bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐Wide Screening in Haploid Stem Cells Reveals Synthetic Lethality Targeting MLH1 and TP53 Deficient Tumours
Authors: Cashman Rivki , Haim‐Abadi Guy , Lezmi Elyad , Philip Hagit , Nissenbaum Jonathan , Viner‐Breuer Ruth , Kozulin Chen , Golan‐Lev Tamar , Gadban Aseel , Spinner‐Potesky Shiri , Yanuka Ofra , Kopper Oded , Benvenisty Nissim 
Published: January 2025

ABSTRACTSynthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death, whereas each of them separately does not. Synthetic lethality can be a useful tool in personalised oncology. MLH1 is a cancer‐related gene that has a central role in DNA mismatch‐repair and TP53 is the most frequently mutated gene in cancer. To identify genetic events that can lead to tumour death once either MLH1 or TP53 is mutated, a genome‐wide genetic screening was performed. Thus, mutations in all protein‐coding genes were introduced into haploid human embryonic stem cells (hESCs) with and without loss‐of‐function mutations in the MLH1 or TP53 genes. These experiments uncovered a list of putative hits with EXO1, NR5A2, and PLK2 genes for MLH1, and MYH10 gene for TP53 emerging as the most promising candidates. Synthetic lethal interactions of these genes were validated genetically or chemically using small molecules that inhibit these genes. The specific effects of SR1848, which inhibits NR5A2, ON1231320 or BI2536, which inhibits PLK2, and blebbistatin, which inhibits MYH10, were further validated in cancer cell lines. Finally, animal studies with CCL xenografts showed the selective effect of the small molecule BI2536 on MLH1‐null tumours and of blebbistatin on TP53‐mutated tumours. Thus, demonstrating their potential for personalised medicine, and the robustness of genetic screening in haploid hESCs in the context of cancer therapeutics.
Exploring the link between inflammation and brain function after metabolic‐bariatric surgery: A year‐long fMRI study
Authors: Szwed Magdalena , Falkowski Adrian , Seitz‐Holland Johanna , Borkowska Alina , Michalik Maciej , Kubicki Marek , Szwed Krzysztof 
Published: January 2025

AbstractBackgroundMetabolic‐bariatric surgery (MBS) transcends weight loss and offers wide‐ranging health benefits, including positive effects on brain function. However, the mechanisms behind these effects remain unclear, particularly in the context of significant postoperative changes in the inflammatory profile characteristic of MBS. Understanding how inflammation influences postoperative brain function can enhance our decision‐making on patient eligibility for MBS and create new opportunities to improve the outcomes of this popular treatment.ObjectiveTo identify brain regions where spontaneous neural activity and functional connectivity are linked with the evolving inflammatory profile following MBS.MethodsWe investigated the relationship between the perioperative ratio of interleukin (IL)‐6 to IL‐10 and both the amplitude of low‐frequency fluctuation (ALFF) and functional connectivity across 375 brain regions. We examined 36 patients at three time points: 1 week before, and 3 and 12 months after laparoscopic sleeve gastrectomy.ResultsInitially, the IL‐6/IL‐10 ratio increased during the early postoperative period but then decreased to levels lower than the preoperative values 1 year after surgery. We observed that ALFF in four subcortical structures decreased with a rising IL‐6/IL‐10 ratio and increased with a declining ratio. Conversely, 16 cortical regions displayed the opposite trend. Additionally, functional connectivity between the left insula and bilateral medial prefrontal cortex increased with a rising IL‐6/IL‐10 ratio and decreased with a declining ratio.ConclusionsOur study is the first to identify brain regions significantly linked to inflammation after MBS. Importantly, many of the discovered areas were previously shown to be involved in the pathogenesis of obesity or are targets of contemporary medical treatments. Consequently, our findings offer valuable insights for future obesity research, especially in the context of potential therapeutic opportunities.
Estimation of Annual Productivity of Sown Rainfed Grasslands Using Machine Learning
Authors: Morais Tiago G. , Jongen Marjan , Tufik Camila , Rodrigues Nuno R. , Gama Ivo , Serrano João , Domingos Tiago , Teixeira Ricardo F. M. 
Published: January 2025

