bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying drug-resistant individual cells within tumors by semi-supervised transfer learning from bulk to single-cell transcriptome
Authors: Huang Kaishun , Liu Hui 
Published: August 2024

AbstractThe presence of pre-existing or acquired drug-resistant cells within the tumor often leads to tumor relapse and metastasis. Single-cell RNA sequencing (scRNA-seq) enables elucidation of the subtle differences in drug responsiveness among distinct cell subpopulations within tumors. A few methods have employed scRNA-seq data to predict the drug response of individual cells to date, but their performance is far from satisfactory. In this study, we propose SSDA4Drug, a semi-supervised few-shot transfer learning method for inferring drug-resistant cancer cells. SSDA4Drug extracts pharmacogenomic features from both bulk and single-cell transcriptomic data using semi-supervised adversarial domain adaptation. This allows us to transfer knowledge of drug sensitivity from bulk-level cell lines to single cells. We conduct extensive performance evaluation experiments across multiple independent scRNA-seq datasets, demonstrating SSDA4Drug’s superior performance over current state-of-the-art methods. Remarkably, with only one or two labeled target-domain samples, SSDA4Drug significantly boosts the predictive performance of single-cell drug responses. Moreover, SSDA4Drug accurately recapitulates the temporally dynamic changes of drug responses during continuous drug exposure of tumor cells, and successfully identifies reversible drug-responsive states in lung cancer cells, which initially acquire resistance through drug exposure but later restore sensitivity during drug holidays. Also, our predicted drug responses consistently align with the developmental patterns of drug sensitivity observed along the evolutionary trajectory of oral squamous cell carcinoma cells. In addition, our derived SHAP values and integrated gradients effectively pinpoint the key genes involved in drug resistance in prostate cancer cells. These findings highlight the exceptional performance of our method in determining single-cell drug responses. This powerful tool holds the potential for identifying drug-resistant tumor cell subpopulations, paving the way for advancements in precision medicine and novel drug development.
DNA polymerase kappa stabilized by PTBP2 interacts with MRE11 and promotes genomic instability in leukemia cells
Authors: Lama Shristi , Barik Bibhudev , IS Sajitha , Sarkar Tannistha , Chanda Sayantan , Behera Monalisa , Behera Subhankar Priyadarshi , Biswas Sutapa , Mohapatra Sonali , Biswas Ghanashyam , Chakraborty Soumen 
Published: August 2024

AbstractPolypyrimidine tract binding protein 2 (PTBP2) is an RNA-binding protein that controls alternative splicing in neuronal, muscle, and Sertoli cells. Our study unveils a novel role of PTBP2 in promoting the excessive production of the DNA polymerase kappa (Polκ) by stabilizing its 3’UTR. We observed an association between its increased expression and the upregulation of PTBP2 in clinical samples of Chronic Myeloid Leukemia (CML).Ptbp2knock-out CML cell lines and patient samples treated with hydroxyurea presented with increased DNA damage, as evidenced by long comet tails and higher levels of the DNA damage marker, γH2AX foci, however overexpression ofPolκin thePtbp2-KO cells restored normal phenotype. The deregulation of the DNA repair pathway is a defining feature of malignancies and is closely associated with genomic instability. POLK was found to interact with MRE11 of the MRN complex, thereby governing the activation of ATM-CHK2. Cells with elevated levels ofPtbp2andPolκdemonstrated increased sister chromatid exchange and BrdU incorporation inex-vivoassays, while multinucleated cells with multipolar spindles were observed inin-vivoassays. Our findings confirm the critical role of the PTBP2-POLK axis in driving genomic instability and bolstering the viability of cells with increased malignancy.
Flower bud cooling protects pollen development and improves fertility during heatwaves
Authors: Jansen Martijn J. , Jansma Stuart Y. , Kuipers Klaske M. , Vriezen Wim H. , Millenaar Frank F. , Montoro Teresa , de Kovel Carolien G.F. , van Eeuwijk Fred A. , Visser Eric J.W. , Rieu Ivo 
Published: August 2024

