bluuebunny/crossref_metadata_2025_split huggingface dataset:
Curated Single Cell Multimodal Landmark Datasets for R/Bioconductor
Authors: Eckenrode Kelly B. , Righelli Dario , Ramos Marcel , Argelaguet Ricard , Vanderaa Christophe , Geistlinger Ludwig , Culhane Aedin C. , Gatto Laurent , Carey Vincent , Morgan Martin , Risso Davide , Waldron Levi 
Published: October 2021

AbstractBackgroundThe majority of high-throughput single-cell molecular profiling methods quantify RNA expression; however, recent multimodal profiling methods add simultaneous measurement of genomic, proteomic, epigenetic, and/or spatial information on the same cells. The development of new statistical and computational methods in Bioconductor for such data will be facilitated by easy availability of landmark datasets using standard data classes.ResultsWe collected, processed, and packaged publicly available landmark datasets from important single-cell multimodal protocols, including CITE-Seq, ECCITE-Seq, SCoPE2, scNMT, 10X Multiome, seqