bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative evaluation of cell-based assay technologies for scoring drug-induced condensation of SARS-CoV-2 nucleocapsid protein
Authors: Quek Rui Tong , Shirazinejad Cyna R. , Young Christina L. , Hardy Kierra S. , Lim Samuel , Elms Phillip J. , McSwiggen David T. , Mitchison Timothy J. , Silver Pamela A. 
Published: September 2024

AbstractProtein-nucleic acid phase separation has been implicated in many diseases such as viral infections, neurodegeneration, and cancer. There is great interest in identifying condensate modulators (CMODs), which are small molecules that alter the dynamics and functions of phase-separated condensates, as a potential therapeutic modality. Most CMODs were identified in cellular high-content screens (HCS) where micron-scale condensates were characterized by fluorescence microscopy. These approaches lack information on protein dynamics, are limited by microscope resolution, and are insensitive to subtle condensation phenotypes missed by overfit analysis pipelines. Here, we evaluate two alternative cell-based assays: high-throughput single molecule tracking (htSMT) and proximity-based condensate biosensors using NanoBIT (split luciferase) and NanoBRET (bioluminescence resonance energy transfer) technologies. We applied these methods to evaluate condensation of the SARS-CoV-2 nucleocapsid (N) protein under GSK3 inhibitor treatment, which we had previously identified in our HCS campaign to induce condensation with well-defined structure-activity relationships (SAR). Using htSMT, we observed robust changes in N protein diffusion as early as 3 hours post GSK3 inhibition. Proximity-based N biosensors also reliably reported on condensation, enabling the rapid assaying of large compound libraries with a readout independent of imaging. Both htSMT and proximity-based biosensors performed well in a screening format and provided information on CMOD activity that was complementary to HCS. We expect that this expanded toolkit for interrogating phase-separated proteins will accelerate the identification of CMODs for important therapeutic targets.
Tolerance Mechanisms in Polysaccharide Biosynthesis: Implications for Undecaprenol Phosphate Recycling inEscherichia coliandShigella flexneri
Authors: Qin Jilong , Hong Yaoqin , Morona Renato , Totsika Makrina 
Published: September 2024

AbstractBacterial polysaccharide synthesis is catalysed on the universal lipid carrier, undecaprenol phosphate (UndP). The cellular UndP pool is shared by other polysaccharide synthesis pathways and in peptidoglycan (PG) biogenesis. Disruptions in cytosolic polysaccharide synthesis steps are detrimental to bacterial survival due to affecting UndP recycling. In contrast, bacteria can survive disruptions in the periplasmic steps, suggesting a tolerance mechanism to mitigate UndP sequestration. Here we investigated tolerance mechanisms to disruptions of polymerases that are involved in UndP-releasing steps in two related polysaccharide synthesis pathways: the enterobacterial common antigen (ECA) and the O antigen (OAg), inEscherichia coliandShigella flexneri. Our study reveals that polysaccharide polymerisation is crucial for efficient UndP recycling. InE. coliK-12, cell survival upon disruptions in OAg polymerase is dependent on a functional ECA synthesis pathway and vice versa. This is because disruptions in OAg synthesis leads to the redirection of the shared lipid-linked sugar substrate UndPP-GlcNAc towards increased ECA production. Conversely, inS. flexneri, the OAg polymerase is essential due to its limited ECA production, which inadequately redirects UndP flow to support cell survival. We propose a model whereby sharing the initial sugar intermediate UndPP-GlcNAc between the ECA and OAg synthesis pathways allows UndP to be redirected towards ECA production, mitigating sequestration issues caused by disruptions in the OAg pathway. These findings suggest an evolutionary buffering mechanism that enhances bacterial survival when UndP sequestration occurs due to stalled polysaccharide biosynthesis, which may allow polysaccharide diversity in the species to increase over time.ImportanceEnzymes involved in bacterial polysaccharide biosynthesis have substrate specificity to ensure the correct polysaccharide is produced at the appropriate place and time. However, this specificity poses a challenge for the diversification of polysaccharide structure and hence function, as the acquisition of a novel oligosaccharide RU would likely disrupt the synthesis pathways, leading to sequestration of the essential universal lipid carrier UndP and ultimately cause cell death. We investigated how cells tolerate disruptions in polysaccharide synthesis pathways and provide evidence that suggests that sharing a common substrate between the synthesis pathways of two common enteric bacterial surface polysaccharides (ECA and OAg), can redirect the flow of UndP. Our study provides insights into the mechanism of how bacteria alleviate sequestration issues, thereby enhancing cell survival which may allow them additional capacity for polysaccharide diversification.
Novel color vision assessment tool: AIM Color Detection and Discrimination
Authors: He Jingyi , Skerswetat Jan , Bex Peter J. 
Published: September 2024

