bluuebunny/crossref_metadata_2025_split huggingface dataset:
A System to Explore the Adaptive Dynamics of Multicopy Plasmids: The Role of Copy Number and Mutation Rate in Evolutionary Outcomes
Authors: Pisera Alexander (Olek) , Liu Chang C. 
Published: December 2024

AbstractMulticopy plasmids are widespread in nature and compose a common strategy for spreading beneficial traits across microbes. However, the role of plasmids in supporting the evolution of encoded genes remains underexplored due to challenges in experimentally manipulating key parameters such as plasmid copy number and mutation rate. In this work, we developed a strategy for controlling copy number in the plasmid-based continuous evolution system, OrthoRep, and used our resulting capabilities to investigate the evolution of a conditionally essential gene under varying CN and mutation rate conditions. Our results show that low CN facilitates the faster enrichment of beneficial alleles while high CN promotes robustness through the maintenance of allelic diversity. High CN also slows the removal of deleterious mutations and increased the fraction of non-functional alleles that could hitchhike during evolution. This study highlights the nuanced relationships between plasmid CN, mutation rate, and evolutionary outcomes, providing insights into the adaptive dynamics of genes encoded on multicopy plasmids and nominating OrthoRep as a versatile tool for studying plasmid evolution.
Mutations inampDcause hyperproduction of AmpC and CphA beta-lactamases and high resistance to beta-lactam antibiotics inChromobacterium violaceum
Authors: Laranjeiro Luís G. , Neme Carlos E. M. , Previato-Mello Maristela , Batista Bianca B. , Henriques Isabel , da Silva Neto José F. 
Published: December 2024

ABSTRACTBacterial resistance to beta-lactam antibiotics mediated by beta-lactamase enzymes is widespread worldwide.Chromobacterium violaceum, an environmental Gram-negative bacteria pathogen, is intrinsically resistant to some beta-lactam antibiotics. In this work, we found that mutations in anampDgene, encoding a peptidoglycan-recycling amidase, cause hyperproduction of two chromosomal beta-lactamases (AmpC and CphA), conferring high beta-lactam resistance inC. violaceum. Susceptibility tests using ΔampC, ΔcphA, andΔampCΔcphAmutant strains revealed specific susceptibility profiles to penicillin, cephalosporin, and carbapenem beta-lactams, suggesting that AmpC is a broad-spectrum beta-lactamase (penicillinase and cephalosporinase), while CphA is a narrow-spectrum metallo-carbapenemase. Beta-galactosidase assays indicate that the expression ofampCandcphAincreased in response to beta-lactams. We isolatedC. violaceumspontaneous mutants resistant to the antibiotic ceftazidime and found that most mutants were also resistant to several other beta-lactams and overexpressedampCandcphA. DNA sequencing of the three paralog genes encoding theC. violaceumAmpD amidases revealed mutations of different types in AmpD1 (CV_0566) in most of the spontaneous mutants, but no mutation was found in AmpD2 or AmpD3. Analysis of single and combined null amidase mutants revealed overexpression of both beta-lactamases and increased resistance to beta-lactams only in mutants with deletedampD1. When introduced intoampD1null or spontaneous mutants, theampD1gene rescued the antibiotic-related phenotypes. The AmpD1 amidase fromC. violaceumhas a unique architecture with an N-terminal acetyltransferase domain. Our work offers new insights into the mechanisms of beta-lactamase-mediated antibiotic resistance and open perspectives to improve the treatment ofC. violaceuminfections.
Development of a cognitive behavioral therapy intervention in Pujehun District, Sierra Leone among pregnant women
Authors: Lee Ashleen , Koroma Aminata , Duncan Joshua A , Bah Abdulai Jawo , Kleban Eliza , Kohlmann Kristin , Lopez-Arteaga Jumeika , Stephenson Kevin , Manary Mark J 
Published: December 2024