AbstractEarly pollen development is a bottleneck for plant fertility in heatwave conditions, thus affecting yield stability. Mechanisms that protect this process and explain variation in tolerance level between genotypes are poorly understood. Here we show that sepal transpiration in young, still closed, flower buds reduces the impact of heat on developing tomato pollen and that this mechanism is enhanced by the major tomato pollen thermotolerance QTL, qPV11. By direct measurement of the flower bud core temperature and transpiration we show this process, which we term ‘flower bud cooling’, depends on heat-induced opening of sepal stomata and that the transpiration enhancing effect of qPV11 requires functional stomatal regulation and is specific to the sepals. Large-scale evaluation of populations in both a production field and greenhouse showed that qPV11 improves pollen viability and fruit set in heatwave-affected complex cultivation environments. These findings highlight enhanced flower bud cooling as a naturally evolved protection mechanism against heatwaves and qPV11 as genetic component in the differential regulation of transpiration between reproductive and vegetative tissues and candidate variant for the breeding of climate-resilient tomato cultivars.
ADAM interact with large protein complexes to regulate Histone modification, gene expression and splicing
Authors: Pandey Ankit , Cousin Helene , Kumar Shiv , Taylor Louis , Chander Ashmita , Coppenrath Kelsey , Shaidani Nikko-Ideen , Horb Marko , Alfandari Dominique 
Published: August 2024

AbstractCranial neural crest (CNC) cells are key stem cells that contribute to most of the facial structures in vertebrates. ADAM (A DisintegrinAndMetalloprotease) proteins are essential for the induction and migration of the CNC. We have shown that Adam13 associates with the transcription factor Arid3a to regulate gene expression. Here we show that Adam13 modulates Histone modifications in the CNC. We show that Arid3a binding to thetfap2αpromoter depends on the presence of Adam13. This association promotes the expression of onetfap2αvariant expressed in the CNC that uniquely activates the expression of gene critical for CNC migration. We show that both Adam13 and human ADAM9 associate with proteins involved in histone modification and RNA splicing, a function critically affected by the loss of Adam13. We propose that ADAMs may act as extracellular sensors to modulate chromatin availability, leading to changes in gene expression and splicing.
Awe is characterized as an ambivalent experience in the human behavior and cortex: integrated virtual reality-electroencephalogram study
Authors: Yi Jinwoo , Han Danny Dongyeop , Oh Seung-Yeop , Cha Jiook 
Published: August 2024

AbstractAmbivalent feelings are a defining feature of awe, which has been understood as a possible source of its psychosocial benefits. However, due to the conventional unidimensional model of affective valence, behavior and neural representation of ambivalent feelings during awe remain elusive. To address this gap, we combined awe-inducing virtual reality clips, electroencephalogram, and a deep learning-based dimensionality reduction technique (N= 43). Behaviorally, awe ratings were precisely predicted by the duration and intensity of ambivalent feelings, not by single valence-related metrics. In the electrophysiological analysis, we identified latent neural space for each participant sharing valence representation structures across individuals and stimuli. In these spaces, ambivalent feelings during awe were distinctly represented from positive and negative ones, and the variability in their distinctiveness specifically predicted awe ratings. Additionally, frontal delta oscillations mainly engaged in differentiating valence representations. Our findings demonstrate that awe is fundamentally an ambivalent experience reflected in both behavior and electrophysiological activities. This work provides a new framework for understanding complex emotions and their neural underpinnings, with potential implications for affective neuroscience and relevant fields.
Percent of lung involved in disease on chest X-ray predicts unfavorable treatment outcome in pulmonary tuberculosis
Authors: Ghanem Marwan , Srivastava Ratnam , Ektefaie Yasha , Hoppes Drew , Rosenfeld Gabriel , Yaniv Ziv , Grinev Alina , Xu Ava Y. , Yang Eunsol , Velásquez Gustavo E. , Harrison Linda , Rosenthal Alex , Savic Radojka M. , Jacobson Karen R. , Farhat Maha R. 
Published: August 2024

