bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventable suicides involving medicines before the covid-19 pandemic: a systematic case series of coroners’ reports in England and Wales
Authors: Anthony Grace , Aronson Jeffrey K. , Brittain Richard , Heneghan Carl , Richards Georgia C. 
Published: July 2023

AbstractBackgroundOver 5000 suicides are registered in England and Wales each year. Coroners’ Prevention of Future Deaths reports (PFDs) share concerns to promote actions to reduce the risks of similar deaths.AimsTo systematically review coroners’ PFDs involving suicides in which a medicine caused or contributed to the death, to identify lessons for suicide prevention.Methods3037 PFDs were screened for eligibility between July 2013 and December 2019. Following data extraction, descriptive statistics and content analysis were performed to assess coroners’ concerns, the recipients, and the response rates to reports.ResultsThere were 734 suicide-related PFDs, with 100 reporting a medicine. Opioids (40%) were the most common class involved in suicide-related PFDs, followed by antidepressants (30%). There was wide geographical variation in the writing of PFDs; coroners in Manchester wrote the most (18%). Coroners expressed 237 concerns; the most common were procedural inadequacies (14%, n=32), inadequate documentation and communication (10%, n=22), and inappropriate prescription access (9%, n=21). 203 recipients received these PFDs, most being sent to NHS trusts (31%), clinical commissioning groups (10%), and general practices (10%), of which only 58% responded to the coroner.ConclusionsConcerns raised by coroners in suicide-related PFDs involving medicines highlight essential gaps in care that require actions from the Government, health services, and prescribers. To aid suicide prevention, PFDs should be disseminated nationally, and responses should be enforced so that actions are taken to prevent suicides.Study protocol registration:https://doi.org/10.17605/OSF.IO/EXJK3
Genomic context sensitizes regulatory elements to genetic disruption
Authors: Ordoñez Raquel , Zhang Weimin , Ellis Gwen , Zhu Yinan , Ashe Hannah J. , Ribeiro-dos-Santos André M. , Brosh Ran , Huang Emily , Hogan Megan S. , Boeke Jef D. , Maurano Matthew T. 
Published: July 2023

SUMMARYEnhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis. Thus it remains unclear to what extent enhancer function at native loci relies on surrounding genomic context. Using the Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the murineIgf2/H19locus, a paradigmatic model of enhancer selectivity. We assembled payloads containing a 157-kb functionalIgf2/H19locus and engineered mutations to genetically direct CTCF occupancy at the imprinting control region (ICR) that switches the target gene of theH19enhancer cluster. Contrasting activity of payloads delivered at the endogenousIgf2/H19locus or ectopically atHprtrevealed that theIgf2/H19locus includes additional, previously unknown long-range regulatory elements. Exchanging components of theIgf2/H19locus with the well-studiedSox2locus showed that theH19enhancer cluster functioned poorly out of context, and required its native surroundings to activateSox2expression. Conversely, theSox2locus control region (LCR) could activate bothIgf2andH19outside its native context, but its activity was only partially modulated by CTCF occupancy at the ICR. Analysis of regulatory DNA actuation across different cell types revealed that, while theH19enhancers are tightly coordinated within their native locus, theSox2LCR acts more independently. We show that these enhancer clusters typify broader classes of loci genome-wide. Our results show that unexpected dependencies may influence even the most studied functional elements, and our synthetic regulatory genomics approach permits large-scale manipulation of complete loci to investigate the relationship between locus architecture and function.HIGHLIGHTSComposite enhancer elements are subject to genomic context effects mapped to a specific architecture of their endogenous loci.Igf2/H19expression is affected by long-range regulatory elements beyond the canonically defined locus, and theH19enhancer cluster in particular relies on the surrounding context at its endogenous locus.TheSox2LCR functions as an autonomous enhancer without requiring additional surrounding context.The influence of genomic context is buffered at intact loci, but manifests more strongly as key regulatory elements are deleted or repositioned.
Surfactant-mediated effects on hydrological and physical soil properties: a data synthesis
Authors: Lehmann Anika , Flaig Maximilian , Dueñas Juan F. , Rillig Matthias C. 
Published: July 2023

