinase 1 (Chk1). Inactivation of ATR during MVM infection leads to the accumulation of damaged DNA and enhancement of virus replication. Although ATR is inactivated, we show that during infection, the Chk1 activation pathway downstream of the initial ATR activating events remained functional. Activation of ATR, and consequently of Chk1, requires interaction with TopBP1, which itself is maintained in proximity to ATR by interaction with the phosphorylated S387 residue of Rad9, part of the Rad9-Hus1-Rad1 (911) complex. Both MVM infection and MVM NS1 overexpression inhibited Rad9 S387 phosphorylation and subsequent ATR activation. ATR inactivation during infection was suppressed by expression of Rad9 bearing a phosphomimetic 387 residue, indicating that this site, and the function it served, was the target of NS1 inhibition. NS1 interaction with CK2α and CK2α enzymatic activity was both required to prevent ATR activation, indicating MVM retargeted this kinase’s activity during infection. Inhibition of the protein phosphatase 2C (PP2C) prevented Rad9 S387 dephosphorylation and Chk1 inactivation during MVM infection and NS1 overexpression revealing its role in the pathway’s suppression.

IMPORTANCE
Infection by the parvovirus minute virus of mice (MVM) causes significant DNA damage and induces a potent DNA damage response (DDR) which the virus exploits to further its replication. The cell responds to infection with an ATM-regulated DDR; however, atypically, the ATR-regulated DDR pathway is disabled during infection. This prevents Chk1 activation, thus allowing the accumulation of damaged DNA which facilitates virus replication. We describe here how MVM, and specifically the main viral replication protein NS1, inhibits ATR activation. Activation of ATR, and consequently Chk1, requires TopBP1 localization into the activating complex via its interaction with a phosphorylated residue of Rad9. We show that NS1 redirects casein kinase 2 to activate a phosphatase in the PP2C family which causes dephosphorylation of this critical residue, thus inhibiting ATR activation. This work provides mechanistic insight into one of the ways by which parvoviruses modify the host DDR response to facilitate their replication.
Acarbose impairs gut
Bacteroides
growth by targeting intracellular glucosidases
Authors: Brown Haley A. , Morris Adeline L. , Pudlo Nicholas A. , Hopkins Ashley E. , Martens Eric C. , Golob Jonathan L. , Koropatkin Nicole M. 
Published: November 2024

ABSTRACT

Acarbose is a type 2 diabetes medicine that prevents dietary starch breakdown into glucose by inhibiting host amylase and glucosidase enzymes. Numerous gut species in the
Bacteroides
genus enzymatically break down starch and change in relative abundance within the gut microbiome in acarbose-treated individuals. To mechanistically explain this observation, we used two model starch-degrading
Bacteroides
,
Bacteroides ovatus
(Bo), and
Bacteroides thetaiotaomicron
(Bt). Bt growth on starch polysaccharides is severely impaired by acarbose, whereas Bo growth is much less affected by the drug. The
Bacteroides
use a starch utilization system (Sus) to grow on starch. We hypothesized that Bo and Bt Sus enzymes are differentially inhibited by acarbose. Instead, we discovered that although acarbose primarily targets the Sus periplasmic GH97 enzymes in both organisms, the drug affects starch processing at multiple other points. Acarbose competes for transport through the TonB-dependent SusC proteins and binds to the Sus transcriptional regulators. Furthermore, Bo expresses a non-Sus GH97 (BoGH97D) when grown in starch with acarbose. The Bt homolog, BtGH97H, is not expressed in the same conditions, nor can overexpression of BoGH97D complement the Bt growth inhibition in the presence of acarbose. This work informs us about unexpected complexities of Sus function and regulation in
Bacteroides
, including variation between related species. Furthermore, this indicates that the gut microbiome may be a source of variable response to acarbose treatment for diabetes.

