bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Crowding Suppresses Mechanical Stress-Driven DNA Strand Separation
Authors: Desai Parth Rakesh , Marko John F. 
Published: December 2024

ABSTRACTMolecular crowding influences DNA mechanics and DNA - protein interactions and is ubiquitous in living cells. Quantifying the effects of molecular crowding on DNA supercoiling is essential to relatingin-vitroexperiments toin-vivoDNA supercoiling. We use single molecule magnetic tweezers to study DNA supercoiling in the presence of dehydrating or crowding co-solutes. To study DNA supercoiling, we apply a stretching force of 0.8 pN to the DNA and then rotate one end of the DNA to induce supercoiling. In a 200 mM NaCl buffer without co-solutes, negatively supercoiled DNA absorbs some of the tortional stress by forming locally melted DNA regions. The base-pairs in these locally melted regions are believed to adopt a configuration where nucleotide base pairing is disrupted. We find that the presence of dehydrating co-solutes like glycerol and ethylene glycol results in further destabilization of base-pairs in negatively supercoiled DNA. The presence of polyethylene glycol, commonly used as crowding agents, suppresses local strand separation and results in plectoneme formation even when DNA is negatively supercoiled. The results presented in this letter suggest many further directions for studies of DNA supercoiling and supercoiled DNA – protein interactions in molecular conditions that approximatein-vivomolecular composition.SIGNIFICANCEAccurate modelling of DNA mechanics is central to interpreting results of single molecule studies of DNA mechanics and DNA-protein interactions. While the effect of molecular conditions on short and relaxed DNA has been studied, the influence of molecular conditions on DNA supercoiling has not been explored. We present the first single molecule study of DNA supercoiling in presence of crowding and dehydrating co-solutes. We observe that co-solutes can increase or completely suppress stress-driven local strand separation in negatively supercoiled DNA. This change of DNA supercoiling is likely to significantly affect the function of DNA-binding proteins. Our results motivate the need for systematic exploration of DNA supercoiling in presence of co-solutes to accurately relatein-vitroDNA-protein interactions toin-vivoDNA-protein interactions.
Multiple-Basin Gō-Martinifor Investigating Conformational Transitions and Environmental Interactions of Proteins
Authors: Yang Song , Song Chen 
Published: December 2024

AbstractProteins are inherently dynamic molecules, and their conformational transitions among various states are essential for numerous biological processes, which are often modulated by their interactions with surrounding environments. Although molecular dynamics (MD) simulations are widely used to investigate these transitions, all-atom (AA) methods are often limited by short timescales and high computational costs, and coarse-grained (CG) implicitsolvent Gō-like models are usually incapable of studying the interactions between proteins and their environments. Here, we present an approach called Multiple-basin Gō-Martini, which combines the recent Gō-Martini model with an exponential mixing scheme to facilitate the simulation of spontaneous protein conformational transitions in explicit environments. We demonstrate the versatility of our method through five diverse case studies: GlnBP, Arc, Hinge, SemiSWEET, and TRAAK, representing ligand-binding proteins, fold-switching proteins,de novodesigned proteins, transporters, and mechanosensitive ion channels, respectively. The Multiple-basin Gō-Martini offers a new computational tool for investigating protein conformational transitions, identifying key intermediate states, and elucidating essential interactions between proteins and their environments, particularly protein-membrane interactions. In addition, this approach can efficiently generate thermodynamically meaningful datasets of protein conformational space, which may enhance deep learning-based models for predicting protein conformation distributions.
Machine Learning Models for Segmentation and Classification of Cyanobacterial Cells
Authors: Huffine Clair A. , Maas Zachary L. , Avramov Anton , Brininger Chris , Cameron Jeffrey C. , Tay Jian Wei 
Published: December 2024

AbstractTimelapse microscopy has recently been employed to study the metabolism and physiology of cyanobacteria at the single-cell level. However, the identification of individual cells in brightfield images remains a significant challenge. Traditional intensity-based segmentation algorithms perform poorly when identifying individual cells in dense colonies due to a lack of contrast between neighboring cells. Here, we describe a newly developed software package called Cypose which uses machine learning (ML) models to solve two specific tasks: segmentation of individual cyanobacterial cells, and classification of cellular phenotypes. The segmentation models are based on the Cellpose framework, while classification is performed using a convolutional neural network named Cyclass. To our knowledge, these are the first developed ML-based models for cyanobacteria segmentation and classification. When compared to other methods, our segmentation models showed improved performance and were able to segment cells with varied morphological phenotypes, as well as differentiate between live and lysed cells. We also found that our models were robust to imaging artifacts, such as dust and cell debris. Additionally, the classification model was able to identify different cellular phenotypes using only images as input. Together, these models improve cell segmentation accuracy and enable high-throughput analysis of dense cyanobacterial colonies and filamentous cyanobacteria.
Androgen receptor drives polyamine synthesis creating a vulnerability for prostate cancer
Authors: Kumar Rajendra , Jonnatan Sheila , Sanin David E , Vakkala Varsha , Kadam Anoushka , Kumar Shivani , Dalrymple Susan L , Zhao Liang , Foley Jackson , Holbert Cassandra E , Nwafor Ashley , Kittane Srushti , Penner Elizabeth , Apostolova Petya , Warner Samuel , Dang Chi V , Toska Eneda , Thompson Elizabeth A , Isaacs John T , De Marzo Angelo M , Pearce Erika L , Stewart Tracy Murray , Casero Robert A , Denmeade Samuel R , Sena Laura A 
Published: December 2024

ABSTRACTSupraphysiological androgen (SPA) treatment can paradoxically restrict growth of castration-resistant prostate cancer with high androgen receptor (AR) activity, which is the basis for use of Bipolar Androgen Therapy (BAT) for patients with this disease. While androgens are widely appreciated to enhance anabolic metabolism, how SPA-mediated metabolic changes alter prostate cancer progression and therapy response is unknown. Here, we report that SPA markedly increased intracellular and secreted polyamines in prostate cancer models. This occurred through AR binding at enhancer sites upstream of theODC1promoter to increase abundance of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine synthesis, and de novo synthesis of polyamines from arginine. SPA-stimulated polyamines enhance prostate cancer fitness, as dCas9-KRAB-mediated inhibition of AR regulation ofODC1or direct ODC inhibition by difluoromethylornithine (DFMO) increased efficacy of SPA. Mechanistically, this occurred in part due to increased activity of S-adenosylmethionine decarboxylase 1 (AMD1), which was stimulated both by AR and by loss of negative feedback by polyamines, leading to depletion of its substrate S-adenosylmethionine and global protein methylation. These data provided the rationale for a clinical trial testing the safety and efficacy of BAT in combination with DFMO for patients with metastatic castration-resistant prostate cancer. Pharmacodynamic studies of this drug combination in the first five patients on trial indicated that the drug combination resulted in effective polyamine depletion in plasma. Thus, the AR potently stimulates polyamine synthesis, which constitutes a vulnerability in prostate cancer treated with SPA that can be targeted therapeutically.
Pasteurized retail dairy enables genomic surveillance of H5N1 avian influenza virus in United States cattle
Authors: Lail Andrew J. , Vuyk William C. , Machkovech Heather , Minor Nicholas R. , Hassan Nura R. , Dalvie Rhea , Emmen Isla E. , Wolf Sydney , Kalweit Annabelle , Wilson Nancy , Newman Christina M. , Tiburcio Patrick Barros , Weiler Andrea , Friedrich Thomas C. , O’Connor David H. 
Published: December 2024