AbstractSoils are under threat of a multitude of anthropogenic factors affecting the complex interplay of various physical and hydrological soil processes and properties. One such factor is the group of surface-active compounds. Surfactants have a broad range of applications, and can reduce solid-liquid interfacial forces and increase wettability and dispersion of particles. Surfactant effects are context-dependent, giving rise to a wide range of reported effects on different soil processes and properties.Here, we evaluate the evidence base of surfactant research on 11 hydrological and physical soil variables. Our goal was to identify knowledge gaps and to test the robustness of proposed surfactant effects.We found that the current knowledge base is insufficient to reach strong data-backed conclusions about effects of surfactants in soils. We identified a unique case of bias in the data as a result of conflated patterns of lab and field studies. We could not support the hypothesis that surfactant charge determines soil effects for any of the tested soil variables.We believe that further experiments on surfactant mediated effects on soil properties and processes are urgently required, paying attention in particular to improving experimental design and data reporting standards.Graphical abstract
Conformational features and interaction mechanisms of VHH antibodies with β-hairpin-like CDR-H3: A case of Nb8-HigB2 interaction
Authors: Yamamoto Koichi , Nagatoishi Satoru , Nakakido Makoto , Kuroda Daisuke , Tsumoto Kouhei 
Published: July 2023

Abstractβ-hairpin conformation is regarded as an important basic motif to form and regulate protein-protein interactions. Single-domain VHH antibodies are potential therapeutic and diagnostic tools, and the third complementarity-determining regions of the heavy chains (CDR-H3s) of these antibodies are critical for antigen recognition. Although the sequences and conformations of the CDR-H3s are diverse, CDR-H3s sometimes adopt β-hairpin-like conformations. However, characteristic features and interaction mechanisms of β-hairpin-like CDR-H3s remain to be fully elucidated. In this study, we investigated the molecular recognition of the anti-HigB2 VHH antibody Nb8, which has a CDR-H3 that forms a β-hairpin-like conformation. The interaction was analyzed by evaluation of alanine-scanning mutants, molecular dynamics simulations, and hydrogen/deuterium exchange mass spectrometry. These experiments demonstrated that positions 93 and 94 (Chothia numbering) in framework region 3, which is right outside CDR-H3 by definition, play pivotal roles in maintaining structural stability and binding properties of Nb8. These findings will facilitate design and optimization of single-domain antibodies.
Targeting CD25-positive lymphoma cells with the antibody-drug conjugate camidanlumab tesirine as single agent or in combination with targeted agents
Authors: Spriano Filippo , Tarantelli Chiara , Cascione Luciano , Gaudio Eugenio , Golino Gaetanina , Scalise Lorenzo , Zucca Emanuele , Stathis Anastasios , Van Berkel Patrick H. , Zammarchi Francesca , Bertoni Francesco 
Published: July 2023

ABSTRACTIntroductionCamidanlumab tesirine (ADCT-301) is a CD25 specific antibody-drug conjugate (ADC) employing SG3199, a highly cytotoxic DNA minor groove cross-linking pyrrolobenzodiazepine dimer. Camidanlumab tesirine has shown early clinical anti-tumor activity in various cancer types, including B- and T-cell lymphomas. Here, we assessed its preclinical activity as single agent in 57 lymphoma cell lines and in combination with selected drugs in T cell lymphomas-derived cell lines.MethodsCell lines were exposed to increasing concentrations of camidanlumab tesirine or to SG3199 for 96h followed by MTT proliferation assay. CD25 expression was measured both at cell surface level via fluorescence quantitation and at RNA level, using various technologies. Combination studies were performed exposing cells to increasing doses of camidanlumab tesirine and of additional drugs.ResultsCamidanlumab tesirine presented much stronger single agentin vitrocytotoxic activity in T than B cell lymphomas.In vitroactivity was highly correlated with CD25 expression both at cell surface level and RNA level. Based on the higher activity in T cell lymphomas, camidanlumab tesirine-containing combinations were evaluated in cell lines derived from peripheral T cell lymphoma, ALK-pos or ALK-neg anaplastic large cell lymphoma. The most active combination partners were everolimus, copanlisib, venetoclax, vorinostat and pralatrexate, followed by bortezomib, romidepsin, bendamustine and 5-azacytidine.ConclusionThe strong camidanlumab tesirine single agent anti-lymphoma activity and the observedin vitrosynergisms with targeted agents support further clinical development of camidanlumab tesirine and identify potential combination partners for future clinical studies.
Cognitive rehabilitation can improve brain injury-induced deficits in behavioral flexibility and impulsivity linked to impaired reward-feedback activity
Authors: Koloski Miranda F. , O’Hearn Christopher M. , Frankot Michelle , Giesler Lauren P. , Ramanathan Dhakshin S. , Vonder Haar Cole 
Published: July 2023

