bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dopamine-induced pruning in monocyte-derived-neuronal-like cells (MDNCs) from patients with schizophrenia
Authors: Bellon Alfredo , Feuillet Vincent , Cortez-Resendiz Alonso , Mouaffak Faycal , Kong Lan , Hong L. Elliot , De Godoy Lilian , Jay Therese M. , Hosmalin Anne , Krebs Marie-Odile 
Published: April 2022

AbstractThe long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine’s pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In this study, we expanded the number of individuals in whom we tested the reproducibility of MDNCs. We also deepened the characterization of MDNCs by comparing its neurostructure to that of human developing neurons. Moreover, we studied MDNCs from 12 controls and 13 patients with SCZ. Patients’ cells differentiate more efficiently, extend longer secondary neurites and grow more primary neurites. In addition, MDNCs from medicated patients expresses less D1R and prune more primary neurites when exposed to dopamine. Haloperidol did not influence our results but the role of other antipsychotics was not examined and thus, needs to be considered as a confounder.
Efficacy of neurostimulation across mental disorders: systematic review and meta-analysis of 208 randomized controlled trials
Authors: Hyde Joshua , Carr Hannah , Kelley Nicholas , Seneviratne Rose , Reed Claire , Parlatini Valeria , Garner Matthew , Solmi Marco , Rosson Stella , Cortese Samuele , Brandt Valerie 
Published: April 2022

AbstractNon-invasive brain stimulation (NIBS), including transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS), is a potentially effective treatment strategy for a number of mental conditions. However, no quantitative evidence synthesis of randomized controlled trials (RCTs) of TMS or tDCS using the same criteria including several mental conditions is available. Based on 208 RCTs identified in a systematic review, we conducted a series of random effects meta-analyses to assess the efficacy of NIBS, compared to sham, for core symptoms and cognitive functioning within a broad range of mental conditions. Outcomes included changes in core symptom severity and cognitive functioning from pre- to post-treatment. We found significant positive effects for several outcomes without significant heterogeneity including TMS for symptoms of generalized anxiety disorder (SMD = −1.8 (95% CI: −2.6 to −1), and tDCS for symptoms of substance use disorder (−0.73, −1.00 to −0.46). There was also significant effects for TMS in obsessive-compulsive disorder (−0.66, −0.91 to −0.41) and unipolar depression symptoms (−0.60, −0.78 to −0.42) but with significant heterogeneity. However, subgroup analyses based on stimulation site and number of treatment sessions revealed evidence of positive effects, without significant heterogeneity, for specific TMS stimulation protocols. For neurocognitive outcomes, there was only significant evidence, without significant heterogeneity, for tDCS for improving attention (−0.3, −0.55 to −0.05) and working memory (−0.38, −0.74 to −0.03) in individuals with schizophrenia. We concluded that TMS and tDCS can benefit individuals with a variety of mental conditions, significantly improving clinical dimensions, including cognitive deficits in schizophrenia which are poorly responsive to pharmacotherapy.
IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist
Authors: Baker Kevin , O’Donnell Charlotte , Bendix Maura , Keogh Samuel , Byrne James , O’Riordain Michael , Neary Peter , Houston Aileen , Brint Elizabeth 
Published: April 2022

AbstractThe IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, shown to play a role in the pathogenesis of intestinal diseases such as Inflammatory Bowel Disease (IBD). Given the link between IBD and colitis –associated cancer, as well as the involvement of other IL-1 family members in intestinal tumorigenesis, the aim of this work was to investigate whether IL-36 cytokines play a role in the pathogenesis of colon cancer. Whilst research to date has focused on the role of IL-36 family members in augmenting the immune response to induce tumour rejection, very little remains known about IL-36R signalling in tumour cells in this context. In this study we demonstrate that expression of IL-36 family member mRNA and protein are significantly increased in colorectal cancer tissue compared to adjacent non-tumour. In vitro assays showed stimulation of colon cancer cell lines with IL-36R agonists resulted in the activation of the pro-tumorigenic phenotypes of increased cellular migration, invasion and proliferation in both 2D and 3D models. In addition, the IL-36 cytokines induced strong expression of pro-inflammatory chemokines in both human and murine cell lines. Intraperitoneal injection of IL-36Ra significantly reduced tumour burden using the subcutaneous CT26 tumour model in syngeneic Balb/mice, and this was associated with a decrease in Ki-67 expression by tumour cells in the IL-36Ra- treated group relative to untreated, suggesting the inhibition of the pro-proliferative signalling of IL-36 agonists resulted in the decreased tumour size. Moreover, colon cancer cells lacking the IL-36R also showed reduced tumour growth and reduced Ki-67 expression in vivo. Taken together, this data suggests that targeting IL-36R signalling may be a useful targeted therapy for colorectal cancer patients with IL-36R+ tumour cells.
Telomere length and mitochondrial DNA copy number in bipolar disorder: identification of a subgroup of young individuals with accelerated cellular aging
Authors: Spano L. , Etain B. , Meyrel M. , Hennion V. , Gross G. , Laplanche J-L. , Bellivier F. , Marie-Claire C. 
Published: April 2022

