bluuebunny/crossref_metadata_2025_split huggingface dataset:
A human high-fidelity DNA polymerase holoenzyme has a wide range of lesion bypass activities
Authors: Dannenberg Rachel L. , Cardina Joseph A. , Washington Helen , Gao Shijun , Greenberg Marc M. , Hedglin Mark 
Published: October 2024

ABSTRACTDuring replication, lagging strand lesions are initially encountered by high-fidelity DNA polymerase (pol) holoenzymes comprised of pol δ and the PCNA sliding clamp. To proceed unhindered, pol δ holoenzymes must bypass lesions without stalling. This entails dNMP incorporation opposite the lesion (insertion) and the 5’ template nucleotide (extension). Historically, it was viewed that high-fidelity pol holoenzymes stall upon encountering lesions, activating DNA damage tolerance pathways that are ultimately responsible for lesion bypass. Our recent study of 4 prominent lesions revealed that human pol δ holoenzymes support insertion and/or bypass for multiple lesions and the extents of these activities depends on the lesion and pol δ proofreading. In the present study, we expand these analyses to other prominent lesions. Collectively, analyses of 10 lesions from both studies reveal that the insertion and bypass efficiencies of pol δ holoenzymes each span a complete range (0 – 100%). Consequently, the fates of pol δ holoenzymes upon encountering lesions are quite diverse. Furthermore, pol δ proofreading promoted holoenzyme progression at 7 of the 10 lesions and did not deter progression at any. Altogether, the results significantly alter our understanding of the replicative capacity of high-fidelity pol holoenzymes and their functional role(s) in lesion bypass.
Direct segmentation of cortical cytoarchitectonic domains using ultra-high-resolution whole-brain diffusion MRI
Authors: Pas Kristofor E. , Saleem Kadharbatcha S. , Basser Peter J. , Avram Alexandru V. 
Published: October 2024

AbstractWe assess the potential of detecting cortical laminar patterns and areal borders by directly clustering voxel values of microstructural parameters derived from high-resolution mean apparent propagator (MAP) magnetic resonance imaging (MRI), as an alternative to conventional template-warping-based cortical parcellation methods. We acquired MAP-MRI data with 200µm resolution in a fixed macaque monkey brain. To improve the sensitivity to cortical layers, we processed the data with a local anisotropic Gaussian filter determined voxel-wise by the plane tangent to the cortical surface. We directly clustered all cortical voxels using only the MAP-derived microstructural imaging biomarkers, with no information regarding their relative spatial location or dominant diffusion orientations. MAP-based 3D cytoarchitectonic segmentation revealed laminar patterns similar to those observed in the corresponding histological images. Moreover, transition regions between these laminar patterns agreed more accurately with histology than the borders between cortical areas estimated using conventional atlas/template-warping cortical parcellation. By cross-tabulating all cortical labels in the atlas– and MAP-based segmentations, we automatically matched the corresponding MAP-derived clusters (i.e., cytoarchitectonic domains) across the left and right hemispheres. Our results demonstrate that high-resolution MAP-MRI biomarkers can effectively delineate three-dimensional cortical cytoarchitectonic domains in single individuals. Their intrinsic tissue microstructural contrasts enable the construction of whole-brain mesoscopic cortical atlases.
Soil microarthropod community assembly at the micro spatial scale - A microcosm manipulation study
Authors: Dirilgen T. , Bolger T. 
Published: October 2024

AbstractOur understanding of soil microarthropod (Acari and Collembola) community assembly and dynamics is somewhat limited compared to aboveground communities. Understanding the processes involved in assembly and the spatial scales at which they occur would help answer the age old question of how so many species and individuals can coexist in soil. We use a microcosm experiment using intact soil cores to explore the processes of selection and dispersal taking place at the micro-spatial scale. We do this by manipulating available pore space and population density, which allows us to indirectly investigate the role of dispersal and biotic interactions in shaping microarthropod community dynamics. Results suggest that there are processes limiting abundance and that communities are sometimes held at abundances below those which the environment could accommodate by abiotic factors. Food and space did not appear to drive the observed patterns; however, findings suggest that abiotic factors may influence dynamics in the field.
Cross-Linguistic Analysis of Speech Markers: Insights from English, Chinese, and Italian Speakers
Authors: Santi Gaia C. , Catricalà Eleonora , Kwan Stephanie , Wong Anson , Ezzes Zoe , Wauters Lisa , Esposito Valentina , Conca Francesca , Gibbons Daniela , Fernandez Eric , Santos-Santos Migual A. , TaFu Chen , Li-Ying Kwan-Chen , Lo R , Tsoh J , Chan Lung-Tat , Garcia Adolfo M. , de Leon Jessica , Miller Zachary , Vonk Jet M.J. , Bruffaerts Rose , Grasso Stephanie M. , Allen Isabel E. , Cappa Stefano F. , Gorno-Tempini Maria Luisa , Tee Boon Lead 
Published: October 2024

AbstractCross-linguistic studies with healthy individuals are vital, as they can reveal typologically common and different patterns while providing tailored benchmarks for patient studies. Nevertheless, cross-linguistic differences in narrative speech production, particularly among speakers of languages belonging to distinct language families, have been inadequately investigated. Using a picture description task, we analyze cross-linguistic variations in connected speech production across three linguistically diverse groups of cognitively normal participants—English, Chinese (Mandarin and Cantonese), and Italian speakers. We extracted 28 linguistic features, encompassing phonological, lexico-semantic, morpho-syntactic, and discourse/pragmatic domains. We utilized a semi-automated approach with Computerized Language ANalysis (CLAN) to compare the frequency of production of various linguistic features across the three language groups. Our findings revealed distinct proportional differences in linguistic feature usage among English, Chinese, and Italian speakers. Specifically, we found a reduced production of prepositions, conjunctions, and pronouns, and increased adverb use in the Chinese-speakers compared to the other two languages. Furthermore, English participants produced a higher proportion of prepositions, while Italian speakers produced significantly more conjunctions and empty pauses than the other groups. These findings demonstrate that the frequency of specific linguistic phenomena varies across languages, even when using the same harmonized task. This underscores the critical need to develop linguistically tailored language assessment tools and to identify speech markers that are appropriate for aphasia patients across different languages.
Verifying Infectious Disease Scenario Planning for Geographically Diverse Populations
Authors: Conrad Jessica R. , Fenimore Paul W. , Moran Kelly R. , Eisenberg Marisa C. 
Published: October 2024

ABSTRACTIn the face of the COVID-19 pandemic, the literature saw a spike in publications for epidemic models, and a renewed interest in capturing contact networks and geographic movement of populations. There remains a general lack of consensus in the modeling community around best practices for spatiotemporal epi-modeling, specifically as it pertains to the infection rate formulation and the underlying contact or mixing model.In this work, we mathematically verify several common modeling assumptions in the literature, to prove when certain choices can provide consistent results across different geographic resolutions, population densities and patterns, and mixing assumptions. The most common infection rate formulation, a computationally low costper capitainfection rate assumption, fails the consistency tests for heterogeneous populations and non-symmetric mixing assumptions. The largest numerical errors occur in the limit of lowest symmetry, whether as sparse geography or preferential travel to highly-populated locations. Future modeling efforts in spatiotemporal disease modeling should be wary of this limitation, particularly when working with more heterogenous or less dense populations.Our results provide guidance for testing that a model preserves desirable properties even when model inputs mask potential problems due to symmetry or homogeneity. We also provide a recipe for performing this type of validation with the objective of strengthening decision support tools.HighlightsDefine common modeling options from the literature for spatiotemporal epidemic modelsVerify common modeling assumptions are consistent for varying population densities and patterns, resolutions, and underlying mixing or contact assumptionsProvide simulation examples of model misspecification and the resulting implications on scenario planning
Enhancing Radiographic Diagnosis: CycleGAN-based methods for reducing cast shadow artifacts in wrist radiographs
Authors: Norris Stanley A , Carrion Daniel , Ditchfield Michael , Gubser Manuel , Seah Jarrel , Badawy Mohamed K 
Published: October 2024

