bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robust discovery of causal gene networks via measurement error estimation and correction
Authors: Biswas Rahul , Brintha V P , Dumrewal Amol , Narayanan Manikandan 
Published: May 2023

AbstractDiscovering causal relations among genes from observational data is a fundamental problem in systems biology, especially in humans where direct gene interventions or perturbations are unethical/infeasible. Furthermore, causality is emerging as an integral factor for building interpretable and generalizable machine-learning models of complex phenotypes. Existing methods can discover causal relations from observed gene expression and matched genetic data using the well-established framework of Mendelian Randomization. But, the prevalence of expression measurement errors can mislead most existing methods into making wrong causal discoveries, especially among genes transcribed at low to moderate levels and using data with large sample size (say thousands as in modern genomic or GWAS studies).In this study, we propose a new framework for causal discovery that is robust against measurement noise by extending an established statistical approach CIT (Causal Inference Test). We specifically developed a two-stage approach called RCD (Robust Causal Discovery), wherein we first estimate measurement error from gene expression data and then incorporate it to get consistent parameter estimates that could be used with appropriately extended statistical tests of correlation or mediation done in the original CIT. By quantifying and accounting for noise in the data, our RCD method is able to significantly outperform the baseline method in recovering ground-truth causal relations among simulated noisy genes and transcription factor to target gene relations among noisy yeast genes using data on 1012 yeast segregants. Encouraged by these results, we applied our RCD to a human setting where perturbations are infeasible and identified several causal relations, including ones involving transcriptional regulators in the skeletal muscle tissue.Data and Code AvailabilityThe code that implements our two-stage RCD framework is available here:https://github.com/BIRDSgroup/RCD; code for reproducing the figures/tables in this manuscript is also provided in this link.
Normal growth curve of choroid plexus in children: Implications for assessing hydrocephalus due to choroid plexus hyperplasia
Authors: Hashimoto Hiroaki , Takemoto Osamu , Nishimoto Keisuke , Moriguchi Gento , Nakamura Motoki , Chiba Yasuyoshi 
Published: May 2023

Structured AbstractObjectivePediatric hydrocephalus requires evaluation while accounting for growth of intracranial structures, but information on choroid plexus growth in children is lacking. This study aimed to create normal growth curves for intracranial volume, choroid plexus volume, and lateral ventricles volume and assess objectively the degree of hydrocephalus due to choroid plexus hyperplasia (CPH) and the effect of surgeries.MethodsThis retrospective study analyzed head computed tomography (CT) scans of pediatric patients with head trauma from Osaka Women’s and Children’s Hospital between April 2006 and April 2023. The study segmented the intracranial volume, choroid plexus, and lateral ventricles and calculated their volumes. The study also calculated correlation coefficients among the three parameters. Patients aged 0 to 10 years were divided into 15 age-related clusters and mean and standard deviation (SD) values were measured in each cluster. Growth curves were created by plotting mean values sequentially. Volume obtained from patients with CPH were z-normalized using mean and SD values and compared.ResultsA total of 222 CT scans (91 from females) were analyzed, and positive correlations were observed among intracranial volume, choroid plexus volume, and lateral ventricles volume, with the strongest correlation between choroid plexus and lateral ventricles volumes. The growth rate of intracranial volume was rapid until approximately 20 months of ages, while those of choroid plexus and lateral ventricles volume increased rapidly by approximately one year of age.After that, the volume reached plateau at 1.5 mL and 10mL in choroid plexus and lateral ventricles volume, respectively. Three patients with CPH were enrolled and quantitatively evaluated by the z-normalized volume (z.v.). Notable abnormal volume of choroid plexus (ranged z.v. 26.00 – 45.85) and lateral ventricles (ranged z.v.40.93 – 123.56) were observed. In two patients, z.v. lateral ventricles volumes improved after surgical interventions. Choroid plexus volume reduced by approximately 20% (from z.v. 45.85 to z.v. 36.95) after bilateral endoscopic plexus coagulation in one patient.ConclusionsThis study provides normal growth curves for intracranial volume, choroid plexus volume, and lateral ventricles volume. Knowledge of normal values enables objective assessment of abnormal values related to hydrocephalus and choroid plexus disease such as CPH.
Delineating clinical and developmental outcomes inSTXBP1-related disorders
Authors: Xian Julie , Thalwitzer Kim Marie , McKee Jillian , Sullivan Katie Rose , Brimble Elise , Fitch Eryn , Toib Jonathan , Kaufman Michael C. , deCampo Danielle , Cunningham Kristin , Pierce Samuel R. , Goss James , Son Rigby Charlene , Syrbe Steffen , Boland Michael , Prosser Ben , Fitter Nasha , Ruggiero Sarah M. , Helbig Ingo 
Published: May 2023

AbstractSTXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental endpoints have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1,281 cumulative patient-years of seizure and developmental histories in 162 individuals withSTXBP1-related disorders and established a natural history framework.STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions inSTXBP1(n=39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n=30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of endpoints revealed high variability during the first five years of life, with emerging stratification between clinical subgroups, most prominently between individuals with and without infantile spasms. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood than compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate, and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories inSTXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.
Has the COVID-19 Pandemic Changed Parental Attitudes and Beliefs Regarding Vaccinating their Children against the Flu?
Authors: Shmueli Liora 
Published: May 2023

AbstractIntroductionThis study assessed whether the COVID-19 pandemic has altered parents’ attitudes toward vaccinating their children against the flu, and the contributing socio-demographic, health-related, and behavioral factors, as well as barriers to school-based vaccination programs.MethodsWe conducted a cross-sectional online survey of parents of children aged 6 months to 11 years in Israel (n=975) between December 21–31, 2022. A multivariate regression was performed to determine predictors of these parents’ willingness to vaccinate their children aged 6 months to 11 years against the flu in the winter of 2023 (December 2022–February 2023).ResultsOverall, 45% of parents stated that they did not intend to vaccinate their children against the flu in the winter of 2023, citing fears of side effects and concerns about vaccine effectiveness. Among those who did not trust the Ministry of Health and pharmaceutical companies prior to the pandemic, this trend increased in 78% of them following the COVID-19 events. In contrast, 39% of parents stated that they had already vaccinated their children against the flu, with an additional 16% intending to do so. Forty-one percent reported an increased intention following the pandemic. Only 37% of parents vaccinated their children at school in grades 2–4, mainly due to a preference for HMO clinics and lack of available nurses at school. The Health Belief Model (HBM) variables, namely, perceived susceptibility, severity and benefits, displayed the largest effect sizes.ConclusionsUnderstanding the impact of the COVID-19 pandemic on parents’ willingness to vaccinate their children against the flu is crucial. Notably, the pandemic has increased vaccine receptivity among some parents. Healthcare providers and public health officials need to address parents’ concerns about the safety and efficacy of the influenza vaccine to improve vaccination rates among children. Implementing school-based vaccination programs is an important strategy for promoting public health, but may be challenging. To increase uptake, nursing staff in student health facilities should be more accessible, and clear explanations about the efficacy of nasal spray vaccinations should be provided.
Molecular surveillance detects high prevalence of the neglected parasiteMansonella ozzardiin the Colombian Amazon
Authors: Dahmer KJ , Palma-Cuero M , Ciuoderis K , Patiño C , Roitman S , Li Z , Sinha A , Hite JL , Bellido Cuellar O , Hernandez-Ortiz JP , Osorio JE , Christensen BM , Carlow CKS , Zamanian M 
Published: May 2023

AbstractMansonellosis is an undermapped insect-transmitted disease caused by filarial nematodes that are estimated to infect hundreds of millions of people globally. Despite their prevalence, there are many outstanding questions regarding the general biology and health impacts of the responsible parasites. Historical reports suggest that the Colombian Amazon is endemic for mansonellosis and may serve as an ideal location to pursue these questions in the backdrop of other endemic and emerging pathogens. We deployed molecular and classical diagnostic approaches to surveyMansonellaprevalence among adults belonging to indigenous communities along the Amazon River and its tributaries near Leticia, Colombia. Deployment of a loop-mediated isothermal amplification (LAMP) assay on blood samples revealed an infection prevalence of ∼40% forMansonella ozzardi. This assay identified significantly more infections than blood smear microscopy or LAMP assays performed using plasma, likely reflecting greater sensitivity and the ability to detect low microfilaremias or occult infections.Mansonellainfection rates increased with age and were higher among males compared to females. Genomic analysis confirmed the presence ofM. ozzardithat clusters closely with strains sequenced in neighboring countries. We successfully cryopreserved and revitalizedM. ozzardimicrofilariae, advancing the prospects of rearing infective larvae in controlled settings. These data suggest an underestimation of true mansonellosis prevalence, and we expect that these methods will help facilitate the study of mansonellosis in endemic and laboratory settings.
Extracellular diadenosine tetraphosphate (Ap4A) is recognized by the plasma membrane purinoreceptor P2K1/DORN1 and closes stomata inArabidopsis thaliana
Authors: Dobrogojski Jędrzej , Nguyen Van Hai , Kowalska Joanna , Borek Sławomir , Pietrowska-Borek Małgorzata 
Published: May 2023

