bluuebunny/crossref_metadata_2025_split huggingface dataset:
The fungal protein Jps1 facilitates unconventional protein secretion through a direct phosphoinositide interaction
Authors: Dali Sanchi , Schultz Michèle , Köster Marian , Kamel Michael , Busch Max , Steinchen Wieland , Hänsch Sebastian , Papadopoulos Athanasios , Reiners Jens , Smits Sander H. J. , Kedrov Alexej , Altegoer Florian , Schipper Kerstin 
Published: March 2024

AbstractProtein secretion is indispensable for essential cellular processes in eukaryotic cells, contributing significantly to nutrient acquisition, defense or communication. Alternative pathways bypassing the endomembrane system collectively referred to as unconventional secretion are gaining increasing attention. A number of important molecules such as cytokines, fibroblast growth factor or viral proteins are being exported through these mechanistically diverse pathways. In the fungal modelUstilago maydis, cytokinesis-dependent unconventional secretion mediates export of the chitinase Cts1 via the fragmentation zone. This membrane-rich compartment is formed during cytokinesis between mother and daughter cells. Recently, we identified Jps1, a previously uncharacterized protein, as a crucial factor for Cts1 localization and export. Combining biochemical experiments andin vivostudies, we here uncover two pivotal features of Jps1: dimerization and phosphoinositide (PIP) binding. Our findings reveal that a conserved structural core domain mediates homodimerization, while surrounding flexible variable regions suggest potential diversification in different basidiomycete species. Jps1 does not harbor a canonical PIP-binding domain but instead specificity of the interaction with the preferred PIP PI(4,5)P2is determined by basic residues. Importantly, loss of PI(4,5)P2binding specificity results in mis-localisation, morphological defects and reduced extracellular Cts1 activity, particularly at low cell densities. This discovery sheds light on previously unknown key features of Jps1, elucidating its role in supporting Cts1 secretion, and representing a crucial step towards understanding the broader implications of unconventional secretion in eukaryotic cells.
Phospho-Tune: Enhanced Structural Modeling of Phosphorylated Protein Interactions
Authors: Glukhov Ernest , Averkava Veranika , Kotelnikov Sergei , Stepanenko Darya , Nguyen Thu , Mitchell Julie C. , Simmerling Carlos , Vajda Sandor , Emili Andrew , Padhorny Dzmitry , Kozakov Dima 
Published: March 2024

AbstractIn computational biology, accurate prediction of phosphopeptide-protein complex structures is essential for understanding cellular functions and advancing drug discovery and personalized medicine. While AlphaFold has significantly improved protein structure prediction, it faces accuracy challenges in predicting structures of complexes involving phosphopeptides possibly due to structural variations introduced by phosphorylation in the peptide component. Our study addresses this limitation by refining AlphaFold to improve its accuracy in modeling these complex structures. We employed weighted metrics for a comprehensive evaluation across various protein families. The enhanced model notably outperforms the original AlphaFold, showing a substantial increase in the weighted average local distance difference test (lDDT) scores for peptides: from 52.74 to 76.51 in the Top 1 model and from 56.32 to 77.91 in the Top 5 model. These advancements not only deepen our understanding of the role of phosphorylation in cellular signaling but also have extensive implications for biological research and the development of innovative therapies.
Nephronophthisis-associated FBW7 mediates cyst-dependent decline of renal function in ADPKD
Authors: Patel Maulin Mukeshchandra , Gerakopoulos Vasileios , Petsouki Eleni , Zimmerman Kurt A. , Tsiokas Leonidas 
Published: March 2024

ABSTRACTNephronophthisis (NPHP) and autosomal dominant Polycystic Kidney Disease (ADPKD) are two genetically distinct forms of Polycystic Kidney Disease (PKD), yet both diseases present with kidney cysts and a gradual decline in renal function. Prevailing dogma in PKD is that changes in kidney architecture account for the decline in kidney function, but the molecular/cellular basis of such coupling is unknown. To address this question, we induced a form of proteome reprogramming by deletingFbxw7encoding FBW7, the recognition receptor of the SCFFBW7E3 ubiquitin ligase in different segments of the kidney tubular system. Deletion ofFbxw7in the medulla led to a juvenile-adult NPHP-like phenotype, where the decline in renal function was due to SOX9-mediated interstitial fibrosis rather than cystogenesis. In contrast, the decline of renal function in ADPKD is coupled to cystic expansion via the abnormal accumulation of FBW7 in the proximal tubules and other cell types in the renal cortex. We propose that FBW7 functions at the apex of a protein network that determines renal function in ADPKD by sensing architectural changes induced by cystic expansion.
Quantitative analysis of cis-regulatory elements in transcription with KAS-ATAC-seq
Authors: Lyu Ruitu , Gao Yun , Wu Tong , Ye Chang , Wang Pingluan , He Chuan 
Published: March 2024

