bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancement of mediodorsal thalamus rescues aberrant belief dynamics in a mouse model with schizophrenia-associated mutation
Authors: Zhou Tingting , Ho Yi-Yun , Lee Ray X. , Fath Amanda B. , He Kathleen , Scott Jonathan , Bajwa Navdeep , Hartley Nolan D. , Wilde Jonathan , Gao Xian , Li Cui , Hong Evan , Nassar Matthew R. , Wimmer Ralf D. , Singh Tarjinder , Halassa Michael M. , Feng Guoping 
Published: January 2024

AbstractOptimizing behavioral strategy requires belief updating based on new evidence, a process that engages higher cognition. In schizophrenia, aberrant belief dynamics may lead to psychosis, but the mechanisms underlying this process are unknown, in part, due to lack of appropriate animal models and behavior readouts. Here, we address this challenge by taking two synergistic approaches. First, we generate a mouse model bearing patient-derived point mutation in Grin2a (Grin2aY700X+/−), a gene that confers high-risk for schizophrenia and recently identified by large-scale exome sequencing. Second, we develop a computationally trackable foraging task, in which mice form and update belief-driven strategies in a dynamic environment. We found thatGrin2aY700X+/−mice perform less optimally than their wild-type (WT) littermates, showing unstable behavioral states and a slower belief update rate. Using functional ultrasound imaging, we identified the mediodorsal (MD) thalamus as hypofunctional inGrin2aY700X+/−mice, andin vivotask recordings showed that MD neurons encoded dynamic values and behavioral states in WT mice. Optogenetic inhibition of MD neurons in WT mice phenocopiedGrin2aY700X+/−mice, and enhancing MD activity rescued task deficits in Grin2aY700X+/−mice. Together, our study identifies the MD thalamus as a key node for schizophrenia-relevant cognitive dysfunction, and a potential target for future therapeutics.
Phosphorylation inhibits intramolecular interactions, DNA-binding and protein interactions of Claspin through disordered/ structured conformation transition
Authors: You Zhiying , Hsiao Hao-Wen , Yang Chi-Chun , Goto Hidemasa , Masai Hisao 
Published: January 2024

AbstractClaspin, known to be highly disordered, plays important roles in replication fork progression, initiation and cellular responses to replication stress. However, regulation of its structure and molecular interactions is not completely understood. We show here, through Proximity-Ligation-Assays, the evidence for intramolecular interaction between the N- and C-terminal segments of Claspin, which depends on the Acidic-Patch [AP] segment near its C-terminus. Interaction of Claspin with DNA and replication factors is highly stimulated in ΔAP mutant and by prior dephosphorylation. The wild-type Claspin inhibits the helicase activity of MCM in an AP-dependent manner. ΔAP and dephosphorylated Claspin exhibit resistance to trypsin digestion compared to wild-type, suggesting the presence of structural domains in the formers. We propose that Claspin is converted from disordered (closed) to structured (open) conformation at initiation, which stimulates its DNA binding and interaction with replication factors and counteracts its helicase inhibitory activity to trigger initiation of DNA replication.
An assessment of the value of deep neural networks in genetic risk prediction for surgically relevant outcomes
Authors: Christensen Mathias A , Sigurdsson Arnór , Bonde Alexander , Rasmussen Simon , Ostrowski Sisse R , Nielsen Mads , Sillesen Martin 
Published: January 2024