AbstractThe 10–15-years decrease in life expectancy observed in individuals with bipolar disorder (BD) has been linked to the concept of accelerated cellular aging. Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) have been proposed as markers of cellular aging and comparisons between individuals with BD and healthy controls (HC) sometimes led to conflicting results. Previous studies had moderate sample sizes and studies combining these two markers into a single analysis are scarce. Using quantitative polymerase chain reaction, we measured both TL and mtDNAcn in DNA (peripheral blood) in a sample of 130 individuals with BD and 78 HC. Regression analyses, receiver operating characteristic (ROC), and clustering analyses were performed. We observed significantly lower TL and mtDNAcn in individuals with BD as compared to HC (respective decrease of 26.5 and 35.8%). ROC analyses showed that TL and mtDNAcn highly discriminated groups (AUC = 0.904 for TL and AUC = 0.931 for mtDNAcn). In the whole population, clustering analyses identified a group of young individuals (age around 36 years), with accelerated cellular aging (both shorter TL and lower mtDNAcn), which consisted mostly of individuals with BD (85.5%). The subgroup of patients with young age but accelerated aging was not characterized by specific clinical variables related to the course of BD or childhood maltreatment. However, patients in this subgroup were more frequently treated with anticonvulsants. Further characterization of this subgroup is required to better understand the molecular mechanisms and the risk factors of accelerated cellular aging in BD.
Ixazomib with cyclophosphamide and dexamethasone in relapsed or refractory myeloma: MUKeight phase II randomised controlled trial results
Authors: Auner Holger W. , Brown Sarah R. , Walker Katrina , Kendall Jessica , Dawkins Bryony , Meads David , Morgan Gareth J. , Kaiser Martin F. , Cook Mark , Roberts Sadie , Parrish Christopher , Cook Gordon 
Published: April 2022

AbstractThe all-oral combination of ixazomib, cyclophosphamide, and dexamethasone (ICD) is well tolerated and effective in newly diagnosed and relapsed multiple myeloma (MM). We carried out MUKeight, a randomised, controlled, open, parallel group, multi-centre phase II trial in patients with relapsed MM after prior treatment with thalidomide, lenalidomide, and a proteasome inhibitor (ISRCTN58227268), with the primary objective to test whether ICD has improved clinical activity compared to cyclophosphamide and dexamethasone (CD) in terms of progression-free survival (PFS). Between January 2016 and December 2018, 112 participants were randomised between ICD (n = 58) and CD (n = 54) in 33 UK centres. Patients had a median age of 70 years and had received a median of four prior lines of therapy. 74% were classed as frail. Median PFS in the ICD arm was 5.6 months, compared to 6.7 months with CD (hazard ratio (HR) = 1.21, 80% CI 0.9–1.6, p = 0.3634). Response rates and overall survival were not significantly different between ICD and CD. Dose modifications or omissions, and serious adverse events (SAEs), occurred more often in the ICD arm. In summary, the addition of ixazomib to cyclophosphamide and dexamethasone did not improve outcomes in the comparatively frail patients enroled in the MUKeight trial.
Hypothesized pathways for the association of vitamin D status and insulin sensitivity with resting energy expenditure: a cross sectional mediation analysis in Australian adults of European ancestry
Authors: Soares Mario J. , Calton Emily K. , Pathak Kaveri , Zhao Yun 
Published: April 2022