IMPORTANCE

Acarbose is a type 2 diabetes medication that works primarily by stopping starch breakdown into glucose in the small intestine. This is accomplished by the inhibition of host enzymes, leading to better blood sugar control via reduced ability to derive glucose from dietary starches. The drug and undigested starch travel to the large intestine where acarbose interferes with the ability of some bacteria to grow on starch. However, little is known about how gut bacteria interact with acarbose, including microbes that can use starch as a carbon source. Here, we show that two gut species,
Bacteroides ovatus
(Bo) and
Bacteroides thetaiotaomicron
(Bt), respond differently to acarbose: Bt growth is inhibited by acarbose, while Bo growth is less affected. We reveal a complex set of mechanisms involving differences in starch import and sensing behind the different Bo and Bt responses. This indicates the gut microbiome may be a source of variable response to acarbose treatment for diabetes via complex mechanisms in common gut microbes.
Beyond boundaries: Depositional environment controls on erodibility, process, and form in rivers incising sedimentary bedrock
Authors: Colaianne Nicholas J. , Shobe Charles M. , Moler Joseph , Benison Kathleen C. , Chilton Kristin D. 
Published: November 2024

Abstract
Bedrock rivers adjust to the properties of the rock into which they incise, imprinting the geologic past on Earth's surface. We compared rock properties and channel form along the Dry Fork in the Allegheny Mountains, West Virginia, as it crosses between Mississippian sandstone and carbonate rock units, to investigate how the depositional history of channel-margin bedrock influences modern channel form. We used thin-section petrography to interpret site-specific depositional environments. We quantified rock strength with point-load testing, discontinuity spacing by measuring bed and fracture spacing, and channel form through cross-section surveys. Petrography indicates that the sandstone was likely deposited in an alluvial fan, while the carbonate formed in a shallow-marine environment. The sandstone has modestly higher point-load strength than the carbonate, but the units differ more dramatically in their discontinuity spacing. The sandstone is thinly (3–10 cm) bedded and densely (50–100 cm) fractured; the carbonate has thicker (45 cm) beds and sparser (180–300 cm) fractures. Sandstone channel cross sections are wider, shallower, and rougher, whereas carbonate cross sections are narrower, deeper, and smoother. Results suggest that a transition from plucking-dominated erosion in the discontinuity-rich sandstone to abrasion- and/or dissolution-dominated erosion in the discontinuity-poor carbonate, rather than differences in rock strength, drives observed morphologic differences. Differences in discontinuity spacing might arise from differential bed thickness between the two units, both because bed boundaries are discontinuities and because thinner beds lead to more densely spaced fractures. We hypothesize that depositional dynamics—the unsteady deposition of an alluvial fan resulting in thin beds versus steady, shallow-marine deposition that deposited thicker beds—explain the observed differences in bed thickness, discontinuity spacing, and modern erosion process dominance and channel form, emphasizing how modern Earth-surface processes are contingent on the geologic past.
Recognising uncertainty: an integrated framework for palliative care in perinatal medicine
Authors: Wilkinson Dominic , Bertaud Sophie , Mancini Alexandra , Murdoch Edile 
Published: November 2024

In perinatal medicine, the number of babies with life-limiting or life-threatening conditions is increasing and the benefits of providing palliative care with a holistic, interdisciplinary approach are well documented. It can be particularly challenging, however, to integrate palliative care into routine care where there exists uncertainty about a baby’s diagnosis or potential outcome.This framework, developed collaboratively by the British Association of Perinatal Medicine (BAPM) and the Association of Paediatric Palliative Medicine (APPM), offers supportive guidance for all healthcare professionals working in perinatal medicine across antenatal and neonatal services. It explicitly acknowledges that palliative care is not just for babies who are dying or who will certainly die in early life; incorporating a palliative approach into antenatal and neonatal care for all babies with an uncertain outcome can be particularly valuable. The framework provides guidance on recognising babies who may benefit from palliative care and outlines the key elements of perinatal palliative care: holistic family support, empowering parents to be parents, parallel planning, symptom management and loss and bereavement care. It provides recommendations for the delivery of palliative care services, advocating for a unified approach that involves all members of the perinatal team, supported by specialist services as needed.This framework calls for a shift in the philosophy and practice of perinatal care to integrate palliative care into the everyday and to recognise and embrace the challenge of uncertain prognosis.
Young adult reflections on life experiences following preterm birth: a cross-sectional descriptive study
Authors: Mackay Cheryl Anne , Gray Caitlin , Campbell Catherine , Sharp Mary 
Published: November 2024