ABSTRACTGrasslands play a critical role in providing diverse ecosystem services. Sown biodiverse pastures (SBP) rich in legumes are an important agricultural innovation that increases grassland productivity and reduces the need for fertilisers. This study developed a machine learning model to obtain spatially explicit estimations of the productivity of SBP, based on field sampling data from five Portuguese farms during four production years (2018–2021) and under two fertilisation regimes (conventional and variable rate). Weather data (such as temperature, precipitation and radiation), soil properties (including sand, silt, clay and pH), terrain characteristics (including elevation, slope, aspect, hillshade and topographic position index), and management data (including fertiliser application) were used as predictors. A variance inflation factor (VIF) approach was used to measure multicollinearity between input variables, leading to only 11 of the 53 input variables being used. Artificial neural network (ANN) methods were used to estimate pasture productivity, and hyper‐parameterization optimization was performed to fine‐tune the model. Plots under variable rate fertilisation were significantly improved by up to 20 kg P ha−1 applied in the same year. Plots under conventional fertilisation benefitted the most from fertilisation in past years. The model demonstrated good generalisation, with similar estimation errors for both the training and test sets: for an average yield of 6096 kg ha−1 in the sample, the root mean squared errors (RMSE) for the training and test sets were respectively 882 and 1125 kg ha−1. These results indicate that the model did not overfit the training data and can be used to estimate SBP productivity maps in the sampled farms. However, further studies are required to asses if the obtained model can be applied to new unseen data.
Laboratory investigation of METTL7A driving MSC osteogenic differentiation through YAP1 translation enhancement via eIF4F recruitment
Authors: Cui Li , Mai Zizhao , Lu Ye , Zheng Jiarong , Lin Pei , Chen Xu , Zheng Yucheng , Lin Yunfan , Guo Bing , Zhao Xinyuan 
Published: January 2025

AbstractAimEffective control of mesenchymal stem cell (MSC) differentiation towards osteogenic lineages is fundamental for bone regeneration. This study elucidates the regulatory role of methyltransferase like 7A (METTL7A) in the osteogenic differentiation of MSCs.MethodologyAlkaline phosphatase staining, Alizarin Red S staining, western blotting, and in vivo studies were conducted to determine the effects of METTL7A depletion or overexpression on the osteogenic differentiation of various types of MSCs. Then the downstream signalling pathways regulated by METTL7A in MSCs were further investigated.ResultsOur findings indicate that METTL7A expression significantly increases during the osteogenic differentiation of MSCs. Furthermore, depletion of METTL7A hindered, whereas its overexpression enhanced, the osteogenic differentiation of MSCs. Mechanistically, METTL7A influences MSC osteogenic differentiation by activating the YAP1‐TEAD1 signalling pathway. It enhances YAP1 expression not only by stabilising YAP1 mRNA but also, crucially, by recruiting the eIF4F complex, thereby boosting the translation efficiency of YAP1 mRNA. Additionally, the YAP1/TEAD1 complex transcriptionally regulates METTL7A expression, creating a positive feedback loop that amplifies osteogenic differentiation.ConclusionsOverall, our study uncovers a previously unknown molecular mechanism of MSC osteogenic differentiation and suggests that activating METTL7A could offer new avenues for enhancing bone regeneration.
High‐voltage electron microscopy analyses for crack‐tip dislocations and their shielding effect on fracture toughness in MgO and Si crystals
Authors: Higashida Kenji , Sadamatsu Sunao , Tanaka Masaki 
Published: January 2025