AbstractBackgroundThe role of vitamin D in human energy expenditure requires confirmation. We explored whether insulin sensitivity (IS)/insulin resistance (IR) mediated the association of vitamin D status (25OHD) on resting energy expenditure (REE).MethodsREE, body composition (by DEXA) and clinical biochemistry of 155 Australian men and women were collated. A hypothesized mediation pathway through IS/IR on the direct association between 25OHD and REE was modeled, using three surrogate indices of IS/IR: McAuley’s insulin sensitivity index (McA), Quantitative insulin sensitivity check index (QUICKI) and triglyceride to glucose ratio (TYG). The modeling was performed on PROCESS SPSS Macro (version 4.0) based on 5000 bootstrapped samples, with and without the adjustment for covariates.ResultsUnadjusted models indicated a sizeable negative mediation by all IS/IR indices but no significant direct effect of 25OHD on REE. On adjustment for covariates, a negative indirect mediation effect of McA [β coefficient (SE) −2.1(0.821); bootstrapped 95% CI:−3.934, −0.703;p < 0.05] and a similar negative mediation of TYG [−1.935 (0.780); bootstrapped 95% CI: (−3.679, −0.622;p < 0.05] was observed. These models also showed a positive direct effect of 25OHD on REE. In contrast, QUICKI made a smaller contribution to the total effect though in the same direction as the other two measures [−0.783 (0.534); bootstrapped 95% CI: (−1.939, 0.134;P > 0.05].ConclusionsA sizeable, partial, negative mediation of IS/IR on the direct relationship between 25OHD and REE, dampened the total effect of vitamin D on REE. Validation of the proposed causal framework would clarify vitamin D’s role in human energy metabolism.
DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes
Authors: Awamleh Zain , Chater-Diehl Eric , Choufani Sanaa , Wei Elizabeth , Kianmahd Rebecca R. , Yu Anna , Chad Lauren , Costain Gregory , Tan Wen-Hann , Scherer Stephen W. , Arboleda Valerie A. , Russell Bianca E. , Weksberg Rosanna 
Published: April 2022

AbstractThe additional sex combs-like (ASXL) gene family—encoded by ASXL1, ASXL2, and ASXL3—is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina’s Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath’s epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.
ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis
Authors: Evans D. Gareth , Mostaccioli Stefania , Pang David , Fadzil O Connor Mary , Pittara Melpo , Champollion Nicolas , Wolkenstein Pierre , Thomas Nick , Ferner Rosalie E. , Kalamarides Michel , Peyre Matthieu , Papi Laura , Legius Eric , Becerra Juan Luis , King Andrew , Duff Chris , Stivaros Stavros , Blanco Ignacio 
Published: April 2022

AbstractA Guideline Group (GG) was convened from multiple specialties and patients to develop the first comprehensive schwannomatosis guideline. The GG undertook thorough literature review and wrote recommendations for treatment and surveillance. A modified Delphi process was used to gain approval for recommendations which were further altered for maximal consensus. Schwannomatosis is a tumour predisposition syndrome leading to development of multiple benign nerve-sheath non-intra-cutaneous schwannomas that infrequently affect the vestibulocochlear nerves. Two definitive genes (SMARCB1/LZTR1) have been identified on chromosome 22q centromeric to NF2 that cause schwannoma development by a 3-event, 4-hit mechanism leading to complete inactivation of each gene plus NF2. These genes together account for 70–85% of familial schwannomatosis and 30–40% of isolated cases in which there is considerable overlap with mosaic NF2. Craniospinal MRI is generally recommended from symptomatic diagnosis or from age 12–14 if molecularly confirmed in asymptomatic individuals whose relative has schwannomas. Whole-body MRI may also be deployed and can alternate with craniospinal MRI. Ultrasound scans are useful in limbs where typical pain is not associated with palpable lumps. Malignant-Peripheral-Nerve-Sheath-Tumour-MPNST should be suspected in anyone with rapidly growing tumours and/or functional loss especially with SMARCB1-related schwannomatosis. Pain (often intractable to medication) is the most frequent symptom. Surgical removal, the most effective treatment, must be balanced against potential loss of function of adjacent nerves. Assessment of patients’ psychosocial needs should be assessed annually as well as review of pain/pain medication. Genetic diagnosis and counselling should be guided ideally by both blood and tumour molecular testing.
Serum proteomics links suppression of tumor immunity to ancestry and lethal prostate cancer
Authors: Minas Tsion Zewdu , Candia Julián , Dorsey Tiffany H. , Baker Francine , Tang Wei , Kiely Maeve , Smith Cheryl J. , Zhang Amy L. , Jordan Symone V. , Obadi Obadi M. , Ajao Anuoluwapo , Tettey Yao , Biritwum Richard B. , Adjei Andrew A. , Mensah James E. , Hoover Robert N. , Jenkins Frank J. , Kittles Rick , Hsing Ann W. , Wang Xin W. , Loffredo Christopher A. , Yates Clayton , Cook Michael B. , Ambs Stefan 
Published: April 2022