AbstractCis-regulatory elements (CREs) are pivotal in orchestrating gene expression throughout diverse biological systems. Accurate identification and in-depth characterization of functional CREs are crucial for decoding gene regulation network and dynamics during cellular processes. In this study, we developed Kethoxal-Assisted Single-stranded DNA Assay for Transposase-Accessible Chromatin with Sequencing (KAS-ATAC-seq) to provide quantitative insights into transcriptional activity of CREs. A main advantage of KAS-ATAC-seq lies in its precise measurement of ssDNA levels within both proximal and distal ATAC-seq peaks, enabling the identification of transcriptional regulatory sequences in genomes. This feature is particularly adept at defining Single-Stranded Transcribing Enhancers (SSTEs). SSTEs are highly enriched with nascent RNA transcription and specific transcription factors (TFs) binding sites that determine cellular identity. Moreover, KAS-ATAC-seq provides a detailed characterization and functional implications of various SSTE subtypes; KAS-ATAC-seq signals on SSTEs exhibit more robust correlation with enhancer activities when compared with ATAC-seq data and active histone mark profiles. Our analysis of promoters and SSTEs during mouse neural differentiation demonstrates that KAS-ATAC-seq can effectively identify immediate-early activated CREs in response to retinoic acid (RA) treatment. We further discovered that ETS TFs and YY1 are critical in initiating early neural differentiation from mESCs to NPCs. Our findings indicate that KAS-ATAC-seq provides more precise annotation of functional CREs in transcription. Future applications of KAS-ATAC-seq would help elucidate the intricate dynamics of gene regulation in diverse biological processes and biomedical applications.
Linked Exposures Across Databases (LEAD): An exposure data aggregation framework to facilitate clinical exposure review
Authors: Samuel Immanuel B.H. , Pollin Kamila , Tschida Sherri , Lu Calvin , Prisco Michelle , Forsten Robert , Ortiz Jose , Barrett John , Reinhard Matthew , Costanzo Michelle 
Published: March 2024

AbstractUnderstanding the health outcomes of military exposures is a critical effort for Veterans, their health care team, and national leaders. Veterans Affairs providers receive reports of military exposure related concerns from 43% of Veterans. Understanding the causal influences of environmental exposures on health is a complex task advancement in exposure science and may require interpreting multiple data sources; particularly when exposure pathways and multi-exposure interactions are ill-defined, as is the case for complex and emerging military service-related exposures. Thus, there is a need to standardize clinically meaningful exposure metrics from different data sources to guide clinicians and researchers with a consistent model for investigating and communicating exposure risk profiles. The Linked Exposures Across Databases (LEAD) framework provides a unifying model for characterizing exposure from different exposure datatypes and databases with a focus on providing clinically relevant exposure metrics. Application of LEAD is demonstrated through comparison of different military exposure data sources: Veteran Military Occupational and Environmental Exposure Assessment Tool (VMOAT), Individual Longitudinal Exposure Record (ILER) database and a military incident report database, the Explosive Ordnance Disposal Information Management System (EODIMS). This cohesive method for evaluating military exposures leverages established information with new sources of data and has the potential to influence how military exposure data is integrated into exposure health care and investigational models.
Age-Specific All-Cause Mortality Disparities by Race and Ethnicity During the COVID-19 Pandemic
Authors: Faust Jeremy Samuel , Renton Benjamin , Bongiovanni Tasce , Chen Alexander Junxiang , Sheares Karen Dorsey , Du Chengan , Essien Utibe R. , Fuentes-Afflick Elena , Haywood Trent , Khera Rohan , King Terris , Li Shu-Xia , Lin Zhenqiu , Lu Yuan , Marshall Andrew D.A. , Ndumele Chima D. , Opara Ijeoma , Loarte-Rodriguez Tina , Sawano Mitsuaki , Taparra Kekoa , Taylor Herman A. , Watson Karol E. , Yancy Clyde W. , Krumholz Harlan M. 
Published: March 2024