AbstractHighly pathogenic avian influenza (HPAI) viruses with H5 hemagglutinin (HA) genes (clade 2.3.4.4b) are causing an ongoing panzootic in wild birds. Circulation of these viruses is associated with spillover infections in multiple species of mammals, including a large, unprecedented outbreak in American dairy cattle. With limited testing of dairy herds, there is an unmet need for genomic surveillance. Infected cattle can shed high amounts of HPAI H5N1 viruses in milk, allowing detection in pasteurized retail dairy samples. Over a 2-month sampling period in one Midwestern city, we obtained dairy products processed in 20 different states. Here we demonstrate that a tiled-amplicon sequencing approach produced over 90% genome coverage at greater than 20x depth from 5 of 13 viral RNA positive samples. A combination of RT-qPCR testing and sequencing from retail dairy products can be a useful component of a One Health framework for responding to the avian influenza outbreak in cattle.
Estimating recent trends in UK alcohol sales from alcohol duty revenue
Authors: Angus Colin , Schöley Jonas 
Published: December 2024

AbstractBackground and AimsThe onset of the COVID-19 pandemic led to significant changes in individual-level alcohol consumption and a sharp increase in heavy drinking in the UK. More recently, high rates of inflation, the resulting ‘cost-of-living crisis’ and reforms to alcohol taxation have affected the affordability of alcohol, but little is understood about how these changes have impacted on alcohol sales and consumption. We aimed gain insights into recent trends in alcohol sales by assessing changes in alcohol duty revenue collected by the UK government since 2020.Design and SettingWe used published data on UK alcohol duty revenue to model trends from 2010-2019. We forecasted these trends through to October 2024 using a novel statistical approach and compared these forecasts to observed receipts.MeasurementsMonthly inflation-adjusted alcohol duty receipts received by the UK Treasury in pounds sterling for beer, cider, spirits and wine.FindingsDuring the pandemic, alcohol duty receipts fell during lockdowns and rose as restrictions were subsequently lifted. Since 2022 alcohol duty receipts have been consistently below the historical trend, with a gradually increasing deficit in wine receipts and comparable deficit in spirits receipts that began sharply in late 2022. The reforms to the alcohol duty system in August 2023 do not appear to have significantly affected these trends.ConclusionsOur findings suggest that the ‘cost of living crisis’ in 2022/23 has led to a fall in alcohol sales relative to the pre-pandemic trend. The magnitude of this fall differs by beverage type, indicating that wine and spirits drinkers may have changed their behaviour more than beer and cider drinkers.
Structural plasticity following deep brain stimulation of the internal capsule in treatment resistant depression
Authors: Zhong Z. , Bergfeld I.O. , de Kwaasteniet B.P. , Luigjes J. , Mocking R.J.T. , van Laarhoven J. , Notten P. , Beute G. , van den Munckhof P. , Schuurman P.R. , Denys D.A.J.P. , van Wingen G.A. 
Published: December 2024

AbstractObjectiveDeep brain stimulation (DBS) targeting the ventral anterior limb of the internal capsule (vALIC) shows potential as treatment for treatment resistant depression (TRD). While DBS alters brain function, it is not yet known whether it also induces anatomical alterations. Here we investigated the long-term effects of vALIC DBS on brain structure using structural magnetic resonance imaging.MethodsWe included data from twelve patients with TRD before DBS surgery and after DBS parameter optimization, and from sixteen matched healthy controls at a comparable time interval to control for test-retest effects. To investigate the short-term effects of DBS deactivation after parameter optimization, thirteen patients were additionally scanned after double-blind periods of active and sham stimulation. Voxel-based morphometry analysis was used to identify volumetric differences.ResultThe group x time interaction showed significant changes in anterior thalamic gray matter volume, with a relative reduction in TRD patients compared to controls. Follow-up analysis suggested that this was related to larger thalamic volume at baseline in DBS non-responders. A direct comparison between responders and non-responders showed an additional interaction in the posterior thalamus and hippocampus, which was also related to larger volumes at baseline in non-responders. The comparison between active and sham stimulation during the crossover phase did not show significant differences.ConclusionThese results show that long-term vALIC DBS is associated with a reduction in thalamic volume compared to healthy controls, suggesting that long-term DBS induces focal structural plasticity.
The exploration of the characteristics of lower extremity deep venous thromboembolism in patients at admission to a tertiary general hospital in a fourth-tier city in China
Authors: Pan Jianghao , Sun Jianming , Song Jiaming , Fu Guangyin , Lei Yong , Wang Le 
Published: December 2024

