bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in internalizing and externalizing problems in Dutch children and adolescents receiving youth care before and during the COVID-19 pandemic
Authors: Broek Emma M. , De Meyer Ronald , van der Rijken Rachel , Zijlmans Josjan , van Oers Hedy A. , Luijten Michiel A.J. , Alrouh Hekmat , Popma Arne , Bartels Meike , Vermeiren Robert R.J.M. , Polderman Tinca J. C. , Tieskens Jacintha M. 
Published: December 2023

AbstractBackgroundThe COVID-19 pandemic had serious effects on the mental health of children and adolescents. However, it is unclear how the pandemic may have affected treatment effects and outcomes in youth care. We investigated if treatment effects and externalizing and internalizing problems of children and adolescents receiving youth care were affected by the COVID-19 pandemic.MethodsWe used data from children and adolescents in youth care (N= 1,090,Mage= 12.85 (SD= 2.83; range = 8-18 years)). Internalizing and externalizing problems were assessed at the start and end of treatment using the Child Behavior Checklist. We inspected change in internalizing and externalizing problems and clinical status at the end of treatment to investigate treatment effects, and the level of problems at the start and end of treatment. Outcomes were compared between three groups: children treated entirely before the COVID-19 pandemic, children who experienced the transition into COVID-19 measures during treatment, and children treated entirely during the pandemic.ResultsWe did not find evidence that the pandemic affected treatment effectiveness. However, fewer children who were treated during the pandemic recovered from externalizing problems compared to children treated before the pandemic. Children who received treatment entirely during the pandemic also showed more internalizing and externalizing problems at both the start and end of their treatment, and children who experienced the transition into the pandemic showed elevated externalizing problems at both timepoints.ConclusionsAlthough the change in internalizing and externalizing problems from start to end of treatment was not affected by the pandemic, our findings that children are entering and leaving care with more problems suggest that child mental health has deteriorated since the pandemic.
Plasma p-tau212: antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology
Authors: Kac Przemysław R. , González-Ortiz Fernando , Emeršič Andreja , Dulewicz Maciej , Koutarapu Srinivas , Turton Michael , An Yang , Smirnov Denis , Kulczyńska-Przybik Agnieszka , Varma Vijay , Ashton Nicholas J. , Montoliu-Gaya Laia , Camporesi Elena , Winkel Izabela , Paradowski Bogusław , Moghekar Abhay , Troncoso Juan C. , Brinkmalm Gunnar , Resnick Susan M , Mroczko Barbara , Kvartsberg Hlin , Gregorič Kramberger Milica , Hanrieder Jörg , Čučnik Saša , Harrison Peter , Zetterberg Henrik , Lewczuk Piotr , Thambisetty Madhav , Rot Uroš , Galasko Douglas , Blennow Kaj , Karikari Thomas K. 
Published: December 2023

AbstractBlood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Thereafter, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n=388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a novel peripherally accessible biomarker of AD pathophysiology.
Exploratory electronic health record analysis with ehrapy
Authors: Heumos Lukas , Ehmele Philipp , Treis Tim , Upmeier zu Belzen Julius , Namsaraeva Altana , Horlava Nastassya , Shitov Vladimir A. , Zhang Xinyue , Zappia Luke , Knoll Rainer , Lang Niklas J. , Hetzel Leon , Virshup Isaac , Sikkema Lisa , Roellin Eljas , Curion Fabiola , Eils Roland , Schiller Herbert B. , Hilgendorff Anne , Theis Fabian J. 
Published: December 2023

AbstractWith progressive digitalization of healthcare systems worldwide, large-scale collection of electronic health records (EHRs) has become commonplace. However, an extensible framework for comprehensive exploratory analysis that accounts for data heterogeneity is missing. Here, we introduce ehrapy, a modular open-source Python framework designed for exploratory end-to-end analysis of heterogeneous epidemiology and electronic health record data. Ehrapy incorporates a series of analytical steps, from data extraction and quality control to the generation of low-dimensional representations. Complemented by rich statistical modules, ehrapy facilitates associating patients with disease states, differential comparison between patient clusters, survival analysis, trajectory inference, causal inference, and more. Leveraging ontologies, ehrapy further enables data sharing and training EHR deep learning models paving the way for foundational models in biomedical research. We demonstrated ehrapy’s features in five distinct examples: We first applied ehrapy to stratify patients affected by unspecified pneumonia into finer-grained phenotypes. Furthermore, we revealed biomarkers for significant differences in survival among these groups. Additionally, we quantify medication-class effects of pneumonia medications on length of stay. We further leveraged ehrapy to analyze cardiovascular risks across different data modalities. Finally, we reconstructed disease state trajectories in SARS-CoV-2 patients based on imaging data. Ehrapy thus provides a framework that we envision will standardize analysis pipelines on EHR data and serve as a cornerstone for the community.
Exome-wide tandem repeats confer large effects on subcortical volumes in UK Biobank participants
Authors: Panoyan Mary Anne , Shi Yuxin , Abbatangelo Cristina L , Adler Nina , Moo-Choy Ashley , Parra Esteban J , Polimanti Renato , Hu Pingzhao , Wendt Frank R 
Published: December 2023