ABSTRACTBACKGROUNDThe end of the public health emergency provides an opportunity to fully describe disparities during the Covid-19 pandemic.METHODSIn this retrospective cohort analysis of US deaths during the Covid-19 public health emergency (March 2020-April 2023), all-cause excess mortality and years of potential life lost (YPLL) were calculated by race or ethnicity overall and by age groups (ages <25 years, 25-64 years, ≥65 years). Temporal correlations with Covid-19-specific mortality were measured.RESULTS>1.38 million all-cause excess deaths and ~23 million corresponding YPLL occurred during the pandemic. Had the rate of excess mortality observed among the White population been observed among the total population, >252,300 (18%) fewer excess deaths, and >5,192,000 fewer (22%) YPLL would have occurred. The highest excess mortality rates were among the American Indian/Alaska Native (AI/AN, 822 per 100,000; ~405,700 YPLL) and the Black (549 per 100,000; ~4,289,200 YPLL) populations. The highest relative increase in mortality was observed in the AI/AN population (1.34; 95% CI 1.31-1.37), followed by Hispanic (1.31; 95% CI 1.27-1.34), Native Hawaiian or Other Pacific Islander (1.24; 95% CI 1.21-1.27), Asian (1.20; 95% CI 1.18-1.20), Black (1.20; 95% CI 1.18-1.22) and White (1.12; 95% CI 1.09-1.15) populations. Greater disparities occurred among children and adults <65 years.CONCLUSIONSExcess mortality occurred in all groups during the Covid-19 pandemic, with disparities by race and ethnicity, especially in younger and middle-aged populations. >252,000 and 5.2 million fewer YPLL would have been observed had increases in mortality among the total population been similar to the White population.
Copy number variants differ in frequency across genetic ancestry groups
Authors: Schultz Laura M. , Knighton Alexys , Huguet Guillaume , Saci Zohra , Jean-Louis Martineau , Mollon Josephine , Knowles Emma E.M. , Glahn David C. , Jacquemont Sébastien , Almasy Laura 
Published: March 2024

AbstractCopy number variants (CNVs), which are duplicated or deleted genomic segments larger than 1000 base pairs1, have been implicated in a variety of neuropsychiatric and cognitive phenotypes2-4. In the first large-scale of examination of genome-wide CNV frequencies across ancestry groups, we found that deleterious CNVs are less prevalent in non-European ancestry groups than they are in European ancestry groups of both the UK Biobank (UKBB) and a US replication cohort (SPARK). We also identified specific recurrent CNVs that consistently differ in frequency across ancestry groups in both the UKBB and SPARK. These ancestry-related differences in CNV prevalence present in both an unselected community population and a family cohort enriched with individuals diagnosed with autism spectrum disorder (ASD) strongly suggest that genetic ancestry should be considered when probing associations between CNVs and health outcomes.
Prevalence and Cumulative Incidence of Mortality Associated with Cardiovascular-Kidney-Metabolic Syndrome in the United States
Authors: Claudel Sophie E. , Schmidt Insa M. , Waikar Sushrut S. , Verma Ashish 
Published: March 2024

AbstractBackgroundTo inform public health policies regarding disease management, it is crucial to comprehend the prevalence and mortality rates linked to various stages of Cardiovascular-Kidney-Metabolic (CKM) syndrome.MethodsA longitudinal study was conducted using National Health and Nutrition Examination Survey (NHANES) data (1999-2018) from 50,624 U.S. adults, defining CKM syndrome stages based on the 2023 American Heart Association (AHA) Presidential Advisory Statement. The investigation aimed to assess changes in 10-and 15-year adjusted cumulative incidences of cardiovascular mortality with each CKD syndrome stage and describe the cross-sectional prevalence of CKM syndrome from 1999 to 2020.ResultsCKM syndrome prevalence by stage was as follows: Stage 0, 12.5% (95% CI, 12.0-12.9); Stage 1, 16.7% (95% CI, 16.2-17.2); Stage 2, 40.0% (95% CI, 38.4-39.6); Stage 3, 22.9% (95% CI, 22.5-23.4); Stage 4, 8.9% (95% CI, 8.6-9.2). Over a median 9.5-year follow-up, 2,557 participants experienced cardiovascular death. The proportion of participants in Stages 0 and 3 decreased, while Stage 1 increased. The 15-year adjusted cumulative incidences of cardiovascular mortality were: Stage 0, 4.8% (95% CI 3.1-6.6); Stage 1, 5.3% (95% CI 4.0-6.6); Stage 2, 7.9% (95% CI 8.1-10.3); Stage 3, 9.2% (95% CI 8.1-10.3); Stage 4, 15.6% (95% CI 14.7-16.6). The absolute risk difference between CKM Stage 4 and Stage 0 at 15 years was 10.8% (95% CI 8.8-12.8).ConclusionsOur findings showed a graded increase in cardiovascular mortality associated with each CKM stage. The trends observed by stage prevalence emphasize critical opportunities for stabilizing risk factors, thereby preventing adverse cardiovascular outcomes.
PACT-3D, a Deep Learning Algorithm for Pneumoperitoneum Detection in Abdominal CT Scans
Authors: Chiu I-Min , Huang Teng-Yi , Kuo Kuei-Hong 
Published: March 2024