AbstractRadiology may better define tuberculosis (TB) severity and guide duration of treatment. We aimed to systematically study baseline chest X-rays (CXR) and their association with TB treatment outcome using real-world data. We used logistic regression to associate TB treatment outcomes with CXR findings, including percent of lung involved in disease (PLI), cavitation, and Timika score, alone or in combination with other clinical characteristics, stratifying by drug resistance status and HIV (n = 2,809). We fine-tuned convolutional neural nets (CNN) to automate PLI measurement from the CXR DICOM images (n = 5,261). PLI is the only CXR finding associated with unfavorable outcome across drug resistance and HIV subgroups [Rifampicin-susceptible disease without HIV, adjusted odds ratio (aOR) 1·11 (1·01, 1·22), P-value 0·025]. The most informed model of baseline characteristics tested predicts outcome with a validation mean area under the curve (AUC) of 0·769. PLI and Timika (AUC 0·656 and 0·655 respectively) predict unfavorable outcomes better than cavitary information (best AUC 0·591). The addition of PLI improves prediction compared to sex and age alone (AUC 0·680 and 0·627, respectively).PLI>25% provides a better separation of favorable and unfavorable outcomes compared to PLI>50%. The best performing ensemble of CNNs has an AUC 0·850 for PLI>25% and mean absolute error of 11·7% for the PLI value. PLI is better than cavitation for predicting unfavorable treatment outcome in pulmonary TB in non-clinical trial settings and it can be accurately and automatically predicted with CNNs.One Sentence SummaryThe percent of lung involved in disease improves prediction of unfavorable outcomes in pulmonary tuberculosis when added to clinical characteristics.
Clinical practice guidelines for the care of patients with a chronic subdural haematoma: multidisciplinary recommendations from presentation to recovery
Authors: Stubbs DJ , Davies BM , Edlmann E , Ansari A , Bashford TH , Braude P , Bulters D , Camp S , Carr G , Coles JP , DeMonteverde-Robb D , Dhesi J , Dinsmore J , Evans NR , Foster E , Fox E , Froom I , Gillespie CS , Gray N , Grieve K , Hartley P , Lecky F , Kolias A , Jeeves J , Joannides A , Minett T , Moppett I , Nathanson MH , Newcombe V , Outtrim JG , Owen N , Peterman L , Ralhan S , Shipway D , Sinha R , Thomas W , Whitfield P , Wilson SR , Zolnourian A , Dixon-Woods M , Menon DK , Hutchinson PJ 
Published: August 2024

AbstractIntroductionA cSDH is an encapsulated collection of fluid and blood degradation products in the subdural space. It is increasingly common, affecting older people and those living with frailty. Currently, no guidance exists to define optimal care from onset of symptoms through to recovery. This paper presents the first consensus- built recommendations for best practice in the care of cSDH, co-designed to support each stage of the patient pathway.MethodsGuideline development was led by a multidisciplinary Steering Committee with representation from diverse clinical groups, professional associations, patients, and carers. Literature searching to identify relevant evidence was guided by core clinical questions formulated through facilitated discussion with specially convened working groups. A modified Delphi exercise was undertaken to build consensus on draft statements for inclusion in the guideline using survey methodology and an in-person meeting. The proposed guideline was subsequently endorsed by the Society for British Neurological Surgeons, Neuroanaesthesia and Critical Care Society, Association of Anaesthetists, British Association of Neuroscience Nurses, British Geriatric Society, and Centre for Perioperative Care.ResultsWe identified that high quality evidence was generally lacking in the literature, although randomised controlled trial (RCT) data were available to inform specific recommendations on aspects of surgical technique and use of corticosteroids. The final guideline represents the outcome of synthesising the available evidence as well as consensus-built expert opinion and patient involvement. The guideline comprises 67 recommendations across 8 major themes, covering: presentation and diagnosis, neurosurgical triage and shared decision-making, non-operative management, perioperative management (including of anticoagulation), timing of surgery, intraoperative care, postoperative care, rehabilitation and recovery.ConclusionsWe present the first multidisciplinary guideline for the care of patients with cSDH. The recommendations reflect a paradigm shift in the care of cSDH, recognising and formalising the need for multidisciplinary and collaborative clinical management and communication and decision-making with patients delivered effectively across secondary and tertiary care.
DNA methylation patterns contribute to changes of cellular differentiation pathways in leukocytes with LOY from patients with Alzheimer’s disease
Authors: Jąkalski Marcin , Bruhn-Olszewska Bożena , Rychlicka-Buniowska Edyta , Davies Hanna , Sarkisyan Daniil , Siedlar Maciej , Baran Jarosław , Węglarczyk Kazimierz , Jaszczynski Janusz , Ryś Janusz , Gedraitis Vilmantas , Filipowicz Natalia , Klich-Rączka Alicja , Kilander Lena , Ingelsson Martin , Dumanski Jan P. 
Published: August 2024