AbstractThis report outlines the development of a novel therapeutic intervention to address perinatal depression (PND) in Pujehun District, a rural area in Sierra Leone marked by high illiteracy rates and socio-economic challenges. PND poses significant health risks for both mothers and their children yet remains largely unaddressed due to stigma and limited resources.In collaboration with the Mental Health Coalition – Sierra Leone, Project Peanut Butter established the first cognitive behavioral therapy (CBT) service in the district for women with PND. This process began with the creation of the first mental health counseling service in the district for women with postnatal depression, along with the selection and training of female counselors. A culturally adapted CBT curriculum was developed, designed to empower participants to reintegrate into their communities. Additionally, a novel screening tool was introduced to effectively diagnose PND in pregnant women in low-literacy settings.This model serves as a replicable framework for similar initiatives in high illiteracy contexts, with the goal of improving maternal mental health and ultimately infant development.
Characterization of Dynamic Adaptation to Stressors using Multi-System Stimulus-Response Data: The Study of Physical Resilience in Aging Pilot
Authors: Bandeen-Roche Karen , Zhu Jiafeng , Xue Qian-Li , Buta Brian , Laskow Thomas , Walston Jeremy D. , Varadhan Ravi 
Published: December 2024

AbstractResilience to stressors has emerged as a major gerontological concept aiming to promote more positive outcomes for older adults. Achieving this aim relies on determining mechanisms underlying capacity to respond resiliently. This paper seeks proof of principle for the hypothesis that physical aspects of said capacity are rooted in the fitness of one’s physiology governing stress response, conceptualized as a dynamical system.The Study of Physical Resilience in Aging (“SPRING”) leveraged stimulus-response experiments to characterize physiological fitness in older adults scheduled for one of three major stressors: Total knee replacement, incident hemodialysis, or bone marrow transplant in hematological cancer. Here we analyze Holter monitor time series, cortisol responses to adrenocorticotropic hormone (ACTH) stimulation, and repeated diurnal salivary cortisol assessment in the SPRING pilot (n=79). Principal components analysis was applied anticipating steady-state and “adaptation” mechanisms underlying the repeated physiological measures. Analytic features evidenced these mechanisms, supporting construct validity. Component scores were analyzed by major stressor, hypothesized surrogate physiologic measures (physical frailty phenotype, self-report of health), and demographic, health and behavioral characteristics. Scores differed substantially by stressor type and the surrogate physiologic measures, evidencing criterion validity.Our data support that HRV, ACTH and salivary cortisol stimulus-response data jointly assess adaptation capacity across a variety of major stressors. We believe that SPRING is the first study in humans to concurrently query multiple physiologic systems using stimulus-response tests. Our findings lay groundwork for future validation with further data and to better forecast resilience of older adults to clinical stressors.
Patient safety education in undergraduate medical curricula: a concept analysis and scoping review protocol
Authors: Bowman-Newmark Jonathan , Brock Evangeline , Vosper Helen 
Published: December 2024

ABSTRACTObjectiveThis study aims to establish how the phenomenon of patient safety education manifests within undergraduate medical curricula. The specific objectives are to conduct a concept analysis, in order to make explicit the concept of patient safety education and inform its operational definition. Thereafter, to conduct a scoping review, in order to systematically map what educational content is taught, who is taught that content, and how that content is taught.IntroductionPreliminary searches identified four extant systematic reviews, published between 2010 and 2022, which investigated different aspects of how patient safety education manifested within undergraduate medical curricula. Notwithstanding, those findings do not provide a sufficiently robust basis to inform contemporaneous discourse.Eligibility criteriaThe participants, concept, and context framework will be used to determine the evidence sources eligible for inclusion in the scoping review. Eligible participants will include learners matriculated on undergraduate medical programmes, and the educators that teach learners on those programmes. The concept will be patient safety education, according to an operational definition that will be established. Eligible contexts will include the taught curricula of undergraduate programmes in medicine.MethodsAn exploratory and descriptive study that will sequentially implement the Walker and Avant framework for concept analysis and the updated JBI methodology for scoping reviews. Eight electronic databases and one internet search engine will be utilised to identify sources published between 1 May 2014 and 30 November 2024. Pre-defined eligibility criteria will be used to select sources. Data will be extracted and analysed, and findings will be presented.
Community Threat, Positive Parenting, and Accelerated Epigenetic Aging: Longitudinal Links from Childhood to Adolescence
Authors: Metrailer Georgette , Tavares Karina , Pault Mikayla Ver , Lopez Adamari , Denherder Shane , Hernandez Valencia Everlyn , DiMarzio Karissa , Highlander April , Merrill Sarah M. , Rojo-Wissar Darlynn M. , Parent Justin 
Published: December 2024

AbstractEarly Life Adversity (ELA) has been linked to accelerated epigenetic aging. While positive parenting is hypothesized to buffer the detrimental effects of ELA on child development, its role in mitigating epigenetic age acceleration remains unclear. Data from 2,039 children (49.7% female) in the Future of Families and Child Wellbeing Study (FFCWS) were included in the current study (46.7% Black, 26.5% Hispanic, 19% White non-Hispanic). Home and community threat and observed parenting were measured from ages 3 to 9. Salivary epigenetic age acceleration was measured at ages 9 and 15. Positive parenting reduces the pace of epigenetic aging in low, but not high, community-threat environments. Interventions across home and community environments may be necessary to prevent ELA’s biological embedding.
Bradykinin Measurement by LC-MS/MS in Hereditary Angioedema Subjects Enhanced by Cold Activation
Authors: Chen Jinguo , Wu Yunkou , Chiao Joseph , Yu J. Joanna , Yu Jing , Scarupa Mark D. , Wan Lili , Li H. Henry 
Published: December 2024

AbstractBackgroundBradykinin (BK) is a key mediator responsible for swelling episodes in hereditary angioedema due to C1INH deficiency/dysfunction (HAE-C1INH). Current BK measurement faces many challenges primarily related to very low levels and instability, and is not feasible for application in clinical settings.ObjectiveThis study aimed to develop a novel method to overcome the issues in current protease inhibitor-based methods for measuring endogenous BK and its metabolites.MethodsThe blood from HAE-C1INH and healthy volunteers were collected and subjected to cold activation for contact system. Cold-induced BK and its major metabolites were measured via Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The protocol was established according to the US FDA bioanalytical validation guidelines as a CLIA laboratory-developed test. The BK measurement was optimized based on blood sample types, collection methods, time windows, and temperature/storage conditions.ResultsEDTA whole blood samples without protease inhibitors incubated at 4 degree for 1 to 3 days produced over 100-fold differences in total BK levels between HAE-C1INH subjects and healthy volunteers (324.3 +/- 54.7 ng/mL, n=33; vs 2.3 +/- 0.3 ng/mL, n = 43; mean +/- S.E.M., p < 0.001). The sensitivity and specificity were 90.9% and 97.1% respectively. BK levels highly correlated with the plasma kallikrein activity in the same samples.ConclusionsWhole blood under cold activation demonstrated remarkable elevation of BK levels in HAE-C1INH subjects, while minimally affecting healthy individuals. The assay has validated accuracy, precision and stability. It may serve as a reliable and robust tool for HAE diagnosis and management.Clinical ImplicationCold-induced Bradykinin measurement can be used as a new biomarker for diagnosis, disease monitoring and guiding therapeutic options for HAE-C1INH and other bradykinin-mediated angioedema (AE-BK), with or without identifiable genetic mutations.
Thoracic Aorta Measurement Extraction from Computed Tomography Radiology Reports Using Instruction Tuned Large Language Models
Authors: Erez Ely , Dankwa Sedem , Tuttle McKenzie , Nasir Afsheen , Vallabhajosyula Prashanth , Schneider Eric B. , Assi Roland , Ong Chin Siang 
Published: December 2024

AbstractChest computed tomography (CT) is essential for diagnosing and monitoring thoracic aortic dilations and aneurysms, conditions that place patients at risk of complications such as aortic dissection and rupture. However, aortic measurements in chest CT radiology reports are often embedded in free-text formats, limiting their accessibility for clinical care, quality improvement and research purposes. In this study, we developed a multi-method pipeline to extract structured aortic measurements from radiology reports, and compared the performance of fine-tuned BERT-based models with instruction-tuned Llama large language models (LLMs). Applying the best-performing method to a real-world large chest CT radiology report database, we generated a comprehensive aortic measurement dataset that facilitates big data aortic disease research.
A single cell and spatial genomics atlas of human skin fibroblasts in health and disease
Authors: Steele Lloyd , Admane Chloe , Chakala Keerthi Priya , Foster April , Gopee Nusayhah Hudaa , Koplev Simon , Mazin Pasha , Olabi Bayanne , Roberts Kenny , Tudor Catherine , Winheim Elena , Annusver Karl , Correa-Gallegos Donovan , Forsthuber Agnes , Francis Luc , Frech Sophie , Ganier Clarisse , Layton Thomas , Liu Yingzi , Yuan Hao , Gudjonsson Johann E. , Lichtenberger Beate M. , Mahil Satveer , Nanchahal Jagdeep , O’Toole Edel A , Plikus Maksim , Rinkevich Yuval , Rognoni Emanuel , Smith Catherine , Teichmann Sarah A , Kasper Maria , Lotfollahi Mohammad , Haniffa Muzlifah 
Published: December 2024

AbstractFibroblasts are critical cells that shape the architecture and cellular ecosystems in multiple tissues. Understanding fibroblast heterogeneity and their spatial context in health and disease has enormous clinical relevance. In this study, we constructed a spatially-resolved atlas of human skin fibroblasts from healthy skin and 23 skin disorders. We define 6 major skin fibroblast populations in health and a further three skin disease-specific fibroblast subtypes, and demonstrate the fibroblast composition in different types of skin disease. We characterise a human-specific fibroblastic reticular cell (FRC)-like subtype in the skin perivascular niche and postulate their origin from prenatal skin lymphoid tissue organiser (LTo)-like cells. We also show that inflammatory myofibroblasts (IL11+MMP1+CXCL5+IL7R+) are a conserved fibroblast subtype in inflammatory disorders and cancers across multiple human tissues. We provide a harmonised nomenclature for skin fibroblasts that integrates previous findings from human skin and other tissues.
FAIRSCAPE: An Evolving AI-readiness Framework for Biomedical Research
Authors: Al Manir Sadnan , Levinson Maxwell Adam , Niestroy Justin , Churas Christopher , Parker Jillian A. , Clark Timothy 
Published: December 2024

AbstractMotivationArtificial intelligence (AI) applications require explainability (XAI) for FAIR, ethical deployment, whether in the clinic or in the laboratory. Richly descriptive XAI metadata representing how pre-model data were obtained, characterized, transformed, and distributed, should be available along with the data prior to training and application of AI models.ResultsThe FAIRSCAPE framework generates, packages, and integrates critical pre-model XAI descriptive metadata, including deep provenance graphs and data dictionaries with feature validation on uploaded data, software, and computations, with special reference to biomedical datasets. It provides ethical and semantic characterization of the dataset along with licensing and availability information, and integrates seamlessly with NIH-recommended generalist repositories. The server is cloud-compliant and implemented in Python3. Client software in Python3 is callable from the command line or directly as python functions. We provide a REST API, and a GUI-based client in javascript is also available.Availability and implementationThe code is freely available under MIT license and is hosted athttps://fairscape.github.io/, along with comprehensive documentation and tutorials.
WASp activity in macrophages prevents mechano-induced inflammation by protecting the nuclear envelope
Authors: Amadio Roberto , Bracchetti Giulia , Alraies Zahraa , Piperno Giulia Maria , Rodriguez Lucia Lopez , Maurin Mathieu , Conti Martina , Andolfi Laura , Castiello Maria Carmina , Ferrua Francesca , Villa Anna , Aiuti Alessandro , Lennon-Dumenil Ana-Maria , Benvenuti Federica 
Published: December 2024

AbstractMutations in the immune-specific actin regulator WASp induce a proinflammatory state in myeloid cells, whose underlying causes remain poorly defined. Here, we applied microfabricated tools that mimic tissue mechanical forces to explore the role of WASp in connecting mechano-sensing to the activation of inflammatory responses in macrophages. We show that WASp-deficient macrophages carry alterations in nuclear structure and undergo increased blebbing and nuclear rupture when exposed to mechanical confinement. High-resolution imaging indicates that WASp drives the formation of protective perinuclear actin structures in response to confinement. Functionally, a proinflammatory gene signature linked to nuclear envelope rupture is preferentially active in confined WASp null macrophages, which partially depends on the cGAS-STING pathway of cytosolic DNA sensing. Analysis of transcriptional datasets of human and mouse tissue macrophages confirmed elevated inflammatory activation in WASp null cells. Together, these data uncover that WASp restricts pro-inflammatory activation of macrophages by preserving nuclear integrity in confined environments, providing novel clues to understand inflammatory activation in Wiskott-Aldrich Syndrome.
YDS-Ternoplex: Surpassing AlphaFold 3-Type Models for Molecular Glue-Mediated Ternary Complex Prediction
Authors:   The Statistical Mechanics Inference Team, Che Xing 
Published: December 2024