ABSTRACTThe human subcortex is involved in memory and cognition. Structural and functional changes in subcortical regions is implicated in psychiatric conditions. We performed an association study of subcortical volumes using 15,941 tandem repeats (TRs) derived from whole exome sequencing (WES) data in 16,527 unrelated European ancestry participants. We identified 17 loci, most of which were associated with accumbens volume, and nine of which had fine-mapping probability supporting their causal effect on subcortical volume independent of surrounding variation. The most significant association involvedNTN1-[GCGG]Nand increased accumbens volume (β=5.93, P=8.16x10-9). Three exonic TRs had large effects on thalamus volume (LAT2-[CATC]Nβ=-949, P=3.84x10-6andSLC39A4-[CAG]Nβ=-1599, P=2.42x10-8) and pallidum volume (MCM2-[AGG]Nβ=-404.9, P=147x10-7). These genetic effects were consistent measurements of per-repeat expansion/contraction effects on organism fitness. With 3-dimensional modeling, we reinforced these effects to show that the expanded and contractedLAT2-[CATC]Nrepeat causes a frameshift mutation that prevents appropriate protein folding. These TRs also exhibited independent effects on several psychiatric symptoms, includingLAT2-[CATC]Nand the tiredness/low energy symptom of depression (β=0.340, P=0.003). These findings link genetic variation to tractable biology in the brain and relevant psychiatric symptoms. We also chart one pathway for TR prioritization in future complex trait genetic studies.
Loss of Adaptive DNA Breaks in Alzheimer’s Disease Brains
Authors: Zhang Xiaoyu , Haeri Mohammad , Swerdlow Russell H. , Wang Ning 
Published: December 2023

AbstractBackgroundDNA breaks accumulate in Alzheimer’s disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes (IEGs). This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks (DSBs).ObjectiveTo characterize how AD impacts adaptive DNA breaks at nervous system genes.MethodsWe leveraged the ability of DNA single- and double-strand breaks to activate poly(ADP-ribose) polymerases (PARPs) that conjugate poly(ADP-ribose) (PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented (ND) autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing.ResultsAlthough the AD brains contained 19.9 times more PAR peaks than the ND brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting γH2AX, which marks DNA double-strand breaks (DSBs). In addition, TOP2B expression was significantly decreased in the AD brains.ConclusionAlthough AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.
Can structure predict function at individual level in the human connectome?
Authors: Smolders Lars , De Baene Wouter , Rutten Geert-Jan , van der Hofstad Remco , Florack Luc 
Published: December 2023