AbstractIn this study, characteristics of dislocation structures around a crack‐tip in both crystals of MgO and Si were investigated using high‐voltage electron microscopy (HVEM). The interaction between a crack and dislocations was analyzed to discuss the effect of crack‐tip plasticity on fracture toughness. The present paper first demonstrates a dislocation configuration around a crack‐tip in a MgO thin crystal, where the plastic zone called 45°‐shear type is dominant under the plane stress condition. Then, the slip systems necessary for brittle‐to‐ductile transition in ionic crystals with the rock‐salt structure are discussed based on the temperature dependence of stress‐strain relationships and the aspect of crack front observed in NaCl crystals. Second, crack‐tip dislocations near the surface of bulk Si crystals are exhibited based on the 3D analyses using HVEM tomography. We focus on a newfound plastic zone being perpendicular to the crack plane, which is different from either 45°‐shear type or the hinge type generally well‐known. The dislocation loops observed in this plastic zone fundamentally have a crack‐tip shielding effect to increase fracture toughness. Still, in addition, they contribute to activating crack‐tip dislocations by their localized antishielding field. These analyses reveal a fundamental toughening mechanism for crystalline materials.
Vitamin D3–VDR and vitamin A‐RAR affect IL‐13 and IFNγ secretion from human CD4+ T cells directly and indirectly via competition for their shared co‐receptor RXR
Authors: Stanisic Tiana , Ewing Emma Uttrup , Lindell Alma , Al‐Jaberi Fatima , Kongsbak‐Wismann Martin 
Published: January 2025

AbstractThe effects of vitamin D and vitamin A in immune cells are mediated through the vitamin D receptor (VDR) and retinoic acid receptor (RAR), respectively. These receptors share the retinoid X receptor (RXR) co‐factor for transcriptional regulation. We investigated the effects of active vitamin D3 (1,25(OH)2D3) and 9‐cis retinoic acid (9cRA) on T helper (TH)1 and TH2 cytokines and transcription factors in primary human blood‐derived CD4+ T cells. We aimed to address the discrepancies in this field, particularly regarding the effects of 9cRA and the vitamins in combination. 1,25(OH)2D3 upregulated IL‐13 and suppressed IFNγ, while 9cRA had the opposite effects. This was largely independent of a TH1/TH2 phenotype shift. Combined vitamin supplementation produced intermediate cytokine levels, not only through transcriptional regulation by VDR‐RXR and RAR‐RXR but also through 1,25(OH)2D3 counteracting the effects of 9cRA on solely 9cRA‐responsive genes. Similar results were observed in hereditary vitamin D‐resistant rickets (HVDRR) patient T cells, where VDR cannot bind to DNA, indicating that RXR binding to either receptor can limit the other's activity. Additionally, we observed downregulated RAR upon 9cRA supplementation and its re‐localization out of the nucleus upon 1,25(OH)2D3 supplementation, suggesting a mechanism of indirect regulation by VDR. VDR protein levels were also upregulated upon 9cRA supplementation, suggesting a novel negative feedback mechanism of 9cRA transcriptional activity, whereby 9cRA promotes its own competitor. This study sets the stage for future research into the combined immunomodulatory mechanisms of 1,25(OH)2D3 and 9cRA, involving both direct transcriptional regulation and indirect regulation via RXR competitive binding.
Changes in household purchasing of soft drinks following the UK soft drinks industry levy by household income and composition: controlled interrupted time series analysis, March 2014 to November 2019
Authors: Rogers Nina Trivedy , Cummins Steven , Pell David , Rutter Harry , Sharp Stephen J , Smith Richard D , White Martin , Adams Jean 
Published: January 2025

BackgroundThe WHO recommends taxes on sugar sweetened beverages (SSBs) to improve population health. We examined changes in volume of and amount of sugar in purchases of soft drinks according to household income and composition, 19 months following the implementation of the UK soft drinks industry levy.MethodsData were from the Kantar Fast Moving Consumer Goods panel, a market research panel which collects data on weekly household purchases (mean weekly number of households=21 908), March 2014–November 2019. Interrupted time series analysis of volume and sugar purchases was used to estimate absolute and relative differences in the volume and amount of sugar in soft drinks, confectionery and alcohol purchased weekly by household income (<£20 000, £20–50 000 or >£50 000) and composition (presence of children (<16 years) in the household (yes or no)), 19 months after soft drinks industry levy (SDIL) implementation, compared with the counterfactual scenario based on pre-announcement trends and using a control group (toiletries).ResultsBy November 2019, purchased weekly sugar in soft drinks fell by 7.46 g (95% CI: 12.05, 2.87) per household but volumes of drinks purchased remained unchanged, compared with the counterfactual. In low-income households, weekly sugar purchased in soft drinks decreased by 14.0% (95% CI: 12.1, 15.9) compared with the counterfactual but in high-income households increased by 3.4% (1.07, 5.75). Among households with children, sugar purchased decreased by 13.7% (12.1, 15.3) but increased in households without children by 5.0% (3.0, 7.0). Low-income households and those with children also reduced their weekly volume of soft drinks purchased by 5.7% (3.7, 7.7) and 8.5% (6.8, 10.2) respectively. There was no evidence of substitution to confectionary or alcohol.ConclusionIn the second year following implementation of the SDIL, effects on sugar purchased were greatest in those with the highest pre-SDIL purchasing levels (low-income households and those with children). The SDIL may contribute to reducing dietary inequalities.Trial registration numberISRCTN18042742. Registered: August 2017.
Effects of aquatic exercise compared with land-based exercise on the body composition and function of older adults with sarcopenia: protocol for a randomised controlled trial
Authors: Sun PeiJie , Yang Jinfeng , Li Na , Yang Weicheng , Yang Jinqi , Ran Jianxin , Cheng Fang , Liao Yuanpeng 
Published: January 2025