AbstractPneumoperitoneum, necessitates surgical intervention in 85-90% of cases, relies heavily on CT scans for diagnosis. Delay or misdiagnosis in detecting pneumoperitoneum can significantly increase mortality and morbidity. Our study introduced PACT-3D, a deep learning model developed to identify pneumoperitoneum in CT images. In this single hospital study, we retrospectively reviewed abdominal CT scans from January 2012 to December 2021, excluded CT of image acquisition error and without reports to form the development dataset for training the model. We evaluated the PACT- 3D model using a simulated test set of 14,039 scans and a prospective test set of 6,351 scans, collected from December 2022 to May 2023 at the same center. PACT-3D achieved a sensitivity of 0.81 and a specificity of 0.99 in retrospective testing, with prospective validation yielding a sensitivity of 0.83 and a specificity of 0.99. Sensitivity improved to 0.95 and 0.98 when excluding cases with a small amount of free air (total volume < 10ml) in simulated and prospective test sets, respectively. By delivering accurate and consistent patient-level predictions and providing segmented masks, PACT- 3D holds significant potential for assisting rapid decision-making in emergency care, thereby potentially improving patient outcomes.
RNA G-quadruplexes and calcium ions synergistically induce Tau phase transitionin vitro
Authors: Yabuki Yasushi , Matsuo Kazuya , Komiya Ginji , Kudo Kenta , Hori Karin , Ikenoshita Susumu , Kawata Yasushi , Mizobata Tomohiro , Shioda Norifumi 
Published: March 2024

AbstractTau aggregation is a defining feature of neurodegenerative tauopathies, including Alzheimer’s disease, corticobasal degeneration, and frontotemporal dementia. This aggregation involves the liquid–liquid phase separation (LLPS) of Tau, followed by its sol–gel phase transition, representing a crucial step in aggregate formation bothin vitroandin vivo. However, the precise cofactors influencing Tau phase transition and aggregation under physiological conditions (e.g., ion concentration and temperature) remain unclear. In this study, we unveil that nucleic acid secondary structures, specifically RNA G-quadruplexes (rG4s), and calcium ions (Ca2+) synergistically facilitated the sol–gel phase transition of human Tau under mimic intracellular ion conditions (140 mM KCl, 15 mM NaCl, and 10 mM MgCl2) at 37□in vitro. In the presence of molecular crowding reagents, Tau formed stable liquid droplets through LLPS, maintaining fluidity for 24 h under physiological conditions. Notably, cell-derived RNA promoted Tau sol–gel phase transition, with G4-forming RNA emerging as a crucial factor. Surprisingly, polyanion heparin did not elicit a similar response, indicating a distinct mechanism not rooted in electrostatic interactions. Further exploration underscored the significance of Ca2+, which accumulate intracellularly during neurodegeneration, as additional cofactors in promoting Tau phase transition after 24 h. Importantly, our findings demonstrate that rG4s and Ca2+synergistically enhance Tau phase transition within 1 h when introduced to Tau droplets. In conclusion, our study illuminates the pivotal roles of rG4s and Ca2+in promoting Tau aggregation under physiological conditionsin vitro, offering insights into potential triggers for tauopathy.
Light-microscopy based dense connectomic reconstruction of mammalian brain tissue
Authors: Tavakoli Mojtaba R. , Lyudchik Julia , Januszewski Michał , Vistunou Vitali , Agudelo Nathalie , Vorlaufer Jakob , Sommer Christoph , Kreuzinger Caroline , Oliveira Barbara , Cenameri Alban , Novarino Gaia , Jain Viren , Danzl Johann 
Published: March 2024