AbstractIntroductionPostoperative complications affect up to 15% of surgical patients constituting a major part of the overall disease burden in a modern healthcare system. While several surgical risk calculators have been developed, none have so far been shown to decrease the associated mortality and morbidity. Combining deep neural networks and genomics with the already established clinical predictors may hold promise for improvement.MethodsThe UK Biobank was utilized to build linear and deep learning models for the prediction of surgery relevant outcomes. An initial GWAS for the relevant outcomes was initially conducted to select the Single Nucleotide Polymorphisms for inclusion in the models. Model performance was assessed with Receiver Operator Characteristics of the Area Under the Curve and optimum precision and recall. Feature importance was assessed with SHapley Additive exPlanations.ResultsModels were generated for atrial fibrillation, venous thromboembolism and pneumonia as genetics only, clinical features only and a combined model. For venous thromboembolism, the ROC-AUCs were 59.6% [59.0%-59.7%], 63.4% [63.2%-63.4%] and 66.1% [65.7%-66.1%] for the linear models and 60.0% [57.8%-61.8%], 63.2% [61.2%-65.0%] and 65.4% [63.6%-67.2%] for the deep learning SNP, clinical and combined models, respectively. For atrial fibrillation, the ROC-AUCs were 60.9% [60.6%-61.0%], 78.7% [78.7%-78.7%] and 80.1% [80.0%-80.1%] for the linear models and 59.9% [.6%-61.3%], 78.8% [77.8%-79.8%] and 79.4% [78.8%-80.5%] for the deep learning SNP, clinical and combined models, respectively. For pneumonia, the ROC-AUCs were 57.3% [56.5%-57.4%], 69.2% [69.1%-69.2%] and 70.5% [70.2%-70.6%] for the linear models and 55.5% [54.1%-56.9%], 69.7% [.5%-70.8%] and 69.9% [68.7%-71.0%] for the deep learning SNP, clinical and combined models, respectively.ConclusionIn this report we presented linear and deep learning predictive models for surgery relevant outcomes. Overall, predictability was similar between linear and deep learning models and inclusion of genetics seemed to improve accuracy.
Multi-ancestry polygenic risk scores for venous thromboembolism
Authors: Jee Yon Ho , Thibord Florian , Dominguez Alicia , Sept Corriene , Boulier Kristin , Venkateswaran Vidhya , Ding Yi , Cherlin Tess , Verma Shefali Setia , Faro Valeria Lo , Bartz Traci M. , Boland Anne , Brody Jennifer A. , Deleuze Jean-Francois , Emmerich Joseph , Germain Marine , Johnson Andrew D. , Kooperberg Charles , Morange Pierre-Emmanuel , Pankratz Nathan , Psaty Bruce M. , Reiner Alexander P. , Smadja David M. , Sitlani Colleen M. , Suchon Pierre , Tang Weihong , Trégouët David-Alexandre , Zöllner Sebastian , Pasaniuc Bogdan , Damrauer Scott M. , Sanna Serena , Snieder Harold ,   Lifelines Cohort Study, Kabrhel Christopher , Smith Nicholas L. , Kraft Peter ,   INVENT Consortium
Published: January 2024

AbstractVenous thromboembolism (VTE) is a significant contributor to morbidity and mortality, with large disparities in incidence rates between Black and White Americans. Polygenic risk scores (PRSs) limited to variants discovered in genome-wide association studies in European-ancestry samples can identify European-ancestry individuals at high risk of VTE. However, there is limited evidence on whether high-dimensional PRS constructed using more sophisticated methods and more diverse training data can enhance the predictive ability and their utility across diverse populations. We developed PRSs for VTE using summary statistics from the International Network against Venous Thrombosis (INVENT) consortium GWAS meta-analyses of European- (71,771 cases and 1,059,740 controls) and African-ancestry samples (7,482 cases and 129,975 controls). We used LDpred2 and PRSCSx to construct ancestry-specific and multi-ancestry PRSs and evaluated their performance in an independent European- (6,261 cases and 88,238 controls) and African-ancestry sample (1,385 cases and 12,569 controls). Multi-ancestry PRSs with weights tuned in European- and African-ancestry samples, respectively, outperformed ancestry-specific PRSs in European- (PRSCSXEUR: AUC=0.61 (0.60, 0.61), PRSCSX_combinedEUR: AUC=0.61 (0.60, 0.62)) and African-ancestry test samples (PRSCSXAFR: AUC=0.58 (0.57, 0.6), PRSCSX_combinedAFR: AUC=0.59 (0.57, 0.60)). The highest fifth percentile of the best-performing PRS was associated with 1.9-fold and 1.68-fold increased risk for VTE among European- and African-ancestry subjects, respectively, relative to those in the middle stratum. These findings suggest that the multi-ancestry PRS may be used to identify individuals at highest risk for VTE and provide guidance for the most effective treatment strategy across diverse populations.
Attribution of invasive group A streptococcal infections to varicella and respiratory virus circulation, the Netherlands, 2010-2023
Authors: de Gier Brechje , van de Kassteele Jan , van Asten Liselotte , Schoffelen Annelot ,   ISIS-AR study group, Hooiveld Mariette , te Wierik Margreet J.M. , van Sorge Nina M. , de Melker Hester E. 
Published: January 2024