BackgroundIncreasingly, preterm-born children are entering adulthood as survival at earlier gestational ages improves. However, there is little understanding of the lived experience in preterm-born adults.MethodsA cross-sectional descriptive study was conducted including young adults from a regional birth cohort of infants born <33 weeks in Western Australia. Participants provided written reflections of their experiences growing up and included messages for future families experiencing preterm birth. Content analysis was conducted according to SRQR (Standards for Reporting Qualitative Research) guidelines. Ethics approval was granted by the Women and Newborn Health Service Ethics Committee.ResultsForty-one adults reflected on their life experiences, and 31 included messages for future families. Two predominant themes were (1) neonatal experiences and (2) experiences from childhood and adulthood which were divided into ‘positive’ and ‘negative’ subthemes. Participants made 44 references to the neonatal period: 31 (70.5%) ‘challenging’ including sickness (17, 54.8%), uncertainty (10, 32.3%), family separation (4, 12.9%); and 13 (29.5%) ‘positive’ including survival (6, 46.2%), support (5, 38.5%), strength (2, 15.4%). Childhood and adulthood was described as ‘positive’ in 119 (73.5%) references including a good life (41, 33.3%), supportive family (20, 16.3%), success (18, 14.6%), strength (18, 14.6%), gratitude (15, 12.2%), positive self-talk (7, 5.7%); and ‘negative’ in 43 (26.5%) including health challenges (19, 44.2%), school difficulties (10, 23.3%), family difficulties (9, 20.9%). Messages for future families included what to expect (56, 75.7%) and helpful advice (18, 24.3%).ConclusionOur preterm-born young adults predominantly describe positive life experiences of childhood and adulthood balanced with an awareness of particular challenges.
Clinical characteristics and optical coherence tomography features of ocular toxoplasmosis inHIV-positive patients: report 1
Authors: Patel Anamika , Saldanha Merlin , Kelagaonkar Anup , Yediballi Thorani , Testi Ilaria , Pavesio Carlos , Pathengay Avinash 
Published: November 2024

PurposeThis study aimed to identify the various clinical characteristics and ocular imaging features of ocular toxoplasmosis (OT) in HIV patients.MethodsObservational retrospective study of 52 eyes of 38 HIV patients with OT.Results68% of patients were male. 53.8% of eyes had keratic precipitates, anterior chamber cells were seen in 61.5%. 57.69% (n=30) eyes had de novo presentation of retinitis and 42.3% (n=22) of eyes had a retinochoroidal scar at presentation. Bilateral presentation was seen in 37% (n=14). Unifocal retinitis was noted in 38.4% (n=20) and 61.5% of eyes had multifocal (multizonal) retinitis (n=32). The most common multizonal involvement was noted in combined zone 1+2(n=14, 26.9%). The average horizontal and vertical measurements retinitis was 8.35 mm and 7.48 mm, respectively. The average area of retinitis was 66.2 mm2. Localised posterior vitreous detachment was seen in 83% of eyes and posterior hyaloid precipitates were noted in (n=7,39%) of eyes. Retinitis without retinal pigment epithelium elevation occurred in 88.8% of cases, compared with retinitis with retinal pigment epithelium elevation seen in 44.4% of eyes. 50% of eyes had thickened choroid beneath the retinitis lesion. Other unique signs of optical coherence tomography (OCT) noted were angular signs of Henle fibre layer hyper-reflectivity sign (n=1), halo lesions with central hypo (n=3) and choroidal excavation (n=1).ConclusionsOT in HIV patients presents with large, bilateral, multifocal retinitis, generally devoid of haemorrhages and can rarely have central clearing. These lesions may present with or without a previous retinochoroidal scar. These lesions have horizontal spread and may not always have thickened choroid on OCT.
Stability and predictability of Bayley Scales of Infant and Toddler Development: evidence from a south Indian birth cohort prospective study
Authors: Koshy Beena , Srinivasan Manikandan , Scharf Rebecca , Strand Tor A , Mohan Venkata Raghava , Beulah Rachel , John Sushil , Muliyil Jayaprakash , Kang Gagandeep 
Published: November 2024