AbstractColor vision assessment is essential in clinical practice, yet different tests exhibit distinct strengths and limitations. Here we apply a psychophysical paradigm, Angular Indication Measurement (AIM) for color detection and discrimination. AIM is designed to address some of the shortcomings of existing tests, such as prolonged testing time, limited accuracy and sensitivity, and the necessity for clinician oversight. AIM presents adaptively generated charts, each a N×M (here 4×4) grid of stimuli, and participants are instructed to indicate either the orientation of the gap in a cone-isolating Landolt C optotype or the orientation of the edge between two colors in an equiluminant color space. The contrasts or color differences of the stimuli are adaptively selected for each chart based on performance of prior AIM charts. In a group of 23 color-normal and 15 people with color vision deficiency (CVD), we validate AIM color against Hardy-Rand-Rittler (HRR), Farnsworth-Munsell 100 hue test (FM100), and anomaloscope color matching diagnosis and use machine learning techniques to classify the type and severity of CVD. The results show that AIM has classification accuracies comparable to that of the anomaloscope, and while HRR and FM100 are less accurate than AIM and an anomaloscope, HRR is very rapid. We conclude that AIM is a computer-based, self-administered, response-adaptive and rapid tool with high test-retest repeatability that has the potential to be suitable for both clinical and research applications.
Resolution ofSLC6A1variable expressivity in a multi-generational family using deep clinical phenotyping andDrosophilamodels
Authors: Jay Kristy L. , Gogate Nikhita , Ezell Kim , Andrews Jonathan C. , Jangam Sharayu V. , Hall Paige I. , Pan Hongling , Pham Kelvin , German Ryan , Gomez Vanessa , Jellinek-Russo Emily , Storch Eric ,   Brain Gene Registry Consortium,   Undiagnosed Diseases Network, Yamamoto Shinya , Kanca Oguz , Bellen Hugo J. , Dierick Herman , Cogan Joy D. , Phillips John A. , Hamid Rizwan , Cassini Thomas , Rives Lynette , Posey Jennifer E. , Wangler Michael F. 
Published: September 2024

AbstractPurposeVariants inSLC6A1result in a rare neurodevelopmental disorder characterized by a variable clinical presentation of symptoms including developmental delay, epilepsy, motor dysfunction, and autism spectrum disorder.SLC6A1haploinsufficiency has been confirmed as the predominant pathway ofSLC6A1-related neurodevelopmental disorders (NDDs), however, the molecular mechanism underlying the variable clinical presentation remains unclear.MethodsHere, through work of the Undiagnosed Diseases Network, we identify an undiagnosed individual with an inherited p.(A334S) variant of uncertain significance. To resolve this case and better understand the variable expressivity withSLC6A1, we assess the phenotypes of the proband with a cohort of cases diagnosed withSLC6A1-related NDDs. We then create an allelic series in theDrosophila melanogasterto functionally characterize case variants.ResultsWe identify significant clinical overlap between the unsolved case and confirmed cases ofSLC6A1-related NDDs and find a mild to severe clinical presentation associated with missense variants. We confirm phenotypes in flies expressingSLC6A1variants consistent with a partial loss-of-function mechanism.ConclusionWe conclude that the p.(A334S) variant is a hypomorphic allele and begin to elucidate the underlying variability inSLC6A1-related NDDs. These insights will inform clinical diagnosis, prognosis, treatment and inform therapeutic design for those living withSLC6A1-related NDDs.
Consensus guidelines for eligibility assessment of pathogenic variants to antisense oligonucleotide treatments
Authors: Cheerie David , Meserve Margaret , Beijer Danique , Kaiwar Charu , Newton Logan , Tavares Ana Lisa Taylor , Verran Aubrie Soucy , Sherrill Emma , Leonard Stefanie , Sanders Stephan J. , Blake Emily , Elkhateeb Nour , Gandhi Aastha , Liang Nicole S. Y. , Morgan Jack T. , Verwillow Anna , Verheijen Jan , Giles Andrew , Williams Sean , Chopra Maya , Croft Laura , Dafsari Hormos Salimi , Davidson Alice E. , Friedman Jennifer , Gregor Anne , Haque Bushra , Lechner Rosan , Montgomery Kylie-Ann , Ryten Mina , Schober Emil , Siegel Gabriele , Sullivan Patricia , Zardetto Bianca , Yu Timothy , Synofzik Matthis , Aartsma-Rus Annemieke , Costain Gregory , Lauffer Marlen C. 
Published: September 2024

AbstractOf the around 7,000 known rare diseases worldwide, disease-modifying treatments are available for fewer than 5%, leaving millions of individuals without specialized therapeutic strategies. In recent years, antisense oligonucleotides (ASOs) have shown promise as individualized genetic interventions for rare genetic diseases. However, there is currently no consensus on which disease-causing DNA variants are suitable candidates for this type of genetic therapy. The Patient Identification Working Group of the N=1 Collaborative (N1C), alongside an international group of volunteer assessors, has developed and piloted consensus guidelines for assessing the eligibility of pathogenic variants towards ASO treatments. We herein present the N1C VARIANT (VariantAssessments towards Eligibility forAntisense OligonucleotideTreatment) guidelines, including the guiding scientific principles and our approach to consensus building. Pathogenic, disease-causing variants can be assessed for the three currently best-established ASO treatment approaches: splice correction, exon skipping, and downregulation of RNA transcripts. A genetic variant is classified as either “eligible”, “likely eligible”, “unlikely eligible”, or “not eligible” in relation to the different approaches, or “unable to assess”. We also review key considerations for assessment for upregulation of transcripts from the wildtype allele, an emerging ASO therapeutic strategy. We provide additional tools and training material to enable clinicians and researchers to use these guidelines for their eligibility assessments. With this initial edition of our N1C VARIANT guidelines, we provide the rare genetic disease community with guidance on how to identify suitable candidates for variant-specific ASO-based therapies and the possibility of integrating such assessments into routine clinical practice.
Risk of Clonal Hematopoiesis of Indeterminate Potential after Cancer Radiation Therapy
Authors: Crants Shelby A. , Olson Sydney S. , Li Yajing , Bejan Cosmin A. , Vlasschaert Caitlyn , Mack Taralynn M. , Pershad Yash , Kishtagari Ashwin , Reed Sarah C. , Croessmann Sarah , Roden Dan M. , Osterman Travis J. , Shinohara Eric T. , Bick Alexander G. , Park Ben H. , Luo Leo Y. 
Published: September 2024

AbstractClonal hematopoiesis of indeterminate potential (CHIP) is a condition associated with aging and increased risk of hematologic malignancies and chronic diseases. While radiation therapy (RT) has been implicated as a risk factor for CHIP, the specific radiation parameters influencing the development of CHIP remain unclear. This study aimed to investigate the association between RT and CHIP and identify relevant radiation parameters affecting CHIP risk. We conducted a retrospective cohort study of cancer patients with RT exposure from an institutional biobank. DNA sequencing was performed to detect mutations in 22 CHIP-associated genes. Multivariable logistic regression models were used to evaluate the association between clinical characteristics, RT parameters, and CHIP. We identified 736 cancer patients with RT exposure and compared their risk of CHIP to a control cohort of 13,605 individuals. RT was found to be an independent risk factor for developing CHIP (OR 1.39, 95% CI 1.08-1.77, p=0.009). The prevalence of CHIP in RT patients was 22.8%. Compared to controls, RT patients showed significantly increased mutations inDNMT3A,PPM1D,TP53,andBRCC3.A positive correlation was observed between CHIP risk and biological equivalent dose of radiation. Stereotactic radiation was also associated with increased CHIP prevalence (OR 2.24, 95% CI 1.14-4.33, p=0.02). This study demonstrates that RT is associated with an increased risk of CHIP development, particularly mutations in DNA damage response genes. These findings have important implications for cancer care and long-term patient monitoring, emphasizing the need for further research into the mechanisms and consequences of RT-related CHIP.Key PointsRadiation therapy significantly increases the risk of developing clonal hematopoiesis of indeterminate potential (CHIP) in cancer patientsCHIP risk is higher in those who receive higher total dose and stereotactic radiation, with increased mutations in DNA damage repair genes
Gait-to-Contact (G2C) - A novel deep learning framework to predict total knee replacement wear from gait patterns
Authors: Perrone Mattia , Simmons Scott , Malloy Philip , Yuh Catherine , Martin John , Mell Steven P. 
Published: September 2024

BackgroundTotal knee replacement (TKR) is the most common inpatient surgery in the US. Studies leveraging finite element analysis (FEA) models have shown that variability of gait patterns can lead to significant variability of wear rates in TKR settings. However, FEA models can be resource-intensive and time-consuming to execute, hindering further research in this area. This study introduces a novel deep learning-based surrogate modeling approach aimed at significantly reducing computational costs and processing time compared to traditional FEA models.MethodsA published method was used to generate 314 variations of ISO14243-3(2014) anterior/posterior translation, internal/external rotation, flexion/extension, and axial loading time series, and a validated FEA model was used to calculate linear wear distribution on the polyethylene liner. A deep learning model featuring a transformer-CNN based encoder-decoder architecture was trained to predict linear wear distribution using gait pattern time series as input. Model performance was evaluated by comparing the deep learning and FEA model predictions using metrics such as mean absolute percentage error (MAPE) for relevant geometric features of the wear scar, structural similarity index measure (SSIM) and normalized mutual information (NMI).ResultsThe deep learning model significantly reduced the computational time for generating wear predictions compared to FEA, with the former training and inferring in minutes, and the latter requiring days. Comparisons of deep learning model wear map predictions to FEA results yielded MAPE values below 6% for most of the variables and SSIM and NMI values above 0.88, indicating a high level of agreement.ConclusionThe deep learning approach provides a promising alternative to FEA for predicting wear in TKR, with substantial reductions in computational time and comparable accuracy. Future research will aim to apply this methodology to clinical patient data, which could lead to more personalized and timely interventions in TKR settings.
Optical imaging of micro-droplets of dried saliva for oral squamous cell carcinoma diagnosis
Authors: Foiani Letícia , Nepomuceno Gabrielle , Toledo Julia , Alves Mariana , Rodrigues Nayara , Bandeira Celso , Alves Mônica , Almeida Janete , Martinho Herculano 
Published: September 2024

AbstractOral cancer, the sixth most common worldwide, is often diagnosed at an advanced stage, impacting patient survival and mortality. Liquid biopsy offers the potential for cancer diagnosis, enabling dynamic tumor monitoring and disease surveillance. Here we validates a novel diagnostic approach using optical images of dried micro-droplets (volume of oneµl) of saliva samples on glass and platinum substrates, employing Logistic Regression and Support Vector Machine (SVM) models. For each model, accuracy, sensitivity, specificity, and area under the ROC curve were calculated. Our findings indicated that optical density and surface area (SA) obtained from optical images of microdroplets are suitable paramters of discriminating oral cavity squamous cell carcinoma and health individuals. SVM models demonstrate impressive accuracy of 88.10% on glass and 95.00% on Pt substrates, ensuring robust and accurate detection of oral cancer based on these salient features.
Neural and Somatic Mechanisms Driving Clinical Improvements in Post-Acute Schizophrenia Spectrum Disorders
Authors: Roell Lukas , Lindner Christoph , Maurus Isabel , Keeser Daniel , Malchow Berend , Schmitt Andrea , Falkai Peter 
Published: September 2024

ABSTRACTBackground:A better mechanistic understanding of schizophrenia spectrum disorders is crucial to develop efficient treatment approaches. Therefore, this study investigated longitudinal interrelations between clinical outcomes, brain structure, and somatic health in post-acute individuals from the schizophrenia spectrum.Methods:A sample of 63 post-acute patients from two independent physical exercise studies were included in the final analyses. Demographic, clinical, cognitive, and somatic data were acquired at baseline and post-intervention, as were structural magnetic resonance imaging scans. Multivariate cross-lagged panel modelling including mediators was used to study the mutual interrelations over time between the clinical, neural, and somatic level.Results:A higher baseline global grey matter volume and larger regional grey matter volumes of the hippocampal formation, precuneus, and posterior cingulate drove improvements in multiple clinical outcomes, such as daily-life functioning, negative symptoms, and cognition. Increases in white matter volume from baseline to post-intervention resulted in significantly reduced positive symptoms and higher daily-life functioning following the intervention.Conclusion:Our findings suggest that stimulating neuroplasticity, especially in the hippocampal formation, precuneus, and posterior cingulate gyrus, may represent a promising treatment target in post-acute schizophrenia spectrum disorders. Physical exercise therapies and other lifestyle interventions, and brain stimulation approaches reflect promising treatment candidates. Given the exploratory character of the statistical analysis performed, these findings need to be replicated in independent longitudinal imaging cohorts of patients with schizophrenia spectrum disorders.
Genetic Interplay Between White Matter Hyperintensities and Alzheimer’s Disease: A Brain-Body Perspective
Authors: Singh Manpreet , Shafighi Kimia , Detcheverry Flavie E. , Dabo Fanta , Housni Ikrame , Narayanan Sridar , Gagliano Taliun Sarah A. , Bzdok Danilo , Badhwar AmanPreet 
Published: September 2024

ABSTRACTMRI-detected white matter hyperintensities (WMH) are often recognized as markers of cerebrovascular abnormalities and an index of vascular brain injury, and are frequently present in individuals with Alzheimer’s disease (AD). Given the emerging bidirectional communication between the brain-body axis in both WMHs and AD, it is important to understand their genetic underpinnings across the whole body. However, literature on this is scarce.We investigated the brain-body axis by breaking down heritability estimates of these phenotypes across the whole body, – i.e., partitioning heritability. Our aims were to identify genetic underpinnings specific to WMHs, and common between WMHs and AD, by assessing (a) the partitioned heritability of WMHs and AD across the brain-body axis with tissue-specific annotations, (b) the partitioned heritability of WMHs and AD across the brain-body axis with cell-specific annotations, and (c) the genes associated with WMHs and AD, and verifying their expression levels across the whole body.Our tissue-specific analysis revealed that WMH-associated SNPs were significantly enriched in tissues beyond the brain, namely liver, cardiovascular, and kidney – with liver being a common tissue enriched for both WMHs and AD. Our cell-specific analysis showed enrichment of vascular endothelial cells across the tissue types enriched for WMHs, highlighting their central role in the development of WMHs. Additionally, our gene-level analysis highlighted overlapping patterns of tissue enrichment for both WMHs and AD, and showed interactions between WMH and AD associated genes.Our findings provide new insights into the systemic influences potentially contributing to WMH pathology, in particular, multi-system endothelial disorder. We hope that our multisystemic genetic findings will stimulate future WMH-research into specific pathways across the brain-body axis.
Design Approaches for Developing Quality Checklists in Healthcare Organizations: A Scoping Review
Authors: Kwong Elizabeth , Cole Amy , Sippo Dorothy , Yu Fei , Adapa Karthik , Shea Christopher M. , Moore Carlton , Das Shiva , Mazur Lukasz 
Published: September 2024

AbstractQuality checklists have demonstrated benefits in healthcare and other high-reliability organizations, but there remains a gap in the understanding of design approaches and levels of stakeholder engagement in the development of these quality checklists. This scoping review aims to synthesize the current knowledge base regarding the use of various design approaches for developing quality checklists in healthcare. Secondary objectives are to explore theoretical frameworks, design principles, stakeholder involvement and engagement, and characteristics of the design methods used for developing quality checklists. The review followed the Preferred Reporting Items for Systematic Reviews 2020 checklist. Seven databases (PubMed, APA PsycInfo, CINAHL, Embase, Scopus, ACM Digital Library, and IEEE Xplore) were searched for studies using a comprehensive search strategy developed in collaboration with a health sciences librarian. Search terms included “checklist” and “user-centered design” and their related terms. The IAP2 Spectrum of Participation Framework was used to categorize studies by level of stakeholder engagement during data extraction. Twenty-nine studies met the inclusion criteria for this review. Twenty-three distinct design methods were identified that were predominantly non-collaborative in nature (e.g., interviews, surveys, and other methods that involved only one researcher and one participant at a given time). Analysis of the levels of stakeholder engagement revealed a gap in studies that empowered their stakeholders in the quality checklist design process. Highly effective, clear, and standardized methodology are needed for the design of quality checklists. Future work needs to explore how stakeholders can be empowered in the design process, and how different levels of stakeholder engagement might impact implementation outcomes.