bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional annotation of de novo variants found near GWAS loci associated with cleft lip with or without cleft palate
Authors: Curtis Sarah W. , Cook Laura E. , Paraiso Kitt , Visel Axel , Cotney Justin L. , Murray Jeffrey C. , Beaty Terri H. , Marazita Mary L. , Carlson Jenna C. , Leslie-Clarkson Elizabeth J. 
Published: February 2025

AbstractOrofacial clefts (OFCs) are the most common craniofacial birth defects, affecting 1 in 700 births, and have a strong genetic basis with a high recurrence risk within families. While many of the previous studies have associated common, noncoding genetic loci with OFCs, previous studies onde novovariants (DNVs) in OFC cases have focused on coding variants that could have a functional impact on protein structure, and the contribution of noncoding DNVs to the formation of OFCs has largely been ignored and is not well understood. Therefore, we reanalyzed an existing dataset of DNVs from 1,409 trios with OFCs that had undergone targeted sequencing of known OFC-associated loci. We then annotated these DNVs with information from datasets of predicted epigenetic function during human craniofacial development. Of the 66 DNVs in this cohort, 17 (25.7%) were within a predicted enhancer or promotor region. Two DNVs fell within the same enhancer region (hs1617), which is more than expected by chance (p = 0.0017). The sequence changes caused by these DNVs are predicted to create binding sites not seen in the reference sequence for transcription factors PAX6 and ZBTB7A and to disrupt binding sites for STAT1 and STAT3. This enhancer region is within the same topologically-associated domain asHHAT,SERTAD4, andIRF6, all of which are involved in craniofacial development. All three genes are highly expressed in human neural crest cells. Knockout mice forHhatandIrf6have abnormal embryonic development including a cleft palate, and variants in and aroundIRF6are associated with nonsyndromic and syndromic forms of OFCs in humans. Taken together, this suggests that noncoding DNVs contribute to the genetic architecture of OFCs, with a burden of DNVs in OFC trios in enhancer regions near known OFC-associated genes. Overall, this adds to our understanding of the genetic mechanisms that underly OFC formation.
The Neurocognitive Profile of Post-operative Paediatric Cerebellar Mutism Syndrome: A Systematic Review
Authors: Horne Bethany M. , Attanayake Annisha A. , Aquilina Kristian , Murphy Tara , Malcolm Charlotte P. 
Published: February 2025

ABSTRACTAIM:To systematically review neurocognitive outcomes associated with Post-operative Paediatric Cerebellar Mutism Syndrome (PPCMS), comparing children with and without PPCMS after posterior fossa tumour surgery, and in relation to moderating demographic and clinical risk factors.METHODSPsycInfo, Medline and Embase databases were systematically searched up to December 2024. Studies of children aged 2-18 years with PPCMS who had undergone standardised neurocognitive assessment were included. Quality was appraised using Institute of Health Economics Quality Appraisal Checklist for Case Series and Quality In Prognosis Studies tools. Synthesis without meta-analysis was conducted.RESULTSSixteen studies (PPCMS+n=252, PPCMS-n=590) met criteria for inclusion. Children who experience PPCMS were found to have pronounced, long-term neurocognitive impairments with severely affected processing speed, psychomotor and executive function, and poorer neurocognitive outcomes generally compared to children without PPCMS. Current literature is limited by small samples, lack of diagnostic clarity or routine prospective screening of PPCMS, and limited investigation of factors that may moderate neurocognitive outcomes.INTERPRETATIONChildren with PPCMS have increased vulnerability to neurocognitive impairments which persist beyond the recovery of initial PPCMS symptoms in the post-operative phase. Dedicated research is needed to further our understanding of PPCMS and associated neurocognitive outcomes to inform clinical care.What this paper addsChildren who experience PPCMS after surgery experience significant long-term neurocognitive impairment, with most consistent moderate-severe impairments in processing speed, psychomotor function, and executive function.Children who experience PPCMS have poorer neurocognitive outcomes generally than children treated for posterior fossa tumour without PPCMS, however future research is needed with larger matched samples of children with and without PPCMS.Prospective screening for PPCMS using formal diagnostic criteria in research and clinical practice is recommended, and cognitive development should be monitored in the long-term when PPCMS is identified.Future research is needed to understand the role of potential moderating influences on neurocognitive outcomes, such as duration and severity of mutism, age at surgery, and adjuvant oncology treatments.
Stochastic Assembly and Metabolic Network Reorganization Drive Microbial Resilience in Arid Soils
Authors: Ayala-Ortiz Christian , Freire-Zapata Viviana , Tfaily Malak M. 
Published: February 2025