ObjectivesThere is limited information about the stability and predictability of Bayley Scales of Infant and Toddler Development (BSID) assessing child development in low- and middle-income settings. The objective of the present study was to analyse stability and predictive validity of BSID using an existing birth cohort.DesignProspective birth cohort follow-up study.Setting and participantsA community-based birth cohort of 251 newborns was recruited and followed-up in urban Vellore, South India, until 9 years of age. Using BSID-III, child development was measured at 6, 15, 24 and 36 months. Cognition was assessed using the Wechsler Preschool Primary Scales of Intelligence at 5 years, and the Malin’s Intelligence Scale for Indian Children scale at 7 and 9 years of age. The stability of BSID measurements across time points was expressed by intraclass correlation (ICC) and concordance correlation coefficients. Linear regression was used to describe the predictability of BSID-III of cognition at 5, 7 and 9 years.ResultsThe ICC for domain-wise BSID scores between time points of measurement suggested a weak correlation. The BSID scores at 36 months correlated best with Full-Scale Intelligence Quotient (FSIQ) at 5 years (r: 0.40–0.49), 7 years (r: 0.35–0.48) and 9 years (r: 0.36–0.38). BSID scores at 36 months predicted FSIQ better at 5, 7 and 9 years with R2ranging from 23.3% to 28.6%, when compared with 24 months BSID scores (R2- 16.0% to 25.9%).ConclusionPoor stability and predictability of BSID warrant caution in the predictive projection of early childhood assessments. Better predictability of future cognition of 36 months’ BSID scores highlights its advantage over the 24 months’ assessment.
Scoping review of review methodologies used for guiding evidence-based practice in critical care: a protocol
Authors: Davies Hugh , Watkins Paige Marie , Freeman-Sanderson Amy , Nickels Marc Richard , Ankravs Melissa , Ridley Emma J , Brooks Kate , Udy Andrew A , Massey Debbie 
Published: November 2024

IntroductionA literature review provides a synthesis on a selection of papers about a specific topic. This is used by health practitioners in critical care as in other specialities when making clinical practice decisions. The task of knowledge transfer through the review process of scientific papers involves a variety of methodologies with differing expectations on the quality and rigour that is applied. Exploration on the types of review methodologies selected by the authors of critical care literature may reveal the extent that choice of methodology has on how papers are selected and appraised may influence evidence-based practice recommendations. This scoping review aims to systematically map the breadth of current literature with the objective of identifying the types of review methodologies used by interdisciplinary authors synthesising the literature in adult critical care.Methods and analysisArksey and O’Malley’s approach in conducting a scoping review will be followed and use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review guidelines in the reporting of findings. Papers with diverse review methodologies will be identified by searching four electronic databases (CINAHL/EBSCO, MEDLINE/PubMed, Scopus and Embase). Grey literature will be excluded due to the clinical nature of the review question. Search results will be reviewed independently by two researchers based on title and abstract followed by full-text papers that meet inclusion criteria. Characteristics of review methodologies will be collected and analysed using a tool developed by the interdisciplinary research team.Ethics and disseminationThis scoping review will provide an overview of the types of review methodologies most often undertaken with the interdisciplinary research team synthesising the quality of critical care literature. Scrutiny will be applied to the review methodologies selected, the challenges faced and current trends in the transfer of knowledge towards evidence-based practice. The results will be disseminated by publication through a peer-reviewed journal and by presentation as a part of conference proceedings. Ethics approval is not applicable for this scoping review.
Constipation among workers with depression/anxiety: a retrospective study using a claims database and survey data in Japan
Authors: Karasawa Yusuke , Nozawa Kazutaka , Nomoto Keisuke , Fukudo Shin 
Published: November 2024