AbstractTraumatic brain injury (TBI) affects a large population, resulting in severe cognitive impairments. Although cognitive rehabilitation is an accepted treatment for some deficits, studies in patients are limited in ability to probe physiological and behavioral mechanisms. Therefore, animal models are needed to optimize strategies. Frontal TBI in a rat model results in robust and replicable cognitive deficits, making this an ideal candidate for investigating cognitive rehabilitation. In this study, we report three distinct frontal TBI experiments assessing behavior well into the chronic post-injury period using male Long-Evans rats. First, we evaluated the impact of frontal injury on local field potentials recorded simultaneously from 12 brain regions during a probabilistic reversal learning task (PbR). Next, rats were tested on reversal learning (PbR) or impulsivity (differential reinforcement of low-rate behavior: DRL) and half received salient cues associated with reinforcement contingencies as a form of “cognitive rehabilitation”. After rehabilitation on the PbR task, brains were stained for markers of activity. On the DRL, cues were devalued to determine if beneficial effects persisted on impulsive behavior. TBI resulted in outcome salience deficits evident in task performance and reward-feedback signals occurring at beta frequencies in orbitofrontal cortex (OFC) and associated frontostriatal regions. Cognitive rehabilitation improved flexibility and increased OFC activity. Rehabilitation also reduced impulsivity, even after cues were degraded, which was partially mediated by improvements in timing behavior. The current study established a robust platform for investigating cognitive rehabilitation in animals and identified a strong role for dysfunctional OFC signaling after frontal TBI.
Dual-species proteomics and targeted intervention of animal-pathogen interactions
Authors: Liu Yang Sylvia , Zhang Chengqian , Khoo Bee Luan , Hao Piliang , Chua Song Lin 
Published: July 2023

AbstractComplexity in host-pathogen interactions drives the need to develop sensitive and accurate biochemical techniques to elucidate host and pathogen protein expressions. Current proteomics techniques reveal information from the point of view of either the host or pathogen, but do not provide data on the corresponding partner. While dual-species transcriptomics is increasingly used to study RNA expression in host and pathogen, it remains challenging to simultaneously study host-pathogen proteomes that reflect the direct competition between host and pathogen. UsingCaenorhabditis elegans-Pseudomonas aeruginosainfection model as proof-of-concept, we established a forward+reverse SILAC proteomics approach to simultaneously label and quantify newly-expressed proteins of host and pathogen without physical isolation. We observed iron competition between pathogen iron scavenger and host iron uptake protein, whereP. aeruginosaupregulated pyoverdine synthesis protein (PvdA) and secreted pyoverdine, andC. elegansexpressed ferritin (FTN-2) respectively. Using Galangin as a novel PvdA inhibitor identified by structure-based virtual-screening, targeted intervention of iron competition eliminatedP. aeruginosainfection, and enabled animal survival. Our work provides insights into the mechanisms dictating host-pathogen interactions and offers novel strategies for anti-infective therapy.
Dynamics of giant vesicle assembly from thin lipid films
Authors: Pazzi Joseph , Subramaniam Anand Bala 
Published: July 2023