AbstractBackgroundAfter the lifting of most COVID-19 control measures, many infectious diseases re-emerged in 2022. A strong increase in invasive group A streptococcal (iGAS) infections, among both adults and young children, was reported by several countries. Viral infections such as influenza and varicella, known risk factors for iGAS infection, also increased during 2022. We estimated the proportion of GAS skin and soft tissue infections (SSTI) in children aged 0-5 years attributable to varicella, and the proportion of GAS pneumonia/sepsis in children aged 0-5 and adults attributable to respiratory viruses in the Netherlands.MethodsWe performed time-series regression using weekly data on influenza A and B, RSV, hMPV and SARS-CoV-2, varicella and non-invasive GAS infections, and GAS isolates cultured from blood, lower airways, skin, pus and wounds, from January 2010 to March 2023.ResultsUp to 2022, approximately 50%(95%CI 36-64%) of GAS SSTI in children were attributable to varicella. Between January 2022 and March 2023, 34%(95%CI 24-43%) of GAS SSTI cases were attributable to varicella. Of iGAS pneumonia/sepsis between January 2022 and March 2023, 25%(95%CI 18-31%) and 37%(95% CI 23-53%) was attributable to respiratory virus infections in adults and children, respectively, with the largest contributor being influenza A.ConclusionsVaricella and respiratory virus infections likely contributed to, but only partly explain, the observed iGAS increase among children and adults in 2022-2023 in the Netherlands. Public health measures to control viral infections, such as vaccination against varicella or influenza, might reduce the iGAS disease burden but will not suffice to curb the current high incidence.
Prevalence of Asymptomatic non-Falciparum and Falciparum Malaria in the 2014-15 Rwanda Demographic Health Survey
Authors: Gaither Claudia , Morgan Camille , Kirby Rebecca , Karema Corine , Gashema Pierre , White Samuel J. , Topazian Hillary M. , Geibrecht David , Thwai Kyaw , Wernsman Young Neeva , Boyter Koby , Munyaneza Tharcisse , Mambo Muvunyi Claude , De Dieu Butera Jean , Bailey Jeffrey A. , Mazarati Jean-Baptiste , Juliano Jonathan J. 
Published: January 2024

AbstractSummaryNon-falciparum and asymptomaticPlasmodium falciparummalaria are prevalent across Rwanda, withP. falciparumlinked to poverty, rural areas, and low elevation. Mixed infections are frequent. Molecular surveillance is crucial to guide effective malaria control efforts.BackgroundRecent molecular surveillance suggests an unexpectedly high prevalence of non-falciparum malaria in Africa. Malaria control is also challenged by undetected asymptomaticP. falciparummalaria resulting in an undetectable reservoir for potential transmission. Context-specific surveillance of asymptomaticP. falciparumand non-falciparum species is needed to properly inform malaria control programs.MethodsWe performed quantitative real time PCR for four malaria species in 4,595 primarily adult individuals in Rwanda using the 2014-2015 Demographic Health Survey. We assessed correlates of infection by species to explore attributes associated with each species. AsymptomaticP. ovale spp.,P. malariae, and P. falciparummalaria infection had broad spatial distribution across Rwanda.P. vivaxinfection was rare.ResultsOverall infection prevalence was 23.6% (95%CI [21.7%, 26.0%]), withP. falciparumand non-falciparum at 17.6% [15.9%, 19.0%] and 8.3% [7.0%, 10.0%], respectively. Parasitemias tended to be low and mixed species infections were common, especially where malaria transmission and overall prevalence was the highest.P. falciparuminfection was associated with lower wealth, rural residence and low elevation. Fewer factors were associated with non-falciparum malaria.ConclusionsAsymptomatic non-falciparum malaria andP. falciparummalaria are common and widely distributed across Rwanda in adults. Continued molecular monitoring ofPlasmodium spp.is needed to strengthen malaria control.
The road to achieving viral hepatitis elimination in Suriname: The progress, the challenges and the goals
Authors: Loe-Sack-Sioe Giovanni E. , Neus Anfernee , Woittiez Lycke , Mawie Terrence , Coenjaerts Frank , Donald – Ottevanger Sigrid Mac , Vreden Stephen 
Published: January 2024

AbstractBackgroundViral hepatitis is one of the leading causes of liver failure, cirrhosis, hepatocellular cancer and mortality worldwide and has long had limited treatment options. Estimates suggest that around 30% of the global population has at one point been infected with HBV, while 3.9% are chronically infected. 1.6 – 2.8% of the world population is estimated to be infected with HCV. With the introduction of the HBV birth-dose vaccines, HBV immunoglobulins and the more recent development of the HCV direct-acting antiviral medication, HBV and HCV infections have now become containable diseases. In 2016, all 194 member states of the World Health Organization endorsed the public-health goal to eradicate viral hepatitis by 2030. Yet, as of 2023, only a small group of countries are on course to achieving this goal. Suriname, a small, multi-ethnic country, located in the north of South America, has an intermediate prevalence of HBV and HCV of 3% and 1% respectively. Previously performed studies, however, show strong ethnic clustering in Suriname.AimWith this manuscript we dissect the strategy we developed to tackle the hepatitis challenge in Suriname. We explain the importance of establishing more detailed insight into the geographical distribution of high-prevalence areas, as linked to the ethnic differences in the population. We present the screening and contact tracing approaches and end with our current insights on how to proceed toward further prevention and treatment options. Overall, we provide a blueprint towards eliminating viral hepatitis with simple and effective strategies usable in resource-limited countries with an intermediate to high prevalence of viral hepatitis.
Development of a Novel Risk Score for Predicting One-Year Mortality Risk in Patients with Atrial Fibrillation using XGBoost-Assisted Feature Selection
Authors: Wang Bin , Jin Feifei , Cao Han , Li Qing , Zhang Ping 
Published: January 2024

ABSTRACTBackgroundThere is a lack of tools specifically designed to assess mortality risk in patients with atrial fibrillation (AF). The aim of this study was to utilize machine learning methods for identifying pertinent variables and developing an easily applicable prognostic score to predict 1-year mortality in AF patients.MethodsThis single-center retrospective cohort study based on the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database focused on patients aged 18 years and older with AF. The study thoroughly scrutinized patient data to identify and analyze variables, encompassing demographic variables, comorbidities, scores, vital signs, laboratory test results, and medication usage. The variable importance from XGBoost guided the development of a logistic model, forming the basis for an AF scoring model. Decision curve analysis was used to compare the AF score with other scores. Python and R software were used for data analysis.ResultsA cohort of 59,595 AF patients was obtained from the MIMIC-IV database; these patients were predominantly elderly (median age 77.3 years) and male (55.6%). The XGBoost model effectively predicted 1-year mortality (Area under the curve (AUC): 0.833; 95% confidence intervals: 0.826-0.839), underscoring the significance of the Charlson Comorbidity Index (CCI) and the presence of metastatic solid tumors.The CRAMB score (Charlson comorbidity index, readmission, age, metastatic solid tumor, and blood urea nitrogen maximum) outperformed the CCI and CHA2DS2-VASc scores, demonstrating superior predictive value for 1-year mortality. In the test set, the area under the ROC curve (AUC) for the CRAMB score was 0.756 (95% confidence intervals: 0.748-0.764), surpassing the CCI score of 0.720 (95% confidence intervals: 0.712-0.728) and the CHA2DS2-VASc score of 0.609 (95% confidence intervals: 0.600-0.618). Decision curve analysis revealed that the CRAMB score had a consistently positive effect and greater net benefit across the entire threshold range than did the default strategies and other scoring systems. The calibration plot for the test set indicated that the CRAMB score was well calibrated.ConclusionsThis study’s primary contribution is the establishment of a benchmark for utilizing machine learning models in construction of a score for mortality prediction in AF. The CRAMB score was developed by leveraging a large-sample population dataset and employing XGBoost models for predictor screening. The simplicity of the CRAMB score makes it user friendly, allowing for coverage of a broader and more heterogeneous AF population.
Sphingolipid metabolism orchestrates the establishment of the adult hair follicle stem cell niche to control skin homeostasis
Authors: Peters Franziska , Brodesser Susanne , Kruse Kai , Drexler Hannes C.A. , Hu Jiali , Lukas Dominika , von Stebut Esther , Krönke Martin , Niessen Carien M. , Wickström Sara A. 
Published: January 2024