SummaryDinucleoside polyphosphates (NpnNs) are considered novel signalling molecules involved in the induction of plant defence mechanisms. However, the NpnNs signal recognition and transduction are still enigmatic. Here we report, for the first time, that diadenosine tetraphosphate (Ap4A) is recognized by theArabidopsis thalianapurinoreceptor P2K1/DORN1 (Does Not Respond to Nucleotides 1) and causes stomatal closure.Extracellular Ap4A- and dicytidine tetraphosphate (Cp4C)-induced stomatal closure was observed using a microscope. Reactive oxygen species (ROS) accumulation was determined by staining with nitroblue tetrazolium (NBT) and 3,3ʹ-diaminobenzidine tetrahydrochloride (DAB). Transcriptional changes were determined by quantitative real-time PCR. Wild-type Col-0 and thedorn1-3 A. thalianaknockout mutant were used.Examination of the leaf epidermisdorn1-3mutant provided evidence that P2K1/DORN1 recognizes extracellular Ap4A but not Cp4C. ROS are involved in signal transduction caused by Ap4A and Cp4C, leading to stomatal closure. Ap4A induced and Cp4C suppressed the transcriptional response in wild-type plants. Moreover, indorn1-3leaves, the effect of Ap4A on gene expression was impaired.Our research demonstrated, for the first time, that P2K1/DORN1 is a plant purinoreceptor for Ap4A. This interaction leads to changes in the transcription of signalling hubs in signal transduction pathways.
Protein intrinsically disordered regions have a non-random, modular architecture
Authors: McConnell Brendan S. , Parker Matthew W. 
Published: May 2023

ABSTRACTMotivationProtein sequences can be broadly categorized into two classes: those which adopt stable secondary structure and fold into a domain (i.e., globular proteins), and those that do not. The sequences belonging to this latter class are conformationally heterogeneous and are described as being intrinsically disordered. Decades of investigation into the structure and function of globular proteins has resulted in a suite of computational tools that enable their sub-classification by domain type, an approach that has revolutionized how we understand and predict protein functionality. Conversely, it is unknown if sequences of disordered protein regions are subject to broadly generalizable organizational principles that would enable their sub-classification.ResultsHere we report the development of a statistical approach that quantifies linear variance in amino acid composition across a sequence. With multiple examples we provide evidence that intrinsically disordered regions are organized into statistically non-random modules of unique compositional bias. Modularity is observed for both low and high complexity sequences and, in some cases, we find that modules are organized in repetitive patterns. These data demonstrate that disordered sequences are non-randomly organized into modular architectures and motivate future experiments to comprehensively classify module types and to determine the degree to which modules constitute functionally separable units analogous to the domains of globular proteins.Availability and implementationThe source code, documentation, and data to reproduce all figures is freely available athttps://github.com/MWPlabUTSW/Chi-Score-Analysis.git. The analysis is also available as a Google Colab Notebook (https://colab.research.google.com/github/MWPlabUTSW/Chi-Score-Analysis/blob/main/ChiScore_Analysis.ipynb).
SETDB1 Triple Tudor Domain Ligand, (R,R)-59, Promotes Methylation of Akt1 in Cells
Authors: Uguen Mélanie , Deng Yu , Li Fengling , Shell Devan J. , Norris-Drouin Jacqueline L. , Stashko Michael A. , Ackloo Suzanne , Arrowsmith Cheryl H. , James Lindsey I. , Liu Pengda , Pearce Kenneth H. , Frye Stephen V. 
Published: May 2023

ABSTRACTIncreased expression and hyperactivation of the methyltransferase SETDB1 are commonly observed in cancer and central nervous system disorders. However, there are currently no reported SETDB1-specific methyltransferase inhibitors in the literature, suggesting this is a challenging target. Here, we disclose that the previously reported small-molecule ligand for SETDB1’s Triple Tudor Domain, (R,R)-59, is unexpectedly able to increase SETDB1 methyltransferase activity bothin vitroand in cells. Specifically, (R,R)-59 promotesin vitroSETDB1-mediated methylation of lysine 64 of the protein kinase Akt1. Treatment with (R,R)-59 also increased Akt1 threonine 308 phosphorylation and activation, a known consequence of Akt1 methylation, resulting in stimulated cell proliferation in a dose-dependent manner. (R,R)-59 is the first SETDB1 small-molecule positive activator for the methyltransferase activity of this protein. Mechanism of action studies show that full-length SETDB1 is required for significantin vitromethylation of an Akt1-K64 peptide, and that this activity is stimulated by (R,R)-59 primarily through an increase in catalytic activity rather than a change in SAM binding.Abstract Figure
Molecular motor tug-of-war regulates elongasome cell wall synthesis dynamics inBacillus subtilis
Authors: Middlemiss Stuart , Blandenet Matthieu , Roberts David M , McMahon Andrew , Grimshaw James , Edwards Joshua M , Sun Zikai , Whitley Kevin D , Blu Thierry , Strahl Henrik , Holden Séamus 
Published: May 2023

ABSTRACTMost rod-shaped bacteria elongate by inserting new cell wall material into the inner surface of the cell sidewall. This is performed by class A penicillin binding proteins (PBPs) and a highly conserved protein complex, the elongasome, which moves processively around the cell circumference and inserts long glycan strands that act as barrel-hoop-like reinforcing structures, thereby giving rise to a rod-shaped cell. However, it remains unclear how elongasome synthesis dynamics and termination events are regulated to determine the length of these critical cell-reinforcing structures. To address this, we developed a method to track individual elongasome complexes around the entire circumference ofBacillus subtiliscells for minutes-long periods using single molecule fluorescence microscopy. We found that theB. subtiliselongasome is highly processive and that processive synthesis events are frequently terminated by rapid reversal or extended pauses. We found that cellular levels of RodA regulate elongasome processivity, reversal and pausing. Our single molecule data, together with stochastic simulations, show that elongasome dynamics and processivity are regulated by molecular motor tug-of-war competition between several, likely two, oppositely oriented peptidoglycan synthesis complexes associated with the MreB filament. Our data, thus, demonstrate that molecular motor tug-of-war is a key regulator of elongasome dynamics inB. subtilis, which likely also regulates the cell shape via modulation of elongasome processivity.
Phosphorylated trimeric SOSS1 complex and RNA polymerase II trigger liquid-liquid phase separation at double-strand breaks
Authors: Long Qilin , Sebesta Marek , Sedova Katerina , Haluza Vojtech , Alagia Adele , Liu Zhichao , Stefl Richard , Gullerova Monika 
Published: May 2023

AbstractThe most toxic forms of DNA damage are double-strand breaks (DSBs). We have previously shown that RNA polymerase II (RNAPII), phosphorylated at tyrosine 1 (Y1P) on the C- terminal domain, transcribes RNA at DSBs to promote efficient DNA repair. However, it is still unknown how transcription is regulated at DSBs. Here, we show that the trimeric SOSS1 complex (hSSB1, INTS3, and c9orf80) binds to Y1P RNAPII in response to DNA damage, hSSB1 binds to R-loops, and formation of the SOSS1 complex is required for the coexistence of replication protein A (RPA) and hSSB1 at DSBs. The damage-activated tyrosine kinase c- Abl phosphorylates hSSB1 to enable its binding to Y1P RNAPII and its recruitment to DSBs. Finally, we show bothin vitroandin vivothat the SOSS1 complex and RNAPII form dynamic repair compartments at DSBs via liquid-liquid phase separation (LLPS). The loss of the trimeric SOSS1 leads to impaired DNA repair, highlighting its biological importance in the RNA-dependent DNA damage response.TeaserTrimeric SOSS1 complex and transcription contribute to phase separation at double-strand DNA breaks.
Extensive T1-weighted MRI Preprocessing Improves Generalizability of Deep Brain Age Prediction Models⋆
Authors: Dular Lara , Pernuš Franjo , Špiclin Žiga 
Published: May 2023

AbstractBrain age is an estimate of chronological age obtained from T1-weighted magnetic resonance images (T1w MRI) and represents a simple diagnostic biomarker of brain ageing and associated diseases. While the current best accuracy of brain age predictions on T1w MRIs of healthy subjects ranges from two to three years, comparing results from different studies is challenging due to differences in the datasets, T1w preprocessing pipelines, and performance metrics used. This paper investigates the impact of T1w image preprocessing on the performance of four deep learning brain age models presented in recent literature. Four preprocessing pipelines were evaluated, differing in terms of registration, grayscale correction, and software implementation. The results showed that the choice of software or preprocessing steps can significantly affect the prediction error, with a maximum increase of 0.7 years in mean absolute error (MAE) for the same model and dataset. While grayscale correction had no significant impact on MAE, the affine registration, compared to the rigid registration of T1w images to brain atlas was shown to statistically significantly improve MAE. Models trained on 3D images with isotropic 1mm3resolution exhibited less sensitivity to the T1w preprocessing variations compared to 2D models or those trained on downsampled 3D images. Some proved invariant to the preprocessing pipeline, however only after offset correction. Our findings generally indicate that extensive T1w preprocessing enhances the MAE, especially when applied to a new dataset. This runs counter to prevailing research literature which suggests that models trained on minimally preprocessed T1w scans are better poised for age predictions on MRIs from unseen scanners. Regardless of model or T1w preprocessing used, we show that to enable generalization of model’s performance on a new dataset with either the same or different T1w preprocessing than the one applied in model training, some form of offset correction should be applied.HighlightsIntensive preprocessing improves performance of computationally less demanding models.Models trained on 1mm3MRIs are most insensitive to the choice of preprocessing.Change in preprocessing increased MAE up to 0.7 years for the same model and dataset.Preprocessing software used may impact model performance.Prediction bias is systematic across the whole age span and inherent to each model.