IntroductionSarcopenia is a condition that occurs more frequently in older adults. Although many types of exercise have been used in the treatment of sarcopenia, few studies have been conducted on different interventional environments for sarcopenia. The purpose of this study is to investigate the effects of aquatic exercise and land-based exercise on the body composition and function of participants with sarcopenia.Methods and analysisThis randomised, controlled, single-blinded trial will enrol 45 participants (≥ 65 years) following the diagnostic criteria set by the Asian Working Group for Sarcopenia 2019. Participants will be randomised and assigned to one of three groups (aquatic exercise group, land-based exercise group and control group). Assessments will be conducted four times: initially (before intervention), after 8 weeks (intermediate), after 16 weeks (final) and 16 weeks after the end of intervention (follow-up). The primary outcomes are appendicular skeletal muscle index and handgrip strength, while the secondary outcomes include the Short Physical Performance Battery, 6-minute walk test and the Chinese version of the 36-item short-form of health-related quality of life.Ethics and disseminationEthics approval was obtained from the Ethics Committee of Chengdu Sport University, with permission number CDSUEC2023-125. This study has been registered with the Chinese Clinical Trial Registry (ChiCTR2300077457). All participants will provide written informed consent.Trial registration numberChinese Clinical Trial Registry ChiCTR2300077457.
Tracking Persistent Symptoms in Scotland (TraPSS): a longitudinal prospective cohort study of COVID-19 recovery after mild acute infection
Authors: Sculthorpe Nicholas F , McLaughlin Marie , Cerexhe Luke , Macdonald Eilidh , Dello Iacono Antonio , Sanal-Hayes Nilihan E M , Ingram Joanne , Meach Rachel , Carless David , Ormerod Jane , Hayes Lawrence D 
Published: January 2025

BackgroundCOVID-19 disease results in disparate responses between individuals and has led to the emergence of long coronavirus disease (Long-COVID), characterised by persistent and cyclical symptomology. To understand the complexity of Long-COVID, the importance of symptom surveillance and prospective longitudinal studies is evident.MethodsA 9-month longitudinal prospective cohort study was conducted within Scotland (n=287), using a mobile app to determine the proportion of recovered individuals and those with persistent symptoms and common symptoms, and associations with gender and age.Results3.1% of participants experienced symptoms at month 9, meeting the criteria for Long-COVID, as defined by the National Institute for Health and Care Excellence terminology. The random effects model revealed a significant time (month) effect for infection recovery (p<0.001, estimate=0.07). Fatigue, cough and muscle pain were the most common symptoms at baseline, with fatigue persisting the longest, while symptoms like cough improved rapidly. Older age increased the likelihood of reporting pain (p=0.028, estimate=0.07) and cognitive impairment (p<0.001, estimate=0.93). Female gender increased the likelihood of headaches (p=0.024, estimate=0.53) and post-exertional malaise (PEM) frequency (p=0.05, estimate=137.68), and increased time x gender effect for PEM frequency (p=0.033, estimate=18.96).ConclusionsThe majority of people fully recover from acute COVID-19, although often slowly. Age and gender play a role in symptom burden and recovery rates, emphasising the need for tailored approaches to Long-COVID management. Further analysis is required to determine the characteristics of the individuals still reporting ongoing symptoms months after initial infection to identify risk factors and potential predictors for the development of Long-COVID.
Towards a common definition of hospital-acquired deconditioning in adults: a scoping review
Authors: Westlake Meri , Cowley Alison , Robinson Katie , Gordon Adam L. 
Published: January 2025