AbstractObjectiveWe extend existing techniques by using generative adversarial network (GAN) models to reduce the appearance of cast shadows in radiographs across various age groups.Materials and MethodsWe retrospectively collected 12000 adult and pediatric wrist radiographs, evenly divided between those with and without casts. The test subset consisted of 100 radiographs with cast and 100 without cast. We extended the results from a previous study that employed CycleGAN by enhancing the model using a perceptual loss function and a self-attention layer.ResultsThe CycleGAN model which incorporates a self-attention layer and perceptual loss function delivered the best quantitative performance. This model was applied to images from 20 cases where the original reports recommended CT scanning or repeat radiographs without the cast, which were then evaluated by radiologists for qualitative assessment. The results demonstrated that the generated images could improve radiologists’ diagnostic confidence, in some cases leading to more decisive reports. Where available, the reports from follow-up imaging were compared with those produced by radiologists reading AI-generated images. Every report, except two, provided identical diagnoses as those associated with follow-up imaging. The ability of radiologists to perform robust reporting with downsampled AI-enhanced images is clinically meaningful and warrants further investigation. Additionally, radiologists were unable to distinguish AI-enhanced from unenhanced images.ConclusionThese findings suggest the cast suppression technique could be integrated as a tool to augment clinical workflows, with the potential benefits of reducing patient doses, improving operational efficiencies, reducing delays in diagnoses, and reducing the number of patient visits.
Roles of community and sexual contacts as drivers of clade I mpox outbreaks
Authors: Murayama Hiroaki , Asakura Toshiaki R. , Dickens Borame L. , Foo Jen Han , Jin Shihui , Mukadi Patrick K. , Ejima Keisuke , Jung Sung-mok , Nishi Akihiro , Prem Kiesha , Endo Akira 
Published: October 2024

AbstractInitial investigation into the emerging mpox outbreak of novel clade Ib in eastern Democratic Republic of the Congo has identified signs of sustained human-to-human transmission and epidemiological links to sexual contacts involving female sex workers (FSWs), which have not been observed in previous clade Ia outbreaks. Using mathematical models incorporating age-dependent contact patterns, we quantified the role of frequent sexual interactions as opposed to community contacts in the clade Ib dynamics and found that this additional mode of transmission could explain its increased outbreak potential compared with clade Ia. As with the globally-circulating clade IIb transmitted predominantly among men who have sex with men, our findings reinforce the importance of protecting key population groups, specifically FSWs for clade Ib, in controlling ongoing mpox outbreaks.
The case of alternatives to opioids: How much do physician characteristics matter when treating a diverse population?
Authors: Alva Maria L. , Liu Siying 
Published: October 2024

AbstractRationaleThere is little understanding of the prescription patterns of alternatives to opioids (ALTOS). Monitoring gender and racial health disparities can help with healthcare planning, workforce training, patient education, and awareness.ObjectiveThis study asks whether healthcare professionals, when treating patients of the same race and sex, increase their likelihood of prescribing ALTOs relative to opioids.MethodsWe use national Medicare Part D data from 2013 to 2017 and a machine-learning algorithm informed by census data to define the race of prescribers. We use multivariate regression models to understand the impact of race and sex biases on the extensive margin (e.g., percentage of people receiving ALTOs) and the intensive margin (e.g., the number of ALTOs prescriptions per capita).ResultsBetween 2013 and 2017, there has been an 8.7% increase in the prescriptions of ALTOs. The number of beneficiaries receiving ALTOs increased by 11.4%. In 2017, the number of ALTOs prescriptions per capita written as a fraction of all painkillers was 45%, and the number of beneficiaries receiving ALTOs prescriptions as a fraction of people receiving at least one form of painkillers (ALTOs or opioids) was 49%. A male doctor is 20.4% more likely to prescribe ALTOs as the percentage of same-sex patients increases. A white doctor is 7.4% more likely to prescribe ALTOs as the percentage of same-race patients increases, even when controlling for the socioeconomic status of patients, their age and risk factor, and the state and specialty of the prescriber.ConclusionSex and race concordance between providers and patients are significantly associated with prescribing alternatives to opioids. These systematic differences could be addressed by supporting diversity in the workforce, training, and increasing the minimum amount of time a visit should last.
DeepEXPOKE: A Deep Learning Framework with Polygenic Risk Scores as Knockoffs for Deconvoluting Genetic and Non-Genetic Exposure Risks in Sepsis and Coronary Heart Disease
Authors: Sriram Aditya , Bohn Rebecca , Kernan Kate , Carcillo Joseph , Kim Soyeon , Park Hyun Jung 
Published: October 2024

ABSTRACTThe exposome refers to the totality of environmental, behavioral, and lifestyle exposures an individual experiences throughout one’s lifetime. Due to the modifiability of exposures, identifying the risk exposures on a disease is crucial for effective intervention and prevention of the disease. However, traditional analytical methods struggle to capture the complexities of exposome data: nonlinear effects, correlated exposures, and potential interplay with genetic effects. To address these challenges and accurately estimate exposure effects on complex diseases, we developed DeepEXPOKE, a deep learning framework integrating two types of knockoff features: statistical knockoffs (statKO) and polygenic risk score as knockoffs (PRSKO). DeepEXPOKE-statKO controls exposure correlation and DeepEXPOKE-PRSKO isolates genetic effects, while both can capture nonlinear effects. We applied DeepEXPOKE to predict outcomes of two significant diseases with distinct etiology and clinical presentation: sepsis and coronary heart disease (CHD), demonstrating its performance in comparison to existing machine learning methods. Furthermore, both DeepEXPOKE-PRSKO and DeepEXPOKE-statKO identified metabolites such as glucose and triglycerides as risk factors for sepsis and suggested that their effects are primarily at the non-genetic level, consistent with the role of metabolites in responding to environmental factors. Additionally, DeepEXPOKE-PRSKO uniquely identified asthma as a sepsis risk factor and suggested its effect is partially at the genetic level, offering insights into the conflicting associations observed between the genome data studies and patient data analysis regarding asthma and sepsis risk. Overall, DeepEXPOKE offers a novel DNN approach for identifying and interpreting exposure risk factors, advancing our understanding of complex diseases.
‘Identification of RING E3 pseudoligases in the TRIM protein family’
Authors: Dudley-Fraser Jane , Esposito Diego , McPhie Katherine , Morley-Williams Coltrane , Auchynnikava Tania , Rittinger Katrin 
Published: October 2024

AbstractTRIpartite Motif (TRIM) family proteins have diverse roles across a broad variety of cellular functions, which are largely presumed to depend on their ubiquitin E3 ligase activity, conferred by a RING domain. However, recent reports have shown that some TRIMs lack detectable ubiquitination activity in isolation, despite containing a RING domain. Here, we present parallelin cellulo,in vitro, andin silicostructure-function analyses of the ubiquitin E3 ligase activity and RING domain structural characteristics of whole TRIM protein family. In-depth follow-up studies of this comprehensive dataset reveals a number of ‘pseudoligases’, whose RING domains have structurally diverged at either the homodimerisation or E2∼ubiquitin interfaces, thereby disrupting their ability to catalyse ubiquitin transfer. Together, these data raise intriguing open questions regarding the unknown TRIM functions in physiology and disease.Graphical Abstract
Lineage-aware evolutionary analysis of hepatitis C virus within-host dynamics
Authors: Zhao Lele , Hall Matthew , Giridhar Prahalad , Ghafari Mahan , Kemp Steven , Chai Haiting , Klenerman Paul , Barnes Eleanor , Ansari M. Azim , Lythgoe Katrina 
Published: October 2024

