bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive genetic and functional analysis of FcγRs in rituximab therapy for autoimmunity reveals a key role for FcγRIIIa on NK cells
Authors: Robinson James I , Md Yusof Md Yuzaiful , Davies Vinny , Wild Dawn , Morgan Michael , Taylor John C , El-Sherbiny Yasser , Morris David L , Liu Lu , Rawstron Andy C , Buch Maya H , Plant Darren , Cordell Heather J , Isaacs John D , Bruce Ian N , Emery Paul , Barton Anne , Vyse Timothy J , Barrett Jennifer H , Vital Edward M , Morgan Ann W ,   MASTERPLANS Consortia
Published: August 2021

AbstractB cell depletion using rituximab is widely used to treat autoimmune diseases, but patient response varies. The efficacy of rituximab is limited by the efficiency of depletion. Strategies to improve response include altering rituximab dosing, switching anti-CD20-mAb, alternative B cell targets, or non-B cell targeted therapies. Implementing an appropriate strategy requires understanding of the mechanism(s) of resistance to depletion and, if this varies between individuals, a means to test for it. Rituximab kills B cells via a variety of Fcγ receptor (FcγR)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), as well as non-FcγR mechanisms. We conducted a longitudinal cohort study in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) using two national registries. Qualitative and quantitative FCGR functional variants were measured using multiplexed ligation-dependent probe amplification, supplemented by novel FCGR2C assays.We provide consistent evidence that FCGR3A, specifically increased number of copies of the FCGR3A-158V allele, was the major FcγR gene associated with rituximab response, including clinical response in RA and SLE and depth of B cell depletion in the combined cohort. In SLE, we provide preliminary data suggesting increased FCGR2C ORF copies were also associated with improved clinical response. Furthermore, we demonstrated the impact of disease status and concomitant therapies on both natural killer cell FcγRIIIa expression and rituximab-induced ADCC; demonstrating increased FcγRIIIa expression and FCGR3A genotype were independently associated with clinical response and B cell depletion. Our findings highlight the importance of enhancing FcγR-effector functions, may help stratify patients, and support ongoing development of next-generation CD20 depleting therapeutics.One Sentence SummaryThe high affinity FcγRIIIa allotype on NK cells explains depth of B cell depletion and clinical response in rituximab therapy for autoimmune disease
Imputing cognitive impairment in SPARK, a large autism cohort
Authors: Shu Chang , Snyder LeeAnne Green , Shen Yufeng , Chung Wendy K. 
Published: August 2021

AbstractBackgroundDiverse large cohorts are necessary for dissecting subtypes of autism, and intellectual disability is one of the most robust endophenotypes for analysis. However, current cognitive assessment methods are not feasible at scale.MethodsWe developed five commonly used machine learning models to predict cognitive impairment (FSIQ<80 and FSIQ<70) and FSIQ scores among 521 children with autism using parent-reported online surveys in SPARK, and evaluated them in an independent set (n=1346) with a missing data rate up to 70%. We assessed accuracy, sensitivity and specificity by comparing predicted cognitive level against clinical IQ data.ResultsThe elastic-net model has good performance (AUC=0.876, sensitivity=0.772, specificity=0.803) using 129 predictive features to impute cognitive impairment (FSIQ<80). Top ranked predictive features included parent-reported language and cognitive levels, age at autism diagnosis, and history of services. Prediction of FSIQ<70 and FSIQ scores also showed good prediction performance.ConclusionsWe show cognitive levels can be imputed with high accuracy for children with autism, using commonly collected parent-reported data and standardized surveys. The current model offers a method for large scale autism studies seeking estimates of cognitive ability when standardized psychometric testing is not feasible.Lay summaryChildren with autism who have more severe learning challenges or cognitive impairment have different needs that are important to consider in research studies. When children in our study were missing standardized cognitive testing scores, we were able to use machine learning with other information to correctly “guess” when they have cognitive impairment about 80% of the time. We can use this information in research in the future to develop more appropriate treatments for children with autism and cognitive impairment.
Causal and Associational Language in Observational Health Research: A systematic evaluation
Authors: Haber Noah A. , Wieten Sarah E. , Rohrer Julia M. , Arah Onyebuchi A. , Tennant Peter W.G. , Stuart Elizabeth A. , Murray Eleanor J. , Pilleron Sophie , Lam Sze Tung , Riederer Emily , Howcutt Sarah Jane , Simmons Alison E. , Leyrat Clémence , Schoenegger Philipp , Booman Anna , Dufour Mi-Suk Kang , O’Donoghue Ashley L. , Baglini Rebekah , Do Stefanie , Rosa Takashima Mari De La , Evans Thomas Rhys , Rodriguez-Molina Daloha , Alsalti Taym M. , Dunleavy Daniel J. , Meyerowitz-Katz Gideon , Antonietti Alberto , Calvache Jose A. , Kelson Mark J. , Salvia Meg G. , Parra Camila Olarte , Khalatbari-Soltani Saman , McLinden Taylor , Chatton Arthur , Seiler Jessie , Steriu Andreea , Alshihayb Talal S. , Twardowski Sarah E. , Dabravolskaj Julia , Au Eric , Hoopsick Rachel A. , Suresh Shashank , Judd Nicholas , Peña Sebastián , Axfors Cathrine , Khan Palwasha , Aguirre Ariadne E. Rivera , Odo Nnaemeka U. , Schmid Ian , Fox Matthew P. 
Published: August 2021