AbstractSeveral studies predicting Functional Connectivity (FC) from Structural Connectivity (SC) at an individual level have been published in recent years, each promising increased performance and utility. We investigated three of these studies, analyzing whether the results truly represent a meaningful individual-level mapping from SC to FC. Using data from the Human Connectome Project shared accross the three studies, we constructed a predictor by averaging FC of training data and analyzed its performance in the same way. In each case, we found that this group average FC is an equivalent or better predictor of individual FC than the predictive models in terms of raw prediction performance. Furthermore, we showed that additional analyses performed by the authors of the three studies, in which they attempt to show that their predicted FC has value beyond raw prediction performance, could also be reproduced using the group average FC predictor. This makes it unclear whether any of the three methods represent a meaningful individual-level predictive model. We conclude that either the applied methods are not appropriate for the data, that the sample size is too small, or that the data itself does not contain sufficient information to learn a mapping from SC to FC e.g. due to the amount of noise in MRI measurements. We advise future individual-level studies to always explicitly report their results in comparison to the performance of the group average, and carefully demonstrate that their predictions contain meaningful individual-level information. Finally, we believe that investigating alternatives for the construction of SC and FC may improve the chances of developing a meaningful individual-level mapping from SC to FC.
Kinome focused CRISPR-Cas9 screens in African ancestry patient-derived breast cancer organoids identifies essential kinases and synergy of EGFR and FGFR1 inhibition
Authors: Rowdo Florencia P. Madorsky , Martini Rachel , Ackermann Sarah , Tang Colin , Tranquille Marvel , Irizarry Adriana , Us Ilkay , Alawa Omar , Moyer Jenna , Sigouros Michael , Nguyen John , Assaad Majd Al , Cheng Esther , Ginter Paula S. , Manohar Jyothi , Stonaker Brian , Boateng Richard , Oppong Joseph K. , Adjei Ernest K. , Awuah Baffour , Kyei Ishmael , Aitpillah Frances S. , Adinku Michael O. , Ankomah Kwasi , Osei-Bonsu Ernest B. , Gyan Kofi K. , Hoda Syed , Newman Lisa , Mosquera Juan Miguel , Sboner Andrea , Elemento Olivier , Dow Lukas E. , Davis Melissa B. , Martin M. Laura 
Published: December 2023

AbstractPrecision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapy strategies. These alterations are usually revealed via next generation sequencing of the tumor tissue. Yet, it is clear that some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. This is especially important in under-represented populations, whose mutational landscape and determinants of response to existing therapies are poorly characterized due to limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture in non-physiological conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in 3D-grown patient-derived tumor organoid (PDTO) models. We focused on identifying essential kinases that may translate to options for targeted therapies, including combination therapies. We first established a breast cancer PDTO biobank focused on underrepresented populations, including West African patients. We then performed a negative selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. We identified several previously unidentified kinase targets and showed that combination of FGFR1 and EGFR inhibitors synergizes to block organoids proliferation. Together these data demonstrate feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from under-represented cancer patients, and identify new targets for cancer therapy.
Aberrant methylation and expression of TNXB promote chondrocyte apoptosis and extracullar matrix degradation in hemophilic arthropathy via AKT signaling
Authors: Chen Jiali , Qinghe Zeng , Wang Xu , Xu Rui , Wang Weidong , Huang Yuliang , Sun Qi , Yuan Wenhua , Wang Pinger , Chen Di , Tong Peijian , Jin Hongting 
Published: December 2023

AbstractRecurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N = 5) and osteoarthritis (N = 5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss ofTnxbinF8-/-mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss.Tnxbknockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects followingTnxbknockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.
Microglial phagocytosis of single dying oligodendrocytes is mediated by CX3CR1 but not MERTK
Authors: Olveda Genaro E. , Barasa Maryanne N. , Hill Robert A. 
Published: December 2023

ABSTRACTOligodendrocyte death is common in aging and neurodegenerative diseases. In these conditions, single dying oligodendrocytes must be efficiently removed to allow remyelination and prevent a feed-forward degenerative cascade. Here we used a single-cell cortical demyelination model combined with longitudinal intravital imaging of dual-labeled transgenic mice to investigate the cellular dynamics underlying how brain resident microglia remove these cellular debris. Following phagocytic engagement, single microglia cleared the targeted oligodendrocyte and its myelin sheaths in one day via a precise, rapid, and stereotyped sequence. Deletion of the fractalkine receptor, CX3CR1, delayed microglia engagement with the cell soma but unexpectedly did not affect the clearance of myelin sheaths. Furthermore, and in contrast to previous reports in other demyelination models, deletion of the phosphatidylserine receptor, MERTK, did not affect oligodendrocyte or myelin sheath clearance. Thus, distinct molecular signals are used to detect, engage, and clear sub-compartments of dying oligodendrocytes to maintain tissue homeostasis.
Towards fNIRS Hyperfeedback: A Feasibility Study on Real-Time Interbrain Synchrony
Authors: Kostorz Kathrin , Nguyen Trinh , Pan Yafeng , Melinscak Filip , Steyrl David , Hu Yi , Sorger Bettina , Hoehl Stefanie , Scharnowski Frank 
Published: December 2023