ABSTRACTMicrobial resilience plays a pivotal role in ecosystems as environmental fluctuations impact community functioning and stability. Despite resilience emerging from both individual adaptations and community-level processes, integration of these mechanisms remains enigmatic, particularly in arid environments. These extreme ecosystems, spanning over 45% of Earth’s terrestrial surface, provide a natural laboratory for understanding microbial survival under harsh conditions. Here, we use time-resolved multi-omics to show that resilience results from dynamic microbial network reorganization enabling the coordination between stochastic processes that maintain community stability, and individual stress responses. Additionally, Thermoproteota emerged as a keystone taxon maintaining nitrogen cycling and fostering cross- feeding networks. Its ecological prominence highlights its central role in arid ecosystems, making it an ideal model organism for understanding microbial adaptation to environmental extremes. Our findings bridge the gap between individual adaptations and community-wide resilience, offering a framework for understanding microbial responses to environmental fluctuations and their implications for ecosystem function.
Actin crosslinking is required for force sensing at tricellular junctions
Authors: Taneja Nilay , Moubarak Michael F. , McGovern Meriel J. , Yeoh Kenji , Zallen Jennifer A. 
Published: February 2025

AbstractMechanical forces are essential for tissue morphogenesis, but risk causing ruptures that could compromise tissue function. In epithelial tissues, adherens junctions withstand the forces that drive morphogenesis by recruiting proteins that stabilize cell adhesion and reinforce connections to the actin cytoskeleton under tension. However, how junctional actin networks respond to forcesin vivois not well understood. Here we show that the actin crosslinker Fimbrin is recruited to tricellular junctions under tension and plays a central role in amplifying actomyosin contractility and stabilizing cell adhesion. Loss of Fimbrin results in a failure to reorganize actin under tension and an inability to enhance myosin-II activity and recruit junction-stabilizing proteins in response to force, disrupting cell adhesion. Conversely, increasing Fimbrin activity constitutively activates force-response pathways, aberrantly stabilizing adhesion. These results demonstrate that Fimbrin-mediated actin crosslinking is an essential step in modulating actomyosin dynamics and reinforcing cell adhesion under tension during epithelial remodeling.
DINASTY in NSCLC – a multicenter retrospective study on real-world data using federated analysis
Authors: Öjlert Å. , Bhatnagar P. , Hendriks L.E.L. , Ogliari F.R. , Acker F. , Bolton E. , Bouissou O. , Brash J. , Bynens A.-L. , Cheeseman S. , Fenton H. , Banduge P. Galgane , Gomes A. Lobo , McDonald R. , Mahon P. , Ross E. , Gomez L. Sanchez , Theophanous S. , Zhovannik I. , Helland Å. 
Published: February 2025

AbstractReal-world data is an important complement to randomized controlled trials and can be used to assess whether study results translate well to routine clinical practice and to groups of patients that are often excluded from clinical trials. The aim of thisdiseasenatural history and care qualityassessment (DINASTY) study is to describe treatments, outcomes and care quality for patients with metastatic non-small cell lung cancer using real-world data. The study is a retrospective observational multicenter study conducted within DIGICORE, a non-profit European Economic Interest Grouping, formed to facilitate real-world evidence studies. The study will make use of methods developed within the network. Forty essential variables to describe patients with cancer, treatments and outcomes have been defined within DIGICORE and mapped to the Observational Medical Outcomes Partnership (OMOP) common data model (CDM). The study uses data that is drawn directly from the electronic patient health records at the patient’s local hospital and mapped to OMOP. Data are analyzed using a federated approach, meaning that patient-level data is analyzed locally, and only aggregated results are shared across centers and combined to present results for the full cohort. This method enables the delivery of multicenter studies and the presentation of results in a privacy-preserving way.
Oral microbiome profiles relate to periodontal disease and brain health - a microbiome network analysis in the Hamburg City Health Study
Authors: Petersen Marvin , Walther Carolin , Borof Katrin , Heydecke Guido , Beikler Thomas , Alawi Malik , Müller Christian , Nägele Felix L. , Zyriax Birgit-Christiane , Fiehler Jens , Gallinat Jürgen , Kühn Simone , Twerenbold Raphael , Bang Corinna , Thomalla Götz , Cheng Bastian , Aarabi Ghazal 
Published: February 2025

AbstractThe relationship between oral microbiome composition and brain health in the general population remains poorly understood. In this study, we inferred a microbiome similarity network based on 16S rRNA sequencing data of crevicular fluid collected from 1,026 participants in the Hamburg City Health Study, which revealed a continuous disease gradient mirroring the microbial pathogenicity spectrum of periodontitis. Leveraging this network, we systematically examined associations between periodontal microbiome profiles and 37 brain health-related phenotypes, including cognitive function, brain structure, mental health, inflammatory biomarkers, diet, vascular risk factors, and demographics. We found that higher abundance of periodontitis-related microbial taxa was linked to poorer cognitive performance, lower cortical thickness and subcortical volumes, and elevated leukocyte counts, after adjusting for covariates. Notably, we identified both, previously known as well as novel microbial associations with brain health phenotypes. These findings advance the understanding of the oral microbiome-brain axis, suggesting mechanistic links between periodontal health and brain function with potential implications for future causal and interventional studies.
Evaluation of Progesterone Resistance and the Role of Downregulation Protocols in Endometrial Preparation for Frozen Embryo Transfer in Patients with Recurrent Implantation Failure—A Retrospective Study
Authors: Luo Yuxing , Cen Changshuang , Liu Huaicong , Mo Dan , Fu Pingfang , Liu Xin , Liu Lidan , Wei Lansi , Gan Qiuying , Bi Yin , Yang Yihua , Liang Ting 
Published: February 2025

ABSTRACTThis study investigates the impact of progesterone resistance on endometrial receptivity and evaluates the efficacy of pituitary downregulation combined with hormone replacement therapy (HRT) in improving pregnancy outcomes following frozen embryo transfer (FET). A retrospective analysis was conducted on 147 patients with recurrent implantation failure (RIF) who underwent secretory-phase endometrial biopsy and subsequent FET treatments at the Reproductive Center of the First Affiliated Hospital of Guangxi Medical University between April 2019 and May 2022. Based on biopsy results and endometrial preparations, patients were categorized into four groups: secretory phase + non-downregulated protocol group (n=29), secretory phase + GnRH-a + HRT Protocol group (n=20), proliferative phase + non-downregulated protocol group (n=59), proliferative Phase + GnRH-a + HRT Protocol group (n=39). Endometrial preparation regimens and pregnancy outcomes during the first FET cycle after biopsy were compared. The results showed that there was no statistical difference in the outcome of assisted pregnancy between the different endometrial preparation protocols in the four groups. These findings suggest that the prioritization of down-regulation protocols may not be essential for FET in patients with RIF, even when endometrial biopsy during the implantation window reveals proliferative-phase characteristics.
The aging human brain exhibits reduced cerebrospinal fluid flow during sleep due to both neural and vascular factors
Authors: Bailes Sydney M. , Williams Stephanie D. , Ashenagar Baarbod , Licata Joseph , Bosli Massinissa Y. , Dormes Brandon J. , Yun Hannah J. , Zimmerman Dabriel , Hernandez Moyers Alejandra , Salat David H. , Lewis Laura D. 
Published: February 2025