AbstractWe estimated the degree to which language used in the high profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality.We searched and screened for 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, three reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations.Reviewers rated the causal implication of exposure/outcome linking language as None (no causal implication) in 13.8%, Weak 34.2%, Moderate 33.2%, and Strong 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was “associate” (45.7%). Reviewer’s ratings of linking word roots were highly heterogeneous; over half of reviewers rated “association” as having at least some causal implication.This research undercuts the assumption that avoiding “causal” words leads to clarity of interpretation in medical research.
Temporal Trends in Racial and Ethnic Disparities in Multimorbidity Prevalence in the United States, 1999–2018
Authors: Caraballo César , Mahajan Shiwani , Massey Daisy , Lu Yuan , Ndumele Chima D. , Drye Elizabeth E. , Herrin Jeph , Krumholz Harlan M. 
Published: August 2021

ABSTRACTBackgroundDisparities in multimorbidity prevalence indicate health inequalities. This study sought to determine if gaps in multimorbidity prevalence by race and ethnicity are decreasing over time.Methods and findingsSerial cross-sectional analysis of the National Health Interview Survey from years 1999 to 2018. The study included individuals ≥18 years old, categorized by self-reported race, ethnicity, age, and income. The main outcomes were temporal trends in multimorbidity prevalence based on the self-reported presence of ≥2 of 9 chronic conditions. The study sample included 596,355 individuals (4.7% Asian, 11.8% Black, 13.8% Latino/Hispanic, and 69.7% White). In 1999, the estimated prevalence of multimorbidity was 5.9% among Asian, 17.4% among Black, 10.7% among Latino/Hispanic, and 13.5% among White individuals. Prevalence increased for all racial/ethnic groups during the study period (P<0.005 for each), with no significant change in the differences between them. In 2018, when compared with White people, multimorbidity was more prevalent among Black individuals (+2.5 percent points [95% CI: +0.5, +4.6]) and less prevalent among Asian and Latino individuals (−6.6 points [-8.8, -4.4] and -2.1 points [-4.0, -0.2], respectively). The estimated prevalence of reporting at least 1, 2, 3, or 4 conditions all increased with age across all groups, with Black individuals having the greatest prevalence in each age category. Among those aged ≥30 years, Black people had multimorbidity rates equivalent to those of Latino/Hispanic and White people aged 5 years older, and Asian people aged 10 years older. Notably, the prevalence of multimorbidity diverged between Black people and White people among those aged 30 years, reached its maximum difference of 10.1 percentage points (95% CI: 8.2, 12.1) among those aged 60, and converged to reach similar rates among those aged ≥80.ConclusionsFrom 1999 to 2018, a period of increasing multimorbidity prevalence for all the groups studied, there has not been any significant progress in eliminating disparities between Black and White people. The disparity began among young adults. Public health interventions that prevent the onset of chronic conditions in early life may be needed to eliminate these disparities.
The indoleamine 2,3 dioxygenase pathway drives intratumoral B cell maintenance
Authors: Johnson Burles A. , Aragaki Adam K. , Williams Donna M. , Rogers Ophelia , Mountain Jack , Luo Li , Zhang Wenhao , Xian Lingling , Feng Mingxiao , Chia Lionel , Dordai Dominic , Hahn Noah M. , Desiderio Stephen , Johnson Theodore S. , McConkey David J. , Resar Linda M.S. 
Published: August 2021

