bluuebunny/crossref_metadata_2025_split huggingface dataset:
Familial risk of psychosis in obsessive-compulsive disorder: Impact on clinical characteristics, comorbidity and treatment response
Authors: Balachander Srinivas , Thatikonda Navya Spurthi , Kannampuzha Anand Jose , Bhattacharya Mahashweta , Sheth Sweta , Ramesh Vinutha , Alexander Alen Chandy , Moorthy Muthukumaran , Joseph Mino Susan , Selvaraj Sowmya , Ithal Dhruva , Sreeraj Vanteemar S , John John P , Venkatasubramanian Ganesan , Viswanath Biju , Reddy YC Janardhan , Jain Sanjeev ,   ADBS consortium
Published: April 2022

AbstractBackgroundFamily studies in obsessive-compulsive disorder (OCD) indicate higher rates of psychosis among their first-degree relatives (FDRs). However, the etiological and clinical relationships between the two disorders remain unclear. We compared the clinical characteristics & pharmacological treatment response in patients diagnosed with OCD with a family history of psychosis (OCD-FHP), with a family history of OCD (OCD-FHO) and those with sporadic OCD (OCD-S).MethodsA total of 226 patients who met DSM-IV criteria for OCD (OCD-FHP=59, OCD-FHO=112, OCD-S=55) were included for analysis. All patients were evaluated using the Mini International Neuropsychiatric Interview (MINI 6.0.0), Yale-Brown Obsessive-Compulsive Scale (YBOCS), and the Family Interview for Genetic Studies (FIGS). Treatment response was characterized over naturalistic follow-up.ResultsThe three groups did not differ across any demographic or clinical variables other than treatment response. Patients in the OCD-FHP group were found to have received a greater number of trials with serotonin reuptake inhibitors (SRI) [F(2,223)=7.99, p<0.001], were more likely to have failed ≥ 2 trials of SRIs (χ2=8.45, p=0.014), and less likely to have attained remission (χ2=6.57, p=0.037)ConclusionsWe observed that having a relative with psychosis may predispose to treatment resistance in OCD. Further research on the influence of genetic liability to psychosis on treatment response in OCD may offer novel translational leads.
Persistent post-COVID-19 smell loss is associated with inflammatory infiltration and altered olfactory epithelial gene expression
Authors: Finlay John B. , Brann David H. , Abi-Hachem Ralph , Jang David W. , Oliva Allison D. , Ko Tiffany , Gupta Rupali , Wellford Sebastian A. , Moseman E. Ashley , Jang Sophie S. , Yan Carol H. , Matusnami Hiroaki , Tsukahara Tatsuya , Datta Sandeep Robert , Goldstein Bradley J. 
Published: April 2022

SummaryMost human subjects infected by SARS-CoV-2 report an acute alteration in their sense of smell, and more than 25% of COVID patients report lasting olfactory dysfunction. While animal studies and human autopsy tissues have suggested mechanisms underlying acute loss of smell, the pathophysiology that underlies persistent smell loss remains unclear. Here we combine objective measurements of smell loss in patients suffering from post-acute sequelae of SARS-CoV-2 infection (PASC) with single cell sequencing and histology of the olfactory epithelium (OE). This approach reveals that the OE of patients with persistent smell loss harbors a diffuse infiltrate of T cells expressing interferon-gamma; gene expression in sustentacular cells appears to reflect a response to inflammatory signaling, which is accompanied by a reduction in the number of olfactory sensory neurons relative to support cells. These data identify a persistent epithelial inflammatory process associated with PASC, and suggests mechanisms through which this T cell-mediated inflammation alters the sense of smell.
fMetastatic potential in clonal melanoma cells is driven by a rare, early-invading subpopulation
Authors: Kaur Amanpreet , Cuenca Luciann , Kiani Karun , Busch Gianna T. , Fingerman Dylan , Dunagin Margaret C. , Li Jingxin , Dardani Ian , Sanford Eric M. , Pemberton Jordan , Goyal Yogesh , Weeraratna Ashani T. , Herlyn Meenhard , Raj Arjun 
Published: April 2022