AbstractAging reduces the quality and quantity of sleep, and greater sleep loss over the lifespan is predictive of neurodegeneration and cognitive decline. One mechanism by which sleep loss could contribute to impaired brain health is through disruption of cerebrospinal fluid (CSF) circulation. CSF is the primary waste transport system of the brain, and in young adults, CSF waves are largest during NREM sleep. However, whether sleep-dependent brain fluid physiology changes in aging is not known, due to the technical challenges of performing neuroimaging studies during sleep. We collected simultaneous fast fMRI and EEG data to measure large-scale CSF flow in healthy young and older adults and tested whether there were age-related changes to CSF dynamics during nighttime sleep. We found that sleep-dependent CSF flow was reduced in older adults, and this reduction was linked to impaired frontal EEG delta power and global hemodynamic oscillations during sleep. To identify mechanisms underlying reduced CSF flow, we used sensory and vasoactive stimuli to drive CSF flow in daytime task experiments, and found that both neural and cerebrovascular physiological changes contributed to the disruption of CSF flow during sleep. Finally, we found that this reduction in CSF flow was associated with gray matter atrophy in aging. Together, these results demonstrate that the aging human brain has reduced CSF flow during sleep, and identifies underlying neurovascular mechanisms that contribute to this age-related decline, suggesting targets for future interventions.
Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma
Authors: Nardone Christopher , Gao Jingjing , Seo Hyuk-Soo , Mintseris Julian , Ort Lucy , Yip Matthew C. J. , Negasi Milen , Besschetnova Anna K. , Kamitaki Nolan , Gygi Steven P. , Dhe-Paganon Sirano , Munshi Nikhil , Fulciniti Mariateresa , Greenberg Michael E. , Shao Sichen , Elledge Stephen J. , Gu Xin 
Published: February 2025

SummaryThe midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the midnolin-proteasome complex, revealing how established proteasomal components are repurposed to enable a unique form of proteolysis. While the proteasomal subunit PSMD2/Rpn1 binds to ubiquitinated or ubiquitin-like proteins, we discover that it also interacts with the midnolin nuclear localization sequence, elucidating how midnolin’s activity is confined to the nucleus. Likewise, PSMD14/Rpn11, an enzyme that normally cleaves ubiquitin chains, surprisingly functions non-enzymatically as a receptor for the midnolin ubiquitin-like (Ubl) domain, positioning the substrate-binding Catch domain directly above the proteasomal entry site to guide substrates into the proteasome. Moreover, we demonstrate that midnolin downregulation is critical for the survival of myeloma cells by promoting the expression of its transcription factor substrate IRF4. Our findings uncover the mechanisms underlying the midnolin-proteasome pathway and midnolin downregulation as a driver of multiple myeloma.
Treatment outcome is associated with pre-treatment connectome measures across psychiatric disorders - evidence for connectomic reserve?
Authors: Vriend Chris , Fitzsimmons Sophie M.D.D. , Aarts Inga , Broekhuizen Aniek , van der Werf Ysbrand D. , Douw Linda , Visser Henny A. D. , Thomaes Kathleen , van den Heuvel Odile A. 
Published: February 2025