AbstractMolecular glues represent an innovative class of drugs that enable previously impossible protein-protein interactions, but their rational design remains challenging, a problem that accurate ternary complex modeling can significantly address. Here we present YDS-Ternoplex, a novel computational approach that enhances AlphaFold 3-type models by incorporating enhanced sampling inductive bias during inference to accurately predict molecular glue-mediated ternary complex structures. We demonstrate YDS-Ternoplex’s capabilities across seven diverse test cases, including both E3 ligase-based systems (VHL:CDO1 and CRBN complexes with mTOR-FRB, NEK7, and VAV1-SH3c) and non-E3 ligase complexes (FKBP12 complexes with mTOR-FRB, BRD9 and QDPR). The model achieves remarkable accuracy with RMSD values as low as 1.303 Å compared to experimental structures and successfully predicts novel protein-protein interfaces not present in training data. Notably, in the FKBP12:mTOR-FRB case, YDS-Ternoplex correctly predicts a novel interface configuration instead of defaulting to known interactions present in training data, demonstrating strong generalization capabilities. Our results suggest that strategic enhancement of the inference process through inductive bias can significantly improve ternary complex prediction accuracy, potentially accelerating the development of molecular glue therapeutics for previously undruggable targets.
Biology exams rarely use visual models to engage higher-order cognitive skills
Authors: Uminski Crystal , Cammarota Christian , Couch Brian A. , Wright L. Kate , Newman Dina L. 
Published: December 2024

AbstractVisual models are a necessary part of molecular biology education because submicroscopic compounds and processes cannot be directly observed. Accurately interpreting the biological information conveyed by the shapes and symbols in these visual models requires engaging visual literacy skills. For students to develop expertise in molecular biology visual literacy, they need to have structured experiences using and creating visual models, but there is little evidence to gauge how often undergraduate biology students are provided such opportunities. To investigate students’ visual literacy experiences, we surveyed 66 instructors who taught lower division undergraduate biology courses with a focus on molecular biology concepts. We collected self-reported data about the frequency with which the instructors teach with visual models and we analyzed course exams to determine how instructors incorporated visual models into their assessments. We found that most instructors reported teaching with models in their courses, yet only 16% of exam items in the sample contained a visual model. There was not a statistically significant relationship between instructors’ self-reported frequency of teaching with models and extent to which their exams contained models, signaling a potential mismatch between teaching and assessment practices. Although exam items containing models have the potential to elicit higher-order cognitive skills through model-based reasoning, we found that when instructors included visual models in their exams the majority of the items only targeted the lower-order cognitive skills of Bloom’s Taxonomy. Together, our findings highlight that despite the importance of visual models in molecular biology, students may not often have opportunities to demonstrate their understanding of these models on assessments.
Assessment of Contralateral Efferent Effects in HumanViaECochG
Authors: Verschooten Eric , Strickland Elizabeth A. , Verhaert Nicolas , Joris Philip X. 
Published: December 2024

AbstractEfferent projections from the brainstem to the inner ear are well-described anatomically and physiologically but their precise function remains debated. The medial olivocochlear (MOC) system and its reflex, the MOCR, have been particularly well studied. In animals, anatomical and physiological data are fine-grained and extensive and suggest an important role for the MOCR in anti-masking e.g. to improve the detection of tones in background noise. Extensive behavioral studies in human support this role, but direct linking of behavioral paradigms to the MOCR is challenging because of the difficulty in obtaining appropriate human neural measures. We developed a new approach in which mass potentials were recorded near the cochlea of normal hearing and awake human volunteers to increase the signal-to-noise (SNR) ratio, and examined whether broadband noise to the contralateral ear elicited MOCR anti-masking effects as reported in animals. Probing the mass potential to the onset of brief tones at 4 and 6 kHz, convincing anti-masking or suppressive effects consistent with the MOCR were not detected. We then changed the recording technique to examine the neural phase-locked contribution to the mass potential in response to long, low-frequency tones, and found that contralateral sound suppressed neural responses in a systematic and progressive manner. We followed up with psychophysical experiments in which we found that contralateral noise elevated detection threshold for tones up to 4 kHz. Our study provides a new way to study efferent effects in the human peripheral auditory system and shows that contralateral efferent effects are biased towards low frequencies.