AbstractAnalysis of viral genetic data has previously revealed distinct within-host population structures in both untreated and interferon-treated chronic hepatitis C virus (HCV) infections. While multiple subpopulations persisted during the infection, each subpopulation was observed only intermittently. However, it was unknown whether similar patterns were also present after Direct Acting Antiviral (DAA) treatment, where viral populations were often assumed to go through narrow bottlenecks. Here we tested for the maintenance of population structure after DAA treatment failure. We analysed whole-genome next-generation sequencing data generated from a randomised study using DAAs (the BOSON study). We focused on samples collected from patients (N=84) who did not achieve sustained virological response (i.e. treatment failure) and had sequenced virus from multiple timepoints. For each individual, we tracked concordance in nucleotide variant frequencies through time. Using a sliding window approach, we applied sequenced-based and tree-based clustering algorithms across the entire HCV genome. Finally, we reconstructed viral haplotypes and estimated lineage specific within-host divergence rates from the haplotype phylogenies. Distinct viral subpopulations were maintained among a high proportion of individuals post DAA treatment failure. Using maximum likelihood modelling and model comparison, we found an overdispersion of viral evolutionary rates among individuals, and significant differences in evolutionary rates between lineages within individuals. These results suggest the virus is compartmentalised within individuals, with the varying evolutionary rates due to different viral replication rates or different selection pressures. We propose lineage awareness in future analyses of HCV evolution and infections to avoid conflating patterns from distinct lineages, and to recognise the likely existence of unsampled subpopulations.
Integration of the DD-genome reshapes gene transcription, chromatin architecture and metabolome of allohexaploid wheat leading to enhanced adaptability
Authors: Liu Yanyan , Zhu Tao , Zhou Xinkai , Chen Wei , He Chao , Wang Xin , Chen Chuanye , Wei Jiaqi , Lan Caixia , Liu Mengmeng , Su Handong , Li Qiang , Hu Xin , Bi Siteng , Ouyang Weizhi , Li Xingwang , Mao Hailiang , Kishi Masahiro , Kaufmann Kerstin , Fernie Alisdair R. , Chen Dijun , Yan Wenhao 
Published: October 2024

AbstractThe integration, through hybridization, of the DD genome into domesticated tetraploid wheat gave rise to allohexaploid wheat, the most cultivated wheat globally growing across diverse environmental conditions. However, the regulatory basis of this integration on increased environmental adaptability in allohexaploid remains largely unexplored. Here, we investigated the change of transcriptome, epigenome as well as the chromatin interactome, and metabolome in three independent polyploidization events representing DD genome integration. Our findings reveal that polyploidization events induce the activation of defense-related genes through comprehensive reorganization of epigenome and chromatin architecture. DD integration not only brings an additional gene copy but also activates the homoeologs existing in the A and B subgenomes through chromatin interactions. Furthermore, secondary metabolites represented by alkaloids and flavonoids that are crucial for environmental adaptation, are significantly enriched following polyploidization. Thus, hexaploid wheat exhibits enhanced tolerance to alkalinity, UV-B light stress and high salt conditions was observed. These results highlight the indispensable role of DD genome integration in the adaptability of allohexaploid wheat during its evolution.
β-adrenergic blockers increase cAMP and stimulate insulin secretion through a PKA/RYR2/TRPM5 pathway in pancreatic β-cells in vitro
Authors: Murao Naoya , Morikawa Risa , Seino Yusuke , Shimomura Kenju , Maejima Yuko , Yamada Yuichiro , Suzuki Atsushi 
Published: October 2024

Abstractβ-adrenergic blockers (β-blockers) are extensively used to inhibit β-adrenoceptor activation and subsequent cAMP production in many cell types. In this study, we characterized the effects of β-blockers on mouse pancreatic β-cells. Unexpectedly, high doses (100 μM) of β- blockers (propranolol and bisoprolol) led to a 5–10 fold increase in cAMP levels, enhanced intracellular influx, and stimulated a 2–4 fold increase in glucose-and glimepiride-induced insulin secretion in MIN6-K8 clonal β-cells and isolated mouse pancreatic islets. These effects were observed despite minimal expression of β-adrenoceptors in these cells. Mechanistically, cAMP increase led to ryanodine receptor 2 (RYR2) phosphorylation via protein kinase A (PKA), triggering Ca2+-induced Ca2+release (CICR). CICR then activates transient receptor potential cation channel subfamily M member 5 (TRPM5), resulting in increased Ca2+influx via voltage-dependent Ca2+channels. These effects contradict the conventional understanding of the pharmacology of β-blockers, highlighting the variability in β-blocker actions depending on the experimental context.Graphical abstractAt high concentrations (> 10 μM), the β-adrenergic blocker propranolol paradoxically increased intracellular cAMP levels in pancreatic β-cells. This leads to PKA-induced RYR2 phosphorylation and extracellular Ca2+influx, leading to CICR from the ER. CICR activated TRPM5, which augmented β-cell electrical activity, extracellular Ca2+influx, and insulin secretion.