BackgroundHospital-acquired deconditioning is a term used in clinical practice, describing a loss of physical and/or cognitive function associated with hospitalisation. Previous reviews have addressed interventions, its prevalence in older adults and potential assessment tools. However, each review has reported a core limitation, the need for an agreed-upon definition and diagnostic criteria for hospital-acquired deconditioning.ObjectiveWe aimed to identify key components used to define hospital-acquired deconditioning in adults. We sought to do this by identifying diagnostic criteria, describing how authors operationalised Hospital- Acquired Deconditioning (HAD), and describing differences between HAD and other immobility-linked syndromes. This article focuses on how hospital-acquired deconditioning is understood and operationalised.DesignA scoping review using the Joanna Briggs Institute methodology for evidence synthesis.Eligibility criteriaPublished in English after 1 January 1990, investigating adults over 18, set in inpatient rehabilitation or acute care settings, and including either a definition or description of hospital-acquired deconditioning or an outline of strategies to assess, prevent or manage hospital-acquired deconditioning.Sources of evidencePublished and grey literature, no restriction was placed on study design.Charting methodsRelevant data, where available, was extracted from each source using a proprietary data extraction template.ResultsOne hundred and three articles were included from 2403 retrieved results. Thirty-three were from rehabilitation or post-acute care settings, 53 from acute care, 15 from intensive care and two from other settings. The literature was diverse in methodology and research question addressed. Hospital-acquired deconditioning was poorly defined, no consistent patterns were identified in aetiology and sequelae; diagnostic criteria were not fully agreed on.ConclusionsThe literature on hospital-acquired deconditioning is large, diverse and incomplete. Further work is required to develop a shared definition of hospital-acquired deconditioning, enabling researchers to coalesce for better understanding of the phenomenon, and clinicians, in turn, to better treat and mitigate against it.Review registrationOSF:https://osf.io/b5sgw/
Association between early ondansetron use and the risk of sepsis in intensive care unit patients: a secondary data of the Medical Information Mart for Intensive Care IV database
Authors: Liu Xuan , Liu Enhe , Kou Qiuye 
Published: January 2025

ObjectiveThis study planned to analyse the association between ondansetron use within 24 hours before intensive care unit (ICU) admission to within 48 hours after ICU admission and the risk of sepsis in ICU patients.DesignA cohort study.Setting and participantsData of 65 366 participants in Medical Information Mart for Intensive Care IV from ICU in the Beth Israel Deaconess Medical Center.Primary and secondary outcome measuresSepsis was the primary outcome, which indicated patients with documented or suspected infection and acute change in total Sequential Organ Failure Assessment (SOFA) score ≥2 points. In-hospital mortality was the secondary outcome.ResultsThere were 6737 patients with early ondansetron use. In total, 1646 patients suffered sepsis. According to the data from multivariate cox regression model, compared with participants without early ondansetron use, the risk of sepsis was reduced in participants with early ondansetron use relative to those without HR (HR=0.84, 95% CI: 0.76 to 0.93). The risk of in-hospital mortality was reduced in those with early ondansetron use (HR=0.63, 95% CI: 0.55 to 0.72). Subgroup analysis revealed that the association between early ondansetron use and decreased risk of sepsis was significant in participants aged <65 years, men, not complicated with trauma, no surgery, systemic inflammatory response syndrome ≥2, Charlson Comorbidity Index ≥2, with ventilation use, without antibiotics use or without insulin use. In both patients with SOFA <3 or SOFA ≥3, early ondansetron use was correlated with a reduced risk of sepsis.ConclusionPatients with early ondansetron use had lower odds of experiencing sepsis than patients without early ondansetron use, which might provide a reference for the management of sepsis in ICU patients.