AbstractThe information-processing capability of the brain’s cellular network depends on the physical wiring pattern between neurons and their molecular and functional characteristics. Mapping neurons and resolving their individual synaptic connections can be achieved by volumetric imaging at nanoscale resolution with dense cellular labeling. Light microscopy is uniquely positioned to visualize specific molecules but dense, synapse-level circuit reconstruction by light microscopy has been out of reach due to limitations in resolution, contrast, and volumetric imaging capability. Here we developed light-microscopy based connectomics (LICONN). We integrated specifically engineered hydrogel embedding and expansion with comprehensive deep-learning based segmentation and analysis of connectivity, thus directly incorporating molecular information in synapse-level brain tissue reconstructions. LICONN will allow synapse-level brain tissue phenotyping in biological experiments in a readily adoptable manner.One-Sentence SummaryHydrogel expansion enables molecularly informed reconstruction of brain tissue at synaptic resolution with light microscopy.
Phase Separation and Aggregation of α-Synuclein Diverge at Different Salt Conditions
Authors: Sternke-Hoffmann Rebecca , Sun Xun , Menzel Andreas , Pinto Miriam Dos Santos , Venclovaitė Urtė , Wördehoff Michael , Hoyer Wolfgang , Zheng Wenwei , Luo Jinghui 
Published: March 2024

AbstractThe coacervation and structural rearrangement of the protein alpha-synuclein (αSyn) into cytotoxic oligomers and amyloid fibrils are considered pathological hallmarks of Parkinson’s disease. While aggregation is recognized as the key element of amyloid diseases, liquid-liquid phase separation (LLPS) and its interplay with aggregation have gained increasing interest. Previous work showed that factors promoting or inhibiting amyloid formation have similar effects on phase separation. Here, we provide a detailed scanning of a wide range of parameters including protein, salt and crowding concentrations at multiple pH values, revealing different salt dependencies of aggregation and phase separation. The influence of salt on aggregation under crowded conditions follows a non-monotonic pattern, showing increased effects at medium salt concentrations. This behavior can be elucidated through a combination of electrostatic screening and salting-out effects on the intramolecular interactions between the N-terminal and C-terminal regions of αSyn. By contrast, we find a monotonic salt dependence of phase separation due to the intermolecular interaction. Furthermore, we observe the time evolution of the two distinct assembly states, with macroscopic fibrillar-like bundles initially forming at medium salt concentration but subsequently converting into droplets after prolonged incubation. The droplet state is therefore capable of inhibiting aggregation or even dissolving the aggregates through a variety of heterotypic interactions, thus preventing αSyn from its dynamically arrested state.
Coxiella burnetii-containing vacuoles interact with host recycling-endosomal proteins Rab11a and Rab35 for vacuolar expansion
Authors: Hall Brooke A. , Senior Kristen E. , Ocampo Nicolle T. , Samanta Dhritiman 
Published: March 2024

AbstractCoxiella burnetiiis a gram-negative obligate intracellular bacterium and a zoonotic pathogen that causes human Q fever. Although acute Q fever manifests as atypical pneumonia, chronic infection may lead to life-threatening endocarditis. The lack of effective antibiotics and a licensed vaccine forCoxiellain the U.S. warrants further research intoCoxiellapathogenesis. Within the host cells,Coxiellareplicates in an acidic phagolysosome-like vacuole termedCoxiella-containing vacuole (CCV). Previously, we have shown that the CCV pH is critical forCoxiellasurvival and that theCoxiellaType 4B secretion system regulates CCV pH by inhibiting the host endosomal maturation pathway. However, the trafficking pattern of the ‘immature’ endosomes inCoxiella-infected cells remained unclear. Our recent CCV localization screen with host Rab proteins revealed that recycling endosome-associated proteins Rab11a and Rab35 localize to the CCV during infection, suggesting that CCV interacts with host recycling endosomes during maturation. Interestingly, only a subset of CCVs were Rab11a or Rab35-positive at any given time point. A quantitation of Rab11a/Rab35-positive CCVs at 3- and 6-days post-infection (dpi) revealed that at 3 dpi, ∼52% of CCVs were positive for Rab11a, whereas only ∼39% CCVs were positive for Rab35. This pattern reversed at 6-dpi, when only ∼22% of CCVs were positive for Rab11a and ∼64% of CCVs were positive for Rab35. These data suggest that the CCV preferentially interacts with Rab11a and Rab35-positive recycling endosomes depending on the stage of maturation. Furthermore, we observed a significant increase in Rab11a and Rab35 fluorescent intensity inCoxiella-infected cells compared to mock cells suggesting thatCoxiellaincreases the recycling endosome content in infected cells. Finally, a siRNA-mediated knockdown of both Rab11a and Rab35 resulted in significantly smaller CCVs, suggesting that recycling endosomal Rab proteins are essential for CCV expansion. Overall, our data, for the first time, show that the CCV dynamically interacts with host recycling endosomes for vacuolar expansion and potentially uncovers novel host cell factors essential forCoxiellapathogenesis.