AbstractB cells have been implicated as central regulators of immune responses in settings as diverse as mammalian pregnancy, mucosal tolerance, chronic infection states, autoimmunity, and the tumor microenvironment. Despite the established importance of B cells in these environments, the mechanisms by which B cells are maintained in these contexts remain undefined. Here, we report that IDO1 pathway inhibition with D-1-methyl-tryptophan (D-1MT) and linrodostat significantly decreases tumor infiltrating B (TIL-B) cells in a preclinical model of melanoma. Single cell RNA sequencing (scRNAseq) of murine melanoma demonstrate TIL-B cells are heterogeneous but primarily express markers consistent with an immune stimulatory phenotype. D-1MT decreases splenic B cells and bone marrow derived B cell precursors in tumor-bearing mice, suggesting that IDO1 pathway inhibition impedes B cell maturation. D-1MT decreases intratumoral myeloid derived suppressor cells (MDSCs), which are essential for maintenance of TIL-B cells. Unlike D-1MT, genetic deletion of tumor Ido1 does not impact TIL-B or MDSC numbers. In human solid tumors, intratumoral IDO1 expression consistently associates with high expression of a pan-B cell gene signature, and in patients with melanoma, scRNAseq analysis of tumor samples revealed most TIL-B cells express IDO1. Collectively, our data reveal the impact of pharmacologic IDO1 inhibition on B cells, which may have therapeutic implications for patients with solid tumors by informing the design of future oncology clinical trials.
M-CAMP™: A cloud-based web platform with a novel approach for species-level classification of 16S rRNA microbiome sequences
Authors: Schriefer Andrew E. , Kumar Brajendra , Zolti Avihai , Preetam R , Didier Adam , Nirmal MG , Nadiv Nofar , Perez Michael , Mahankuda Santosh Kumar , Kumar Pankaj , Greeshma G T , Tenney Aaron , Bourner Maureen , Lezer Shira , Zhong Fei , Daniely Michal , Liu Yang 
Published: August 2021

AbstractThe M-CAMP™ (Microbiome Computational Analysis for Multiomic Profiling) Cloud Platform was designed to provide users with an easy-to-use web interface to access best in class microbiome analysis tools. This interface allows bench scientists to conduct bioinformatic analysis on their samples and then download publication-ready graphics and reports. The core pipeline of the platform is the 16S-seq taxonomic classification algorithm which provides species-level classification of Illumina 16s sequencing. This algorithm uses a novel approach combining alignment and kmer based taxonomic classification methodologies to produce a highly accurate and comprehensive profile. Additionally, a comprehensive proprietary database combining reference sequences from multiple sources was curated and contains 18056 unique V3-V4 sequences covering 11527 species. The M-CAMP™ 16S taxonomic classification algorithm was validated on 52 sequencing samples from both public and in-house standard sample mixtures with known fractions. Compared to current popular public classification algorithms, our classification algorithm provides the most accurate species-level classification of 16S rRNA sequencing data.
Signaling and transcriptional networks governing late synovial joint development
Authors: Bian Qin , Cheng Yu-Hao , Su Emily Y. , Tan Yuqi , Kim Dong Won , Wang Hong , Yoo Sooyeon , Blackshaw Seth , Cahan Patrick 
Published: August 2021