AbstractThere is evidence that tumor immunobiology and immunotherapy response may differ between African American and European American prostate cancer patients. Here, we determine if men of African descent harbor a unique systemic immune-oncological signature and measure 82 circulating proteins in almost 3000 Ghanaian, African American, and European American men. Protein signatures for suppression of tumor immunity and chemotaxis are elevated in men of West African ancestry. Importantly, the suppression of tumor immunity protein signature associates with metastatic and lethal prostate cancer, pointing to clinical importance. Moreover, two markers, pleiotrophin and TNFRSF9, predict poor disease survival specifically among African American men. These findings indicate that immune-oncology marker profiles differ between men of African and European descent. These differences may contribute to the disproportionate burden of lethal prostate cancer in men of African ancestry. The elevated peripheral suppression of tumor immunity may have important implication for guidance of cancer therapy which could particularly benefit African American patients.
Biological invasions facilitate zoonotic disease emergences
Authors: Zhang Lin , Rohr Jason , Cui Ruina , Xin Yusi , Han Lixia , Yang Xiaona , Gu Shimin , Du Yuanbao , Liang Jing , Wang Xuyu , Wu Zhengjun , Hao Qin , Liu Xuan 
Published: April 2022

AbstractOutbreaks of zoonotic diseases are accelerating at an unprecedented rate in the current era of globalization, with substantial impacts on the global economy, public health, and sustainability. Alien species invasions have been hypothesized to be important to zoonotic diseases by introducing both existing and novel pathogens to invaded ranges. However, few studies have evaluated the generality of alien species facilitating zoonoses across multiple host and parasite taxa worldwide. Here, we simultaneously quantify the role of 795 established alien hosts on the 10,473 zoonosis events across the globe since the 14thcentury. We observe an average of ~5.9 zoonoses per alien zoonotic host. After accounting for species-, disease-, and geographic-level sampling biases, spatial autocorrelation, and the lack of independence of zoonosis events, we find that the number of zoonosis events increase with the richness of alien zoonotic hosts, both across space and through time. We also detect positive associations between the number of zoonosis events per unit space and climate change, land-use change, biodiversity loss, human population density, and PubMed citations. These findings suggest that alien host introductions have likely contributed to zoonosis emergences throughout recent history and that minimizing future zoonotic host species introductions could have global health benefits.
Historically inconsistent productivity and respiration fluxes in the global terrestrial carbon cycle
Authors: Jian Jinshi , Bailey Vanessa , Dorheim Kalyn , Konings Alexandra G. , Hao Dalei , Shiklomanov Alexey N. , Snyder Abigail , Steele Meredith , Teramoto Munemasa , Vargas Rodrigo , Bond-Lamberty Ben 
Published: April 2022

AbstractThe terrestrial carbon cycle is a major source of uncertainty in climate projections. Its dominant fluxes, gross primary productivity (GPP), and respiration (in particular soil respiration, RS), are typically estimated from independent satellite-driven models and upscaled in situ measurements, respectively. We combine carbon-cycle flux estimates and partitioning coefficients to show that historical estimates of global GPP and RS are irreconcilable. When we estimate GPP based on RS measurements and some assumptions about RS:GPP ratios, we found the resulted global GPP values (bootstrap mean $${149}_{-23}^{+29}$$

149

−
23

+
29

Pg C yr−1) are significantly higher than most GPP estimates reported in the literature ($${113}_{-18}^{+18}$$

113

−
18

+
18

Pg C yr−1). Similarly, historical GPP estimates imply a soil respiration flux (RsGPP, bootstrap mean of $${68}_{-8}^{+10}$$

68

−
8

+
10

Pg C yr−1) statistically inconsistent with most published RS values ($${87}_{-8}^{+9}$$

87

−
8

+
9

Pg C yr−1), although recent, higher, GPP estimates are narrowing this gap. Furthermore, global RS:GPP ratios are inconsistent with spatial averages of this ratio calculated from individual sites as well as CMIP6 model results. This discrepancy has implications for our understanding of carbon turnover times and the terrestrial sensitivity to climate change. Future efforts should reconcile the discrepancies associated with calculations for GPP and Rs to improve estimates of the global carbon budget.
Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses
Authors: Rodríguez-Ubreva Javier , Arutyunyan Anna , Bonder Marc Jan , Del Pino-Molina Lucía , Clark Stephen J. , de la Calle-Fabregat Carlos , Garcia-Alonso Luz , Handfield Louis-François , Ciudad Laura , Andrés-León Eduardo , Krueger Felix , Català-Moll Francesc , Rodríguez-Cortez Virginia C. , Polanski Krzysztof , Mamanova Lira , van Dongen Stijn , Kiselev Vladimir Yu. , Martínez-Saavedra María T. , Heyn Holger , Martín Javier , Warnatz Klaus , López-Granados Eduardo , Rodríguez-Gallego Carlos , Stegle Oliver , Kelsey Gavin , Vento-Tormo Roser , Ballestar Esteban 
Published: April 2022

AbstractCommon variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.