AbstractGiant unilamellar vesicles (GUVs) are micrometer-scale lipid assemblies that emulate key characteristics of biological cell membranes. GUVs can be obtained when solid-supported thin films of lipids are hydrated in aqueous solutions. However, a comprehensive understanding of their assembly dynamics has been lacking, impeding mechanistic insights. Here, we report the time dependence of the distribution of sizes and molar yield of GUVs obtained through a novel ‘stopped-time’ technique. We compare three commonly used techniques, PAPYRUS (Paper-Abetted amPhiphile hYdRation in aqUeous Solutions) gentle hydration, and electroformation. We demonstrate that all three techniques show sigmoidal yield curves. Yields increase monotonically before reaching a plateau, with surprisingly high yields 60 seconds after hydration. Gentle hydration shows limited time evolution in contrast to PAPYRUS and electroformation. Exploration of bud dynamics on the surfaces uncovers bud emergence, diameter growth, and merging phenomena. To provide a comprehensive explanation of our observations, we employ the thermodynamic budding and merging model. This work expands our understanding of GUV assembly dynamics and offers fundamental insights into the underlying thermodynamic principles governing this process.
WITHDRAWN: Biallelic mutation ofSUPV3L1causes an inherited leukodystrophy-associated neurodevelopmental disorder due to aberrant mitochondrial double stranded RNA processing
Authors: Green Lydia , Hamilton Noémie , Elpidorou Marilena , Harris Erica L. , Douglas Andrew , Ounap Katrin , Maroofian Reza , Rose Ailsa M.S. , Elworthy Stone , Renshaw Stephen A , Low Elizabeth C. , Prescott Trine , Soberg Kristoffer , Al-Maawali Almunder , Al-Zuhaibi Sana , Futaisi Amna Al , Calame Daniel , Al-Thihli Khalid , Sheridan Eamonn G. , Johnson Colin A. , Livingston John , Crow Yanick J. , Poulter James A 
Published: July 2023

Withdrawal StatementThe authors have withdrawn their manuscript owing to an error identified by the corresponding author. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Burden of diarrhea and antibiotic use among children in low-resource settings preventable byShigellavaccination: a simulation study
Authors: Brennhofer Stephanie A , Platts-Mills James A , Lewnard Joseph A , Liu Jie , Houpt Eric R , Rogawski McQuade Elizabeth T 
Published: July 2023

ABSTRACTBackgroundShigellais a leading cause of diarrhea and dysentery in children in low resource settings, which is frequently treated with antibiotics. The primary goal of aShigellavaccine would be to reduce mortality and morbidity associated withShigelladiarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery.MethodsWe used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to estimate the impact of two one-dose (6 or 9 months) and three two-dose (6 & 9 months, 9 & 12 months, and 12 & 15 months)Shigellavaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. To estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use under each vaccination scenario, Monte Carlo simulations with random sampling were performed.FindingsWe analyzed 9392 diarrhea episodes and 15697 antibiotic courses among 1715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100-child years. AShigellavaccine given at 9 & 12 months prevented 1.7 (95% CI: 1.3, 2.1) severeShigelladiarrhea episodes (46.5% reduction), 11.0 (95% CI: 10.0, 11.9)Shigelladiarrhea episodes of any severity (35.9% reduction), 3.1 (95% CI: 2.6, 3.7) F/M courses (2.9% reduction overall), 5.8 (95% CI: 5.2, 6.6) antibiotic courses (1.0% reduction overall), and 6.3 (95% CI: 5.2, 7.5) F/M (3.2% reduction) and 11.2 (95% CI: 9.7, 12.9) antibiotic (1.2% reduction) exposures to bystander pathogens, respectively, per 100-child years.InterpretationAShigellavaccine could make substantial reductions inShigelladiarrhea, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use would be modest.FundingWellcome Trust, Bill & Melinda Gates Foundation
The structural covariance of reading-related brain regions in adults and children with typical reading skills and developmental dyslexia
Authors: Haugg Amelie , Frei Nada , Lutz Christina , Di Pietro Sarah V. , Karipidis Iliana I. , Brem Silvia 
Published: July 2023

AbstractStructural covariance (SC) is a promising approach for investigating brain organization within the domain of literacy and developmental disorders as it thought to reflect both functional and structural information. This study presents a first-of-its-kind exploration of SC in reading-related brain regions across different ages and reading abilities.Whole-brain SC analyses were conducted for six key regions of the reading network, including an anterior and posterior subdivision of the visual word form area (VWFA). We compared SC matrices of typically reading adults (N=134) and children (N=110), and between typically reading children and children with dyslexia (N=68).Our results showed significant associations between reading-related brain regions in typically reading adults. We observed significant SC between the posterior VWFA and the left occipital cortex, and between the anterior VWFA and the left superior temporal gyrus and left inferior frontal gyrus. Typical-reading adults and children did not differ significantly in SC. However, typically reading children demonstrated significantly higher SC between the inferior parietal lobule (IPL) and other reading-related brain regions than children with dyslexia.Our findings provide support for a functional and structural division of the VWFA and underscore the crucial role of the IPL in fluent reading.
Accurate and Rapid Molecular Subgrouping of High-Grade Glioma via Deep-learning-assisted Label-free Fiberoptic Raman Spectroscopy
Authors: Liu Chang , Wang Jiejun , Shen Jianghao , Chen Xun , Ji Nan , Yue Shuhua 
Published: July 2023

AbstractGlioma are often impossible to visualize discrimination within different grades and staging, especially for glioma molecular subgrouping which is highly related with surgery strategy and prognosis. Based on glioma guideline published on 2021, molecular subgroups such as IDH, 1p/19q etc. need to be detected to classify the subgroups (astrocytoma, oligodendroglioma, GBM) from high-grade glioma and guide the personalized treatment. However, timely intraoperative technology is limited to identify molecular subgroups of glioma tissues. To address this problem, we develop a deep learning-guided fiberoptic Raman diagnostic platform to assess its ability of real-time high-grade glioma molecular subgrouping. The robust Raman diagnostic platform is established using convolutional neural networks (ResNet) together with fingerprint spectra acquired within 3 seconds. We have acquired a total of 2358 Raman spectra from 743 tissue sites (astrocytoma: 151; oligodendroglioma:150; GBM: 442) of 44 high-grade glioma patients (anaplastic astrocytoma: 7; anaplastic oligodendroglioma:8; GBM: 29). The optimized ResNet model provides an overall mean diagnostic accuracy of 84.1% (sensitivity of 87.1% and specificity of 81.5%) for identifying 7 molecular subgroups (e.g., IDH, 1p/19q, MGMT, TERT, EGFR, Chromosome 7/10, CDKN2A/B) of high-grade glioma, which is superior to the best diagnosis performance using PCA-SVM and UMAP. We further investigate the saliency map of the best ResNet models using the correctly predicted Raman spectra. The specific Raman features that are related to the tumor-associated biomolecules (e.g., collagens, and lipids) validate the robustness of ResNet diagnostic model. This potential intraoperative technology may therefore be able to diagnosis molecular subgroups of high-grade glioma in real time, making it an ideal guide for surgical resection and instant post-operative decision-making.
A RabGAP-Rab GTPase pair regulates plant autophagy and immunity
Authors: Yuen Enoch Lok Him , Leary Alexandre Y , Clavel Marion , Tumtas Yasin , Mohseni Azadeh , Picchianti Lorenzo , Jamshidiha Mostafa , Pandey Pooja , Duggan Cian , Cota Ernesto , Dagdas Yasin , Bozkurt Tolga O 
Published: July 2023

AbstractPlants rely on autophagy and membrane trafficking to tolerate stress, combat infections, and maintain cellular homeostasis. However, the molecular interplay between autophagy and membrane trafficking is poorly understood. Using an AI-assisted approach, we identified Rab3GAP-like (Rab3GAPL) as an important membrane trafficking node that controls plant autophagy negatively. Rab3GAPL suppresses autophagy by binding to ATG8, the core autophagy adaptor, and deactivating Rab8a, a small GTPase essential for autophagosome formation and defense-related secretion. Rab3GAPL fromNicotiana benthamiana, but not its mutated form deficient in ATG8 binding, reduced autophagic flux inN. benthamianaand Arabidopsis. Furthermore,Rab3GAPL-knockout mutants of the liverwortMarchantia polymorphaexhibited enhanced autophagic flux under both normal and heat stress conditions, suggesting that Rab3GAPL’s negative regulatory role in autophagy is conserved in land plants. Beyond autophagy regulation, Rab3GAPL modulates focal immunity against the oomycete pathogenPhytophthora infestansby preventing defense-related secretion. Altogether, our results suggest that Rab3GAPL acts as a molecular rheostat to coordinate autophagic flux and defense-related secretion by restraining Rab8a-mediated trafficking. This unprecedented interplay between a RabGAP-Rab pair and ATG8 sheds new light on the intricate membrane transport mechanisms underlying plant autophagy and immunity.