AbstractMetastasis occurs when tumor cells leave the primary tumor site and disseminate to distal organs. Even though most cells remain in the primary tumor, the circumstances by which a small fraction of them disseminate remain unclear. Here, we show that a rare, highly invasive subpopulation of melanoma cells can be detected within clonal cell lines due to non-genetic fluctuations in gene expression. The highly invasive phenotype was intrinsic to the cells, independent of their environment, and was marked by transiently high levels ofSEMA3Cexpression, as revealed by RNA-sequencing analysis. Furthermore, the invasive subpopulation drove the bulk dissemination of tumor cells to distal locations in a mouse model of melanoma. The transcription factorNKX2.2regulated the proportion of invasive cells in the melanoma 1205Lu cell line. Furthermore, an overall tradeoff between proliferation and invasion in single cells was observed. Our results suggest that phenotypes like metastasis may arise from intrinsic differences stemming from non-genetic fluctuations between single cells.
scTour: a deep learning architecture for robust inference and accurate prediction of cellular dynamics
Authors: Li Qian 
Published: April 2022

AbstractDespite the continued efforts to computationally dissect developmental processes using single-cell genomics, a batch-unaffected tool that is able to both infer and predict the underlying dynamics is lacking. Here, I present scTour, a novel deep learning architecture to perform robust inference and accurate prediction of the cellular dynamics in diverse processes. For inference, scTour can efficiently and simultaneously estimate the developmental pseudotime, intronic read-independent vector field, and transcriptomic latent space under a single, integrated framework. For prediction, scTour can precisely reconstruct the underlying dynamics of unseen cellular states or an independent dataset agnostic to the model. Of note, both the inference and prediction are invariant to batch effects. scTour’s functionalities are successfully applied to a variety of biological processes from 17 datasets such as cell differentiation, reprogramming and zonation, providing a comprehensive infrastructure to investigate the cellular mechanisms underpinning development in an efficient manner.
The Effects of Vitamin E Analogues α-Tocopherol and γ-Tocotrienol on the Human Osteocyte Response to Ultra-high Molecular Weight Polyethylene Wear Particles
Authors: Ormsby Renee T , Hosaka Kunihiro , Evdokiou Andreas , Odysseos Andreani , Findlay David M , Solomon Lucian B. , Atkins Gerald J 
Published: April 2022

AbstractPolyethylene (PE) liners are a common bearing surface of orthopaedic prostheses. Wear particles of ultra-high molecular weight PE (UHMWPE) contribute to periprosthetic osteolysis, a major cause of aseptic loosening. Vitamin E is added to some PE liners to prevent oxidative degradation. Osteocytes, an important cell type for controlling both bone mineralisation and bone resorption, have been shown to respond UHMWPE particles by upregulating pro-osteoclastogenic and osteocytic osteolysis. Here, we examined the effects of the vitamin E analogues α-tocopherol and γ-tocotrienol alone or in the context of UHMWPE particles on human osteocyte gene expression and mineralisation behaviour. Human osteoblasts differentiated to an osteocyte-like stage were exposed to UHMWPE wear particles in the presence or absence of either α-Tocopherol or γ-Tocotrienol. Both α-Tocopherol and γ-Tocotrienol induced antioxidant-related gene expression. UHMWPE particles independently upregulated antioxidant gene expression, suggesting an effect of wear particles on oxidative stress. Both vitamin E analogues strongly induced OPG mRNA expression and γ-Tocotrienol also inhibited RANKL mRNA expression, resulting in a significantly reduced RANKL:OPG mRNA ratio (p < 0.01) overall. UHMWPE particles reversed the suppressive effect of α-Tocopherol but not of γ-Tocotrienol on this pro-osteoclastogenic index. UHMWPE particles also upregulated osteocytic-osteolysis related gene expression. Vitamin E analogues alone or in combination with UHMWPE particles also resulted in upregulation of these genes. Consistent with this, both vitamin E analogues promoted calcium release from mineralised cultures of osteocyte-like cells. Our findings suggest that while vitamin E may suppress osteocyte support of osteoclastogenesis in the presence of UHMWPE particles, the antioxidant effect may induce osteocytic osteolysis, which could promote periprosthetic osteolysis. It will be important to conduct further studies of vitamin E to determine the long-term effects of its inclusion in prosthetic materials.
A deep reinforcement learning approach to reconstructing quaternary structures of protein dimers through self-learning
Authors: Soltanikazemi Elham , Roy Raj S. , Quadir Farhan , Cheng Jianlin 
Published: April 2022