AbstractBackgroundDuring synovial joint development, cavitation marks the end of the emergence of new cell types and the onset of the consolidation of cell type specific programs. However, the transcriptional programs that regulate this crucial stage prior to joint maturation are incompletely characterized. Gdf5-lineage cells give rise to the majority of joint constituents such as articular cartilage, meniscus, ligament, and tendon. Therefore, to explore pre-maturation of the synovial joint, we performed single cell RNA-Seq analysis of 1,306 Gdf5-lineage cells from the murine knee joint at E17.5.ResultsUsing computational analytics and in situ hybridization, we identified nine sub-states contributing to articular cartilage, meniscus, cruciate ligament, synovium, lining, and surrounding fibrous tissue. We identified a common progenitor population that is predicted to give rise to ligamentaocytes, articular chondrocytes, and lining cells. We further found that while a large number of signaling pathways orchestrate the differentiation of this progenitor to either ligamentocytes or to lining cells, only continued FGF signaling guides these cells to a default chondrocyte fate.ConclusionsOur single cell transcriptional atlas is a resource that can be used to better understand and further study synovial joint development and the reactivation of embryonic programs in diseases such as osteoarthritis.
Oxo-M and 4-PPBP Delivery via Multi-Domain Peptide Hydrogel Toward Tendon Regeneration
Authors: Park Ga Young , Tarafder Solaiman , Lewis Samantha , Park Soomin , Park Ryunhyung , Siddiqui Zain , Kumar Vivek , Lee Chang H. 
Published: August 2021

AbstractWe have recently identified novel small molecules, Oxo-M and 4-PPBP, which specifically stimulates endogenous tendon stem/progenitor cells (TSCs) leading to potential regenerative healing of fully-transected tendons. Here we investigated an injectable, multi-domain peptide (MDP) hydrogel providing a controlled delivery of the small molecules for regenerative tendon healing. We investigated the release kinetics of Oxo-M and 4-PPBP from MDP hydrogels and the effect of MDP-released small molecules on tenogenic differentiation of TSCs and in vivo tendon healing. In vitro, MDP showed a sustained release of Oxo-M and 4-PPBP and a slower degradation compared to fibrin. In addition, tenogenic gene expression was significantly increased in TSC with MDP-released Oxo-M and 4-PPBP as compared to the fibrin-released. In vivo, MDP releasing Oxo-M and 4-PPBP significantly improved tendon healing, likely associated with prolonged effects of Oxo-M and 4-PPBP on suppression of M1 macrophages and promotion of M2 macrophages. Comprehensive analyses including histomorphology, digital image processing, and modulus mapping with nanoindentation consistently suggested that Oxo-M and 4-PPBP delivered via MDP further improved tendon healing as compared to fibrin-based delivery. In conclusion, MDP delivered with Oxo-M and 4-PPBP may serve as an efficient regenerative therapeutic for in situ tendon regeneration and healing.
Optical mini-stroke of thalamic networks impairs sleep stability, topography and cognition
Authors: Lenzi I , Borsa M , Czekus C , Rusterholz T , Bassetti C. L. , Gutierrez Herrera C 
Published: August 2021

AbstractModelling stroke in animals remains a challenge for translational research, especially for the infraction of small subcortical arteries. Using combined fibre optics and photothrombosis technologies, we developed a novel model of optically-induced infarcts (Opto-STROKE). Combining our model with electrophysiological recordings in freely-behaving mice, we studied early and late consequent patho-physiological changes in the dynamics of sleep-wake circuits and cognitive performance. Here, focusing on inducing Opto-STROKE lesions in the intralaminar thalamus (IL), which in humans cause severe impairments of arousal, cognition, and affective symptoms, our model recapitulated important deficits on sleep disorders presented in humans including arousal instability, concurrent to an augmented slow-wave activity and a reduction gamma power bands during wakefulness. Moreover, during NREM sleep, spindle density was decreased and topographically shifted to frontal cortices when compared to control animals. Remarkably, gamma power and spindle density were correlated with decreased pain threshold and impaired prefrontal cortex-dependent working memory in Opto-STROKE mice relative to controls. Collectively, our combined method influences both anatomical and functional outcomes of the classical stroke procedures and offers new insights on the fundamental role of the media thalamus as a hub for the regulation of both sleep-wake architecture and cognition.
Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct
Authors: Li Zhenzhou , McConnell Heather L. , Stackhouse Teresa L. , Pike Martin M. , Zhang Wenri , Mishra Anusha 
Published: August 2021

AbstractNeurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ∼75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-HETE, either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of EP4 receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levelsin vivoand increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying neurovascular coupling impairment after stroke. Our results suggest that the brain’s energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.
Reorganizations of latency structure within white matter from wakefulness to sleep
Authors: Guo Bin , Zhou Fugen , Zou Guangyuan , Jiang Jun , Zou Qihong , Gao Jiahong 
Published: August 2021

AbstractPrevious studies based on resting-state fMRI (rsfMRI) data have revealed the existence of highly reproducible latency structure, reflecting the propagation of BOLD fMRI signals, in white matter (WM). Here, based on simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data collected from 35 healthy subjects who were instructed to sleep, we explored the alterations of propagations in WM across wakefulness and nonrapid eye movement (NREM) sleep stages. Lagged cross-covariance was computed among voxel-wise time series, followed by parabolic interpolation to determine the actual latency value in-between. In WM, regions including cerebellar peduncle, internal capsule, posterior thalamic radiation, genu of corpus callosum, and corona radiata, were found to change their temporal roles drastically, as revealed by applying linear mixed-effect model on voxel-wise latency projections across wakefulness and NREM sleep stages. Using these regions as seeds, further seed-based latency analysis revealed that variations of latency projections across different stages were underlain by inconsistent temporal shifts between each seed and the remaining part of WM. Finally, latency analysis on resting-state networks (RSNs), obtained by applying k-means clustering technique on group-level functional connectivity matrix, identified a path of signal propagations similar to previous findings in EEG during wakefulness, which propagated mainly from the brainstem upward to internal capsule and further to corona radiata. This path showed inter-RSN temporal reorganizations depending on the paired stages between which the brain transitioned, e.g., it changed, between internal capsule and corona radiata, from mainly unidirectional to clearly reciprocal when the brain transitioned from wakefulness to N3 stage. These findings suggested the functional role of BOLD signals in white matter as a slow process, dynamically modulated across wakefulness and NREM sleep stages, and involving in maintaining different levels of consciousness and cognitive processes.
The effects of the NMDAR co-agonist D-serine on the structure and function of the optic tectum
Authors: Chorghay Zahraa , Li Vanessa J. , Ghosh Arna , Schohl Anne , Ruthazer Edward S. 
Published: August 2021

AbstractThe N-methyl-D-aspartate type glutamate receptor (NMDAR) is a molecular coincidence detector which converts correlated patterns of neuronal activity into cues for the structural and functional refinement of developing circuits in the brain. D-serine is an endogenous co-agonist of the NMDAR. In this study, we investigated the effects of potent enhancement of NMDAR-mediated currents by chronic administration of saturating levels of D-serine on the developing Xenopus retinotectal circuit. Chronic exposure to the NMDAR co-agonist D-serine resulted in structural and functional changes to the optic tectum. D-serine administration affected synaptogenesis and dendritic morphology in recently differentiated tectal neurons, resulting in increased arbor compaction, reduced branch dynamics, and higher synapse density. These effects were not observed in more mature neurons. Calcium imaging to examine retinotopic map organization revealed that tectal neurons of animals raised in D-serine had sharper visual receptive fields. These findings suggest that the availability of endogenous NMDAR co-agonists like D-serine at glutamatergic synapses may regulate the refinement of circuits in the developing brain.Significance statementN-methyl-D-aspartate receptors (NMDAR) are implicated in activity-dependent circuit plasticity. We used administration of the NMDAR co-agonist D-serine to further examine the role of the NMDAR in circuit development in vivo. D-serine stabilised dendritic arbors specifically of recently differentiated neurons, promoted synaptogenesis, and led to sharper retinotopic receptive fields in the optic tectum. Together, these results support the idea that signaling in response to synaptic current through NMDARs promotes the maturation of developing brain circuits.