AbstractWith the acceleration of the pace of life and the change of people’s living and working habits, the incidence of venous diseases of lower extremity remains high, and even shows an upward trend year by year, which has a great impact on the quality of life and work efficiency of patients. Well, the occurrence and development of lower extremity deep vein thrombosis (LEDVT) is also related to the economic and humanistic characteristics of a certain place.ObjectivesThe purpose of this paper is to retrospectively analyze the medical records of DVT patients in a general hospital of a fourth-tier city in China, and find some noteworthy characteristics, so as to provide some objective evidence for the diagnosis of DVT in similar hospitals.MethodsAdult patients with central LEDVT with or without pulmonary embolism (PE) were retrospectively analyzed. The general condition, concomitant diseases, laboratory tests and other clinical characteristics were analyzed.ResultsA total of 100 patients’ medical records were analyzed. The age was non-normally distributed (p=0.004), which from 31 to 87 (65.3±11.5) years, and 58% of them were 65 years or older. Males (56%) were slightly more than females. Ninety of ninety-four patients’ D-dimer ≥1μgDDU/ml. Fifty-eight were definitely diagnosed with central LEDVT at admission, of which twenty-three were confirmed as PE by CT. Thirty-five patients with leg symptoms, thirty-three patients with chest symptoms, only two patients had both leg and chest symptoms, and thirty-four patients without any obvious symptoms of DVT when they were admitted to the hospital. Only twelve patients were admitted only with LEDVT, and most of the other patients were complicated with other system/organ diseases.ConclusionsLEDVT is more common in elderly patients aged ≥ 65 years. However, the incidence of patients ≥75 years old observed in this study may be limited by the local economic situation and life expectancy. The symptoms can present as many, may be the typical leg symptoms, progression to PE may involve chest symptoms, or it may be neither leg symptoms nor chest symptoms that are masked by the symptoms of other concomitant diseases. LEDVT can be complicated with multiple system/organ diseases. It is necessary to screen for DVT in patients with abnormal D-dimer.
Comparing DXA and MRI body composition measurements in cross-sectional and longitudinal cohorts
Authors: Basty Nicolas , Thanaj Marjola , Whitcher Brandon , Bell Jimmy D , Thomas E Louise 
Published: December 2024

AbstractIn this study we assessed the accuracy of dual X-ray absorptiometry (DXA) compared to magnetic resonance imaging (MRI) for evaluating body composition. Using data from 32,961 participants in the UK Biobank, including 1,928 re-scanned participants after about two and a half years, we examined cross-sectional and longitudinal agreements in DXA and MRI measurements within android and gynoid regions. Our results showed that DXA reliably captured fat measurements but overestimated lean mass compared to MRI, particularly in android regions for men (4.10 vs. 1.74 kg) and women (2.92 vs. 1.10 kg). Longitudinal MRI data revealed a 4-5% muscle and lean mass decrease, undetected by DXA, which showed lean mass increases in women at the follow-up visit. Although DXA is practical for population-level fat assessments, MRI remains the preferred method for detailed and precise longitudinal body composition analysis.
Segmentation of the Human Tongue Musculature Using MRI: Field Guide and Validation in Motor Neuron Disease
Authors: Shaw Thomas B , Ribeiro Fernanda L , Zhu Xiangyun , Aiken Patrick , Bollmann Saskia , Bollmann Steffen , Chang Jeryn , Chidley Kali , Dempsey-Jones Harriet , Eftekhari Zeinab , Gillespie Jennifer , Henderson Robert D , Kiernan Matthew C , Ktena Ira , McCombe Pamela A , Ngo Shyuan T , Taubert Shana T , Whelan Brooke-Mai , Ye Xincheng , Steyn Frederik J , Tu Sicong , Barth Markus 
Published: December 2024