AbstractPredicted interchain residue-residue contacts can be used to build the quaternary structure of protein complexes from scratch. However, only a small number of methods have been developed to reconstruct protein quaternary structures using predicted interchain contacts. Here, we present an agent-based self-learning method based on deep reinforcement learning (DRLComplex) to build protein complex structures using interchain contacts as distance constraints. We rigorously tested the DRLComplex on two standard datasets of homodimeric and heterodimeric dimers (the CASP-CAPRI homodimer dataset and Std_32 heterodimer dataset) using both true and predicted contacts. Utilizing true contacts as input, the DRLComplex achieved a high average TM-score of 0.9895 and 0.9881 and a low average interface RMSD (I_RMSD) of 0.2197 and 0.92 on the two datasets, respectively. When predicted contacts are used, the method achieves the TM-score of 0.73 and 0.76 for homodimers and heterodimers respectively. The accuracy of reconstructed quaternary structures depends on the accuracy of contact predictions. Compared with other optimization methods of reconstructing quaternary structures from interchain contacts, DRLComplex performs similarly to an advanced gradient descent method and better than a Markov Chain Monte Carlo simulation method and a simulated annealing-based method. The source code of DRLComplex is available at:https://github.com/jianlin-cheng/DRLComplex
Gut microbiota composition correlates with disease severity in myelodysplastic syndrome
Authors: Riello Giovanna Barbosa Correia , Mendonça da Silva Priscila , da Silva Oliveira Francisca Andrea , Taiane Germano de Oliveira Roberta , da Silva Francisco Eliclecio Rodrigues , da Frota França Ivo Gabriel , Miyajima Fábio , Melo Vânia Maria Maciel , Pinheiro Ronald Feitosa , Macedo Danielle S. 
Published: April 2022

ABSTRACTThe myelodysplastic syndrome (MDS) is a heterogeneous group of clonal disorders of hematopoietic progenitor cells related to ineffective hematopoiesis and an increased risk of transformation to acute myelogenous leukemia. MDS is divided into categories, namely lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with multilineage dysplasia (MDS-MLD), MDS with excess blasts (MDS-EB). The International Prognostic Classification System (IPSS) ranks the patients as very low, low, intermediate, high, and very high based on disease evolution and survival rates. Evidence points to toll-like receptor (TLR) abnormal signaling as an underlying mechanism of this disease, providing a link between MDS and immune dysfunction. Notably, microbial signals, such as lipopolysaccharide from gram-negative bacteria can activate or suppress TLRs. Therefore, we hypothesized that MDS patients present gut microbiota alterations associated with disease subtypes and prognosis. We sequenced the 16S rRNA gene from fecal samples of 30 MDS patients and 16 healthy elderly controls to test this hypothesis. We observed a negative correlation between Prevotella spp. and Akkermansia spp. in MDS patients compared with the control group. High-risk patients presented a significant increase in the genus Prevotella spp. in relation to the other risk categories. There was a significant reduction in the abundance of the genus Akkermansia spp. in high-risk patients compared with low- and intermediate-risk. There was a significant decrease in the genus Ruminococcus spp. in MDS-EB patients compared with controls. Our findings show a new association between gut dysbiosis and higher-risk MDS, with a predominance of gram-negative bacteria in the gut of these patients.
Gender Moderates the Mediating Pathway between Social Deprivation, Body Mass Index and Physical Activity
Authors: Maltagliati Silvio , Saoudi Ilyes , Sarrazin Philippe , Cullati Stéphane , Sieber Stefan , Chalabaev Aïna , Cheval Boris 
Published: April 2022