ABSTRACTAlzheimer’s disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of chromosome Y (LOY) in leukocytes is strongly associated with AD. We studied here DNA methylation and RNA expression in sorted monocytes and granulocytes with and without LOY from male AD patients. Through multi-omic analysis, we identified new candidate genes and confirmed the involvement of numerous genes previously associated with AD. Our findings highlight LOY-related differences in DNA methylation that occur in gene regulatory regions and are predominantly accompanied by down-regulation of affected genes. Specifically, we observed alterations in key genes involved in leukocyte differentiation:FLI1, involved in early hematopoiesis;RUNX1, essential for blood cell development;RARA, regulating gene expression in response to retinoic acid;CANX, crucial for protein folding;CEBPB, a transcription factor important for immune responses; andMYADM, implicated in cell adhesion and migration. Moreover, protein-protein interaction analysis in granulocytes identified that products of two of these genes,CANXandCEBPB, are key hub proteins. Thus, LOY appears to dysregulate genes involved in leukocyte differentiation and induce higher-level epigenetic changes. This research underscores the potential of multi-omic approaches in pure cell populations to uncover the molecular underpinnings of AD and reinforces the significance of LOY as a pathogenic factor in this disease. Overall, results support the hypothesis that age-related immune cell dysfunction contributes to AD development. Finally, our results link previous analysis showing impact of LOY on leukocyte differentiation, LOY-associated transcriptional dysregulation and GWAS studies of LOY.
Seroepidemiology of human leptospirosis in the Dominican Republic: a multistage cluster survey, 2021
Authors: Nilles Eric J. , Paulino Cecilia Then , Galloway Renee , Aubin Michael de St. , Mayfield Helen J. , Restrepo Angela Cadavid , Dumas Devan , Garnier Salome , Etienne Marie Caroline , Duke William , Peña Farah , Iihoshi Naomi , Abdalla Gabriela , Lopez Beatriz , de la Cruz Lucia , Henríquez Bernarda , Durski Kara , Baldwin Margaret , Loevinsohn Gideon , Rees Eleanor M. , Martin Beatris , Sartorius Benn , Skewes-Ramm Ronald , Gutiérrez Emily Zielinski , Kucharski Adam , Lau Colleen L. 
Published: August 2024

AbstractLittle is known about the epidemiology of leptospirosis in the Dominican Republic, the second most populous country in the Caribbean. We report on findings from a multi-stage household survey across two regions in the country that reveals a previously under-estimated burden of humanLeptospirainfection. Our findings, based on the reference-standard microscopic agglutination test, indicate a complex picture of serogroup diversity, spatial heterogeneity in infection and risk, and a marked discrepancy between reported cases and serologically estimated infections. Given an overall seroprevalence of 11.3% (95% CI: 10.8-13.0%) and a lower estimated force of infection (0.30% per year [0.27% - 0.35%]) the number of infections may exceed national reported case data by 145-fold or more. Icterohaemorrhagiae, associated with severe Weil’s disease, was the most commonly identified serogroup with a serogroup-specific prevalence of 4.4%. Consistent with other settings, risk factors including age, male sex, and rat exposure were associated with higher seroprevalence. Our study highlights the need for targeted public health interventions informed by serogroup-specific dynamics, detailed spatial analyses, knowledge of local animal reservoirs, and strengthened laboratory surveillance to effectively control this pathogen.
Metabolic reaction fluxes as amplifiers and buffers of risk alleles for coronary artery disease
Authors: Foguet Carles , Jiang Xilin , Ritchie Scott C. , Persyn Elodie , Xu Yu , Ben-Eghan Chief , Di Angelantonio Emanuele , Danesh John , Butterworth Adam S. , Lambert Samuel A. , Inouye Michael 
Published: August 2024