AbstractSocial interaction is of fundamental importance to humans. Prior research has highlighted the link between interbrain synchrony and positive outcomes in human social interaction.Neurofeedback is an established method to train one’s brain activity and might offer a possibility to increase interbrain synchrony. Consequently, it would be advantageous to determine the feasibility of creating a neurofeedback system for enhancing interbrain synchrony to benefit human interaction.In this study, we investigated whether the most widely employed metric for interbrain synchrony, namely wavelet transform coherence, can be assessed accurately in near real-time using functional near-infrared spectroscopy (fNIRS), which is recognized for its mobility and ecological suitability for interactive research. To this end, we have undertaken a comprehensive approach encompassing simulations and a re-evaluation of two human-interaction datasets. Our findings indicate the potential for a stable near real-time measurement of wavelet transform coherence for integration durations of about one minute. This would align well with the methodology of an intermittent neurofeedback procedure.Our investigation lays the technical foundation for an fNIRS-based system to measure interbrain synchrony in near real-time. This advancement is crucial for the future development of a neurofeedback training system tailored to enhance interbrain synchrony to potentially benefit human interaction.
Differential interactions of the proteasome inhibitor PI31 with constitutive and immuno-20S proteasomes
Authors: Wang Jason , Kjellgren Abbey , DeMartino George N. 
Published: December 2023

ABSTRACTPI31 (ProteasomeInhibitor of31,000 Daltons) is a 20S proteasome binding protein originally identified as an in vitro inhibitor of 20S proteasome proteolytic activity. Recently reported cryo-electron microscopy structures of 20S-PI31 complexes reveal a surprising structural basis for proteasome inhibition. The natively disordered proline-rich C-terminus of PI31 enters the central chamber in the interior of the cylindrical 20S proteasome and interacts directly with the proteasome’s multiple catalytic threonine residues a manner predicted to inhibit their enzymatic function while evading its own proteolysis. Higher eukaryotes express an alternative form of 20S proteasome featuring genetically and functionally distinct catalytic subunits. This proteasome is expressed in tissues involved in immune function or in response to certain cytokines such as interferon-γ and has been termed “immuno-proteasome.” We examined the relative effects of PI31 on constitutive and immuno-20S proteasomes and show that PI31 inhibits the immuno-20S proteasome (20Si) to a significantly lesser degree than it inhibits constitutive 20S proteasome (20Sc). Unlike 20Sc, 20Si hydrolyzes the carboxyl-terminus of PI31 and this effect contributes to the reduced inhibitory activity of PI31 towards 20Si. These results demonstrate unexpected differential interactions of PI31 with 20Sc and 20Si and document their functional consequences.
Utilizing Non-Invasive Prenatal Test Sequencing Data Resource for Human Genetic Investigation
Authors: Liu Siyang , Huang Shujia , Liu Yanhong , Gu Yuqin , Lin Xingchen , Zhu Huanhuan , Liu Hankui , Xu Zhe , Cheng Shiyao , Lan Xianmei , Li Linxuan , Chen Guo-Bo , Li Hao , Xu Xun , Nielsen Rasmus , Davies Robert W , Albrechtsen Anders , Qiu Xiu , Jin Xin 
Published: December 2023

SummaryNon-invasive prenatal testing (NIPT) employs ultra-low-pass sequencing of maternal plasma cell-free DNA to detect fetal trisomy. With exceptional sensitivity, specificity, and safety, NIPT has gained global adoption, exceeding ten million tests, establishing it as one of the largest human genetic resources. This resource holds immense potential for exploring population genetic variations and their correlations with phenotypes. Here, we present comprehensive methods tailored for analyzing large, low-depth NIPT genetic datasets, involving customized algorithms and software for genetic variation detection, genotype imputation, and genome-wide association analysis. Through evaluations, we demonstrate that, when integrated with appropriate probabilistic models and population-specific haplotype reference panels, accurate allele frequency estimation and high genotype imputation accuracy (0.8 to 0.9) are achievable for genetic variants with alternative allele frequencies between 0.01 and 0.05, at sequencing depths of 0.1x to 0.25x. Additionally, we attained an R-square exceeding 0.9 for estimating genetic effect sizes across various sequencing platforms. These findings establish a robust theoretical and practical foundation for leveraging NIPT data in advancing medical genetic studies, not only in realms of maternal and child health, but also for long-term health outcomes.HighlightsIntroduction of probabilistic model integration for analyzing large-scale, low-pass non-invasive prenatal test (NIPT) sequencing dataEvaluation of protocols for variant detection, genotype imputation, and genome-wide association analyses with NIPT data