AbstractPhysical activity is unequally practiced across populations: relative to more privileged individuals, deprived people are less likely to be physically active. However, pathways underlying the association between deprivation and physical activity remain overlooked. Here, we examined whether the association between several indicators of deprivation (administrative area deprivation and self-reported individual material and social deprivation) and physical activity was mediated by body mass index (BMI). In addition, consistent with an intersectional perspective, we tested whether this mediating pathway was moderated by participants’ gender and we hypothesized that the mediating effect of BMI would be stronger among women, relative to men. We used two independent large-scale studies to test the proposed pathways cross-sectionally and prospectively. In a first sample composed of 5,723 British adults (Study 1), BMI partly mediated the cross-sectional association between administrative area deprivation and self-reported physical activity. Moreover, relative to men, the detrimental effect of deprivation on BMI was exacerbated among women, with BMI mediating 3.1% of the association between deprivation and physical activity among women (vs 1.5% among men). In a second sample composed of 8,358 European older adults (Study 2), our results confirmed the findings observed in Study 1: BMI partly mediated the prospective association between perceived material and social deprivation and self-reported physical activity. Moreover, compared to men, the effect of deprivation on BMI was more pronounced among women, with BMI respectively mediating 8.1% and 3.4% of the association between material and social deprivation and physical activity among women (vs 1.3% and 1.2% among men). These findings suggest that BMI partly explained the detrimental association between deprivation and physical activity, with this effect being stronger among women. Our study highlights the need to further consider how gender may shape the mechanisms behind the association between disadvantaged socio-economic circumstances and physical activity.
Confounder-adjusted MRI-based predictors of multiple sclerosis disability
Authors: Kim Yujin , Varosanec Mihael , Kosa Peter , Bielekova Bibiana 
Published: April 2022

ABSTRACTIntroductionBoth aging and multiple sclerosis (MS) cause central nervous system (CNS) atrophy. Excess brain atrophy in MS has been interpreted as accelerated aging. Current paper tests an alternative hypothesis: MS causes CNS atrophy by mechanism(s) different from physiological aging. Thus, subtracting effects of physiological confounders on CNS structures would isolate MS-specific effects.MethodsStandardized brain MRI and neurological examination were acquired prospectively in 649 participants enrolled in ClinicalTrials.gov Identifier: NCT00794352 protocol. CNS volumes were measured retrospectively, by automated Lesion-TOADS algorithm and by Spinal Cord Toolbox, in a blinded fashion. Physiological confounders identified in 80 healthy volunteers were regressed out by stepwise multiple linear regression. MS specificity of confounder-adjusted MRI features was assessed in non-MS cohort (n=160). MS patients were randomly split into training (n=277) and validation (n=132) cohorts. Gradient boosting machine (GBM) models were generated in MS training cohort from unadjusted and confounder-adjusted CNS volumes against four disability scales.ResultsConfounder adjustment highlighted MS-specific progressive loss of CNS white matter. GBM model performance decreased substantially from training to cross-validation, to independent validation cohorts, but all models predicted cognitive and physical disability with low p-values and effect sizes that outperforms published literature based on recent meta-analysis. Models built from confounder-adjusted MRI predictors outperformed models from unadjusted predictors in the validation cohort.ConclusionGBM models from confounder-adjusted volumetric MRI features reflect MS-specific CNS injury, and due to stronger correlation with clinical outcomes compared to brain atrophy these models should be explored in future MS clinical trials.HighlightsRegressing out physiological confounders affecting volume of CNS structures in healthy volunteers, strengthened correlations between white matter volumes and disability outcomes in MS cohortsAggregating volumetric features into generalized boosting machine (GBM) models outperformed correlations of individual MRI biomarkers with clinical outcomes in MSDeveloped more sensitive and reliable models that predict MS-associated disabilityIndependent validation cohorts show true model performancesDeveloped GBM models should be explored in future MS clinical trials
Pyochelin biotransformation byStaphylococcus aureusshapes bacterial competition withPseudomonas aeruginosain polymicrobial infections
Authors: Jenul C. , Keim K. , Jens J. , Zeiler M. J. , Schilcher K. , Schurr M. , Melander C. , Phelan V.V. , Horswill A.R. 
Published: April 2022

SummaryPseudomonas aeruginosaandStaphylococcus aureusare among the most frequently isolated bacterial species from polymicrobial infections of cystic fibrosis patients and chronic wounds. We applied mass spectrometry guided interaction studies to determine how chemical interaction shapes the fitness and community structure during co-infection of these two pathogens. We demonstrate thatS. aureusis equipped with an elegant mechanism to inactivate pyochelin via the yet uncharacterized methyltransferase Spm (staphylococcalpyochelinmethyltransferase). Methylation of pyochelin abolishes the siderophore activity of pyochelin and significantly lowers pyochelin-mediated intracellular ROS production inS. aureus. In a murine wound co-infection model, aS. aureusmutant unable to methylate pyochelin shows significantly lower fitness as compared to its parental strain. Thus, Spm mediated pyochelin methylation is a novel mechanism to increaseS. aureussurvival duringin vivocompetition withP. aeruginosa.
Organelle-selective click labeling coupled with flow cytometry allows high-throughput CRISPR screening of genes involved in phosphatidylcholine metabolism
Authors: Tsuchiya Masaki , Tachibana Nobuhiko , Nagao Kohjiro , Tamura Tomonori , Hamachi Itaru 
Published: April 2022

AbstractLipids comprise biomembranes and are involved in many crucial cell functions. While cellular lipid synthesis and transport appear to be governed by intricate protein networks, the whole scheme is insufficiently understood. Although functional genome-wide screening should contribute to deciphering the regulatory networks of lipid metabolism, technical challenges remain – especially for high-throughput readouts of lipid phenotypes. Here, we coupled organelle-selective click labeling of phosphatidylcholine (PC) with flow cytometry-based CRISPR screening technologies to convert organellar PC phenotypes into a simple fluorescence readout for genome-wide screening. This technique, named O-ClickFC, was successfully applied in genome-scale CRISPR-knockout screens to identify previously reported genes associated with PC synthesis (PCYT1A, ACACA), vesicular membrane trafficking (SEC23B, RAB5C), and non-vesicular transport (PITPNB, STARD7). Moreover, this work revealed previously uncharacterized roles of FLVCR1 as a new choline transporter; CHEK1 as a post-translational regulator of the PC-synthetic pathway, and TMEM30A as responsible for translocation of PC to the outside of the plasma membrane bilayer. These findings demonstrate the versatility of O-ClickFC as an unprecedented platform for genetic dissection of cellular lipid metabolism.
Neural instructive signals for associative cerebellar learning
Authors: Silva N. Tatiana , Ramírez-Buriticá Jorge , Pritchett Dominique L. , Carey Megan R. 
Published: April 2022

ABSTRACTSupervised learning depends on instructive signals that shape the output of neural circuits to support learned changes in behavior. Climbing fiber inputs to the cerebellar cortex represent one of the strongest candidates in the vertebrate brain for conveying neural instructive signals. However, recent studies have shown that Purkinje cell stimulation can also drive cerebellar learning, and the relative importance of these two neuron types in providing instructive signals for cerebellum-dependent behaviors remains unresolved. Here we used cell-type specific perturbations of climbing fibers, Purkinje cells, and other cerebellar circuit elements to systematically evaluate their contributions to delay eyeblink conditioning. Our findings reveal that while optogenetic stimulation of either climbing fibers or Purkinje cells are capable of driving learning under some conditions, even subtle reductions in climbing fiber signaling completely block learning to natural conditioning stimuli. We conclude that climbing fibers and corresponding Purkinje cell complex-spike events provide essential instructive signals for associative cerebellar learning.
A systems biology approach to disentangle the direct and indirect effects of global transcription factors on gene expression in Escherichia coli
Authors: Iyer Mahesh S. , Pal Ankita , Venkatesh K. V. 
Published: April 2022

AbstractDelineating the pleiotropic effects of global transcriptional factors (TFs) is critical in understanding the system-wide regulatory response in a particular environment. Currently, with the availability of genome-wide TF binding and gene expression data for Escherichia coli, several gene targets can be assigned to the global TFs albeit inconsistently. Here, using a systematic integrated approach with emphasis on metabolism, we characterize and quantify the direct effects as well as the growth-rate mediated indirect effects of global TFs using deletion mutants of FNR, ArcA, and IHF regulators under glucose fermentative condition. Apart from the previous known metabolite-TF interactions, we predicted with high confidence several novel interactions arising from the allosteric effects of the intracellular metabolites. Our combined experimental and compendium level computational analyses revealed the co-expressed genes regulated by these TFs as well as the coordination of the direct and indirect target gene expressions in the context of the economy of intracellular metabolites. Besides, we extended our analysis to combinatorial deletions of these TFs to determine their cross-talk effects as well as conserved patterns of regulatory interactions. Overall, this study leverages the fundamentals of TF-driven regulation which could serve as a better template for deciphering mechanisms underlying complex phenotypes.