ObjectivesTo investigate the prevalence, associated factors, treatment status and burden of constipation in workers with depression or anxiety.Study designThis was a retrospective observational study using a pre-existing database.SettingClaims data from October to November 2022 and data from the survey conducted in November 2022 were extracted from the database.ParticipantsThis study included self-reported workers who completed the survey, after excluding those with major mental disorders diagnosed as distinct from depression or anxiety and constipation due to organic diseases identified by International Classification of Diseases (ICD-10) codes.Outcome measuresThe subjects were divided into three groups: treated depression/anxiety, untreated depression/anxiety and no depression/anxiety. The prevalence of constipation, factors associated with constipation and medications prescribed for constipation were analysed. Work productivity and quality of life (QOL) were compared between three subgroups based on constipation status: treated constipation, untreated constipation and no constipation subgroup.ResultsOf the 18 585 respondents in the analysis population, 950 respondents (5.1%) were classified into the treated depression/anxiety group, 6035 respondents (32.5%) into the untreated depression/anxiety group and the remaining respondents into the no depression/anxiety group (11 600 (62.4%)). The prevalence of constipation was 22.5% in the treated group, 22.3% in the untreated group and 10.4% in the no depression/anxiety group, respectively. Depression and anxiety severity were independently associated with an increased risk of constipation. In all groups, the most commonly prescribed drug class was osmotic laxatives. Work productivity and QOL tended to indicate a greater burden in the untreated constipation subgroup than in the treated or no constipation subgroups.ConclusionsThe prevalence of constipation was twice as high if workers had depression/anxiety. Considering that the comorbidity of constipation with mental disorders may increase multiple burdens, appropriate medical interventions are required to treat both mental (depression/anxiety) and physical (constipation) conditions. This should be widely recognised by physicians and employers.
Effectiveness and cost-effectiveness of guided self-help for depression for autistic adults: the Autism Depression Trial (ADEPT-2) – protocol for a multicentre, randomised controlled trial of a remotely delivered low-intensity intervention
Authors: Mckeon Holly Emily , Cotton Leonora , Aldridge Rona , Cape Alison , Clout Madeleine , Cooper Kate , Dagnan Dave , Dawn Ed , Frost Jessica , Georgakopoulou Aikaterini , Garfield Kirsty , Horwood Jeremy , Ingham Barry , Jervis Vicky , Kessler David , Langdon Peter , Metcalfe Chris , Rai Dheeraj , Realpe Alba , Russell Christine , Sheridan Hannah , Slowinska Karolina , Thorn Joanna , Wen Liping , Wiles Nicola , Russell Ailsa 
Published: November 2024

IntroductionDepression is three to four times more prevalent in autistic people and is related to reduced quality of life. There is a need for empirically supported psychological interventions for depression specifically adapted to meet the needs of autistic adults. ADEPT-2 aims to establish the clinical and cost-effectiveness of an adapted low-intensity psychological intervention (guided self-help) for depression in autistic adults.Methods and analysisA two parallel-group multicentre pragmatic randomised controlled trial investigating the effectiveness of GSH for depression in autistic adults. Participants (n=248) aged ≥18 years with a clinical diagnosis of autism currently experiencing depression will be randomised to GSH or treatment as usual (TAU). GSH is a low-intensity psychological intervention based on the principles of behavioural activation adapted for autism. GSH comprises informational materials for nine individual sessions facilitated online by a GSH coach who has received training and supervision in delivering the intervention. The primary outcome will be Beck Depression Inventory-II depression scores at 16 weeks post randomisation with follow-up measures at 32 and 52 weeks. Additional measures of anxiety, patient-rated global improvement, quality of life, work and social adjustment, positive and negative affect will be measured 16 and 52 weeks post randomisation. The primary health economic analysis will assess the cost-effectiveness of GSH compared with TAU over 52 weeks, from a societal perspective including the National Health Service, personal social services, personal expenses, voluntary services and productivity. An embedded qualitative study will explore the acceptability, experiences and adherence of participants and therapists to treatment principles.Ethics and disseminationThis trial has been approved by the East of England - Essex Research Ethics Committee on 10 June 2022 (REC Reference number: 22/EE/0091). The findings of the research will be submitted for publication in peer-reviewed journals and disseminated in an appropriate format to trial participants and the wider public.Trial registration numberISRCTN17547011.