ABSTRACTBackgroundPredicting treatment efficacy in psychiatric disorders remains challenging, despite the availability of effective interventions. Previous studies suggest a link between brain network topology and treatment efficacy in individual disorders, but cross-disorder investigations are lacking.MethodsWe analyzed pre-treatment MRI data from 177 individuals (113 females) with either obsessive-compulsive disorder (OCD) or post-traumatic stress disorder with comorbid personality disorders (PTSD) that received different non-pharmacological treatments. Using diffusion and resting-state MRI, we constructed structural, functional, and multilayer connectomes and calculated network measures at the global and mesoscale for network integration (global efficiency, eccentricity), segregation (modularity) and their balance (small-worldness). We assessed the relationship between these pre-treatment network measures and treatment improvement using mixed-model and Bayesian analyses and compared them to healthy controls. We also investigated associations between response and treatment-induced changes in network measures.ResultsAcross disorders and treatments, psychiatric cases showed a 41.6±29.6% symptom improvement (62% response rate) after treatment and pre-treatment differences in functional and multilayer network topology compared to healthy controls. Symptom improvement was associated with pre-treatment functional (P=0.04) and structural small-worldness (P=0.01), and multilayer eccentricity (P=0.01), while responders had higher functional modularity (P=0.02). Results were robust across trials and treatments, when adjusting for medication status and showed high credibility in Bayesian analyses. Network change associations with treatment response were only modest.ConclusionsPre-treatment connectome characteristics are related to treatment response, regardless of treatment and psychiatric disorder, and suggest that individual differences in intrinsic features of the human connectome underlie amenability to treatment.
A distinctive subset of microglia positioned at the paraventricular zone are dedicated to cleaning the cerebrospinal fluid
Authors: Zhou Guoyang , He Jian , Mao Baojie , Cheng Guo , Zhang Rui , Wang Qiang , Liu Xiaoli , Zheng Jiaxin , Wang Ming , Zhao Li , Shi Peng , Shen Xiao Z , Wan Shu 
Published: February 2025

ABSTRACTThe interconnected ventricles in the central nervous system are filled with cerebrospinal fluid (CSF) which serves multifaceted roles including bring away metabolic wastes. However, whether there is an inherent “dislodging” mechanism, in addition to CSF drainage and reabsorption, at play for the removal of microparticles in the CSF is unclear. In this study, we identified a subset of microglia distributed in close proximity to the ependymal wall of ventricles. They differed from parenchymal microglia in morphology, behaviors and transcriptomes. In particular, the paraventricular microglia extended transependymal dendrites into the lumen of ventricles and were proficient in sequestering and phagocytosing intraventricular exogenous particles when present. A specific removal of the paraventricular microglia led to an acute ventriculomegaly due to an increased colloid osmotic pressure in the CSF resulting from protein accumulation. Thus, we identified the paraventricular microglia as specific guardians in monitoring and cleaning the CSF.
Bridging Gaps in Antibody Responses and Animal Welfare: Assessing Blood Collection Methods and Vaginal Immunity in Mice Immunized with Intranasal Gonococcal Vaccines
Authors: Chanda Abhishek , Song Yujuan , Nazir Junaid , Lin Chenwei , Cheng Alicia , Sargent Jennifer , Sikora Aleksandra E. 
Published: February 2025

ABSTRACTAssessing antibody titers and functional responses is essential for evaluating vaccine efficacy, yet the impact of blood collection methods on these immunological assessments remains unclear. Retro-orbital (RO) blood collection is commonly used but significant complications can occur. Increasingly, investigators have adopted alternative blood collection approaches, such as saphenous vein (SV) sampling to improve laboratory animal welfare. This study compared RO and SV sampling in the development of aNeisseria gonorrhoeae(Ng) vaccine, evaluating Adhesin Complex Protein (ACP) and multiple transferable resistance (Mtr) E protein (MtrE) as antigen candidates. Epitope mapping revealed that ACP and MtrE possess multiple, highly accessible B-cell and T-cell epitope clusters, reinforcing their immunological potential. Following intranasal immunization with rACP, rACP+CpG, and rMtrE+CpG, we assessed the specificity, magnitude, kinetics, and functional quality of immune responses elicited by the immunization regimens. Out of 45 comparisons, only eight significant differences were detected in antibody titers, while the human serum bactericidal assays revealed no differences between RO and SV in antigen-immunized groups. However, antibodies elicited by rACP alone or ACP+CpG in SV samples restored 30.05% and 75.2% of human lysozyme hydrolytic activity compared to 19.3 and 59.9 % in RO, respectively suggesting that SV sampling may be more reliable for assessing functional antibody responses. Beyond its immunological advantages, SV sampling reduces stress, minimizes ocular trauma, and improves animal welfare, making it a viable alternative to RO collection. Given its widespread use in vaccine research, standardizing SV sampling could improve data reliability, ethical compliance, and translational relevance in preclinical studies.