AbstractThe human tongue is a multifunctional organ with crucial roles in speech and swallowing. However, due to its anatomical characteristics, it is difficult to measure constituent muscle volumes, and few studies have investigated this aspect thoroughly. The present study introduces a novel method and datasets for automatically segmenting the musculature of the human tongue using non-invasive T1-weighted and T2-weighted MRI. We generated accurate and robust volume estimation of five intrinsic tongue muscles and developed and validated a comprehensive volume estimation method combining AI-assisted (deep learning) segmentation and atlas fusion approaches. We showcase its clinical potential in over 200 Magnetic Resonance (MR) scans including a clinically phenotyped cohort of neurodegenerative patients with motor neuron disease (MND). We describe detailed guidelines, publicly available multi-site datasets, and an externally validated normalisation strategy that removes confounding demographic characteristics and will allow generalised application across large publicly available MRI neuroimaging datasets. Results show expected differences in people living with MND; notably, those with clinical evidence of speech and swallowing dysfunction have smaller muscle volumes. As the tongue is generally covered in neuroimaging protocols, we envision that our proposed and validated analysis pipeline will allow the post-hoc analysis of a vast number of datasets. We expect this novel work to enable the investigation of tongue muscle volume as a marker in a wide range of diseases that implicate tongue function, including neurodegenerative diseases, pathological speech disorders and cancer.
Reference-free identification and pangenome analysis of accessory chromosomes in a major fungal plant pathogen
Authors: van Westerhoven Anouk C. , Fokkens Like , Wissink Kyran , Kema Gert , Rep Martijn , Seidl Michael F. 
Published: December 2024

AbstractAccessory chromosomes, found in some but not all individuals of a species, play an important role in pathogenicity and host specificity in fungal plant pathogens. However, their variability complicates reference-based analysis, especially when chromosomes are missing from reference genomes. Pangenome variation graphs offer a reference-free alternative for studying these chromosomes. Here, we constructed a pangenome variation graph forFusarium oxysporum, a major fungal plant pathogen with a compartmentalized genome. To study accessory chromosomes, we constructed a chromosome similarity network and identified eleven conserved core chromosomes and many highly variable accessory chromosomes. Some of these are host-specific and are likely involved in determining host range, which we corroborate by analyzing nearly 600F. oxysporumassemblies. By a reconstruction of pangenome variation graph per homologous chromosomes, we show that these evolve due to extensive structural variation as well as the exchange of genetic material between accessory chromosomes giving rise to these mosaic accessory chromosomes. Furthermore, we show that accessory chromosomes are horizontally transferred in natural populations. We demonstrate that pangenome variation graphs are a powerful approach to elucidate the evolutionary dynamics of accessory chromosomes inF. oxysporumand provides a computational framework for similar analyses in other species that encode accessory chromosomes.
CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity
Authors: Fisher Robert J. , Park Kihyun , Lee Kwangwoon , Pinjusic Katarina , Vanasse Allison , Ennis Christina S. , Ficcaro Scott , Marto Jarrod , Stransky Stephanie , Duke-Cohan Joseph , Geethadevi Anupa , Raabe Eric , Sidoli Simone , Hicks Chad W. , Keskin Derin B. , Wu Catherine J. , Cole Philip A. , Alani Rhoda M. 
Published: December 2024

ABSTRACTEpigenetic complexes tightly regulate gene expression and colocalize with RNA splicing machinery; however, the consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex with RNA splicing factors and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex inhibitor, corin, leading to extensive changes in RNA splicing in melanoma and other malignancies. Using predictive machine learning models and MHC IP-MS, we identify thousands of corin-induced neopeptides derived from unannotated splice sites which generate immunogenic splice-neoantigens. Furthermore, corin reactivates the response to immune checkpoint blockade and promotes dramatic expansion of cytotoxic T cells in an immune cold melanoma model. CoREST complex inhibition thus represents a unique therapeutic opportunity in cancer which creates tumor-associated neoantigens that enhance the immunogenicity of current therapeutics.Statement of SignificanceWe identify a novel role of the CoREST transcriptional repressor complex in regulating pre-mRNA splicing and find that the small molecule inhibitor, corin, promotes alternative splicing events in cancer leading to neoantigen expression and T cell-mediated immunity. This represents a potential approach to promote immunoreactive neoantigen expression in immune-cold tumors.