AbstractBioactive sphingolipids serve as an essential building block of membranes, forming a selective barrier that ensures subcellular compartmentalization and facilitates cell type-specific intercellular communication through regulation of the plasma membrane receptor repertoire. How cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem-cell specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in skin epidermis. Deletion of CerS4 in the epidermis prevents the effective development of the adult hair follicle bulge stem cell (HFSCs) niche due to altered differentiation trajectories of HFSC precursors towards upper hair follicle and inner bulge fates. Mechanistically, HFSC differentiation defects arise from an imbalance of key ceramides and their derivate sphingolipids in HFSCs associated with hyperactivity of canonical Wnt signaling. Impaired HFSC niche establishment leads to disruption of hair follicle architecture and hair follicle barrier function, ultimately triggering a T helper cell 2 - dominated immune infiltration closely resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in epidermal stem cell homeostasis and the role of an intact stem cell niche in maintaining an intact skin barrier.
Single molecule delivery into living cells
Authors: Chau Chalmers C. , Maffeo Christopher M. , Aksimentiev Aleksei , Radford Sheena E. , Hewitt Eric W. , Actis Paolo 
Published: January 2024

AbstractControlled manipulation of cultured cells by delivery of exogenous macromolecules is a cornerstone of experimental biology. Here we describe a platform which uses nanopipettes to deliver defined numbers of macromolecules into cultured cell lines and primary cells at single molecule resolution. In the nanoinjection platform the nanopipette is used as both a scanning ion conductance microscope (SICM) scanning probe and as an injection probe. The SICM is used to position the nanopipette above the cell surface, before the nanopipette is inserted into the cell into a defined location and to a predefined depth. We demonstrate that the nanoinjection platform enables the quantitative delivery of DNA, globular proteins and protein fibrils into cells with single molecule resolution and that delivery results in a phenotypic change in the cell that depends on the identity of the molecules introduced. Using experiments and computational modelling, we also show that macromolecular crowding in the cell increases the signal to noise ratio for the detection of translocation events, thus the cell itself enhances the detection of the molecules delivered.
Computationally guided exploration of borosin biosynthetic strategies
Authors: Lee Aileen R. , Carter Riley S. , Imani Aman S. , Dommaraju Shravan R. , Hudson Graham A. , Mitchell Douglas A. , Freeman Michael F. 
Published: January 2024

AbstractBorosins are ribosomally synthesized and post-translationally modified peptides containing backbone α-N-methylations. Identification of borosin precursor peptides is difficult because (1) there are no conserved sequence elements among borosin precursor peptides and (2) the biosynthetic gene clusters contain numerous domain architectures and peptide fusions. To tackle this problem, we updated the genome mining tool RODEO to automatically evaluate putative borosin BGCs and identify precursor peptides. Enabled by the new borosin module, we analyzed all borosin BGCs found in available sequence data and assigned precursor peptides to previously orphan borosin methyltransferases. Additionally, we bioinformatically predict and experimentally characterize a new fused borosin domain architecture, in which the modified core is N-terminal to the methyltransferase domain. Finally, we demonstrate that a borosin precursor peptide is the native substrate of shewasin A, a previously characterized pepsin-like aspartic peptidase whose native biological function was unknown.
Timing the cerebellum and its connectivity within the social brain
Authors: Ciricugno Andrea , Ferrari Chiara , Battelli Lorella , Cattaneo Zaira 
Published: January 2024

AbstractThe posterior cerebellum is a recently discovered hub of the affective and social brain, with different subsectors contributing to different social functions. However, very little is known aboutwhenthe posterior cerebellum plays a critical role in social processing. Due to its location and anatomy, it has been difficult to use traditional approaches to directly study the chronometry of the cerebellum. To address this gap in cerebellar knowledge, here we investigated for the first time thecausalcontribution of the posterior cerebellum to social processing using a chronometric transcranial magnetic stimulation (TMS) approach. We show that the posterior cerebellum is recruited at an early stage of the emotional processing (starting from 100 ms after stimulus onset), simultaneously with the posterior superior temporal sulcus (pSTS), a key node of the emotional-social brain. Moreover, using a condition-and-perturb TMS approach, we found that the recruitment of the pSTS in emotional processing is dependent on cerebellar activation. Our results are the first to shed light on chronometric aspects of cerebellar function and its causal connectivity with other nodes of the social brain.