AbstractGenome-wide association studies have identified thousands of variants associated with disease risk but the mechanism by which such variants contribute to disease remains largely unknown. Indeed, a major challenge is that variants do not act in isolation but rather in the framework of highly complex biological networks, such as the human metabolic network, which can amplify or buffer the effect of specific risk alleles on disease susceptibility. In our previous work, we established that metabolic models can be leveraged to simulate the emerging metabolic effects of genetically driven variation in transcript levels and estimate personalized metabolic reaction fluxes. Here we use genetically predicted reaction fluxes to perform a systematic search for metabolic fluxes acting as buffers or amplifiers of coronary artery disease (CAD) risk alleles. Our analysis identifies 30 risk locus - reaction flux pairs with significant interaction on CAD susceptibility involving 18 individual reaction fluxes and 8 independent risk loci. Notably, many of these reactions are linked to processes with putative roles in the disease such as the metabolism of inflammatory mediators and fatty acids. In summary, this work establishes proof of concept that biochemical reaction fluxes can have non-additive effects with risk alleles and provides novel insights into the interplay between metabolism and genetic variation on disease susceptibility.
Thomasclavelia ramosais a Signature of Gut Dysbiosis associated with Alcohol-Related Hepatocellular Carcinoma: A First Microbial Culturomics Study
Authors: Wasfy Reham Magdy , Abdoulaye Anissa , Borentain Patrick , Mbaye Babacar , Alou Maryam Tidjani , Caputo Aurelia , Andrieu Claudia , Mottola Giovanna , Levasseur Anthony , Million Matthieu , Gerolami Rene 
Published: August 2024

AbstractBackgroundGut microbiota alteration is implicated in the pathogenesis of alcoholic liver disease (ALD) and HCC. No study has characterized the dysbiosis associated with ALD by microbial culturomics, an approach that certifies viability and allows the characterization of pathobiont strain candidates.MethodsA case-control study was conducted on patients with ALD without HCC (ALD-NoHCC) (n=16), ALD with HCC (ALD-HCC) (n=19), and controls (n=24). 16S rRNA amplicon sequencing and microbial culturomics were used as complementary methods for gut microbiome profiling.ResultsBy microbial culturomics,Thomasclavelia ramosawas the most enriched and detected in all ALD samples (100%), while it was cultivated in only a small proportion of controls (20%, p < 0.001). By 16S rRNA amplicon sequencing and 3-groups linear discriminant analysis,T. ramosawas increased explicitly in the ALD-HCC group (LDA-score > 5, p < 0.05).ConclusionsT. ramosa,identified by culturomics and 16 rRNA sequencing, is associated with ALD and ALD-HCC. Alongside the recently reported in vitro genotoxicity of this species in colorectal cancer, this species has been identified as a candidate oncobiont in ALD-HCC.HighlightsThe gut microbiota signature of ALD and ALD-HCC was explored by microbial culturomics and 16S amplicon sequencingBy culturomics,T. ramosawas the most enriched and cultured from all included ALD patients, but in only 20% of controls (p < 0.05).T. ramosawas significantly associated with alcohol-related HCC by 16S sequencing.T. ramosais identified as a putative oncobiont associated with ALD-HCC, thus opening new avenues for diagnosis and treatment.Graphical abstract
Rethinking the residual approach: Leveraging machine learning to operationalize cognitive resilience in Alzheimer’s disease
Authors: Birkenbihl Colin , Cuppels Madison , Boyle Rory T. , Klinger Hannah M. , Langford Oliver , Coughlan Gillian T. , Properzi Michael J. , Chhatwal Jasmeer , Price Julie C. , Schultz Aaron P. , Rentz Dorene M. , Amariglio Rebecca E. , Johnson Keith A. , Gottesman Rebecca F. , Mukherjee Shubhabrata , Maruff Paul , Lim Yen Ying , Masters Colin L. , Beiser Alexa , Resnick Susan M. , Hughes Timothy M. , Burnham Samantha , Tunali Ilke , Landau Susan , Cohen Ann D. , Johnson Sterling C. , Betthauser Tobey J. , Seshadri Sudha , Lockhart Samuel N. , O’Bryant Sid E. , Vemuri Prashanthi , Sperling Reisa A. , Hohman Timothy J. , Donohue Michael C. , Buckley Rachel F. 
Published: August 2024

AbstractCognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer’s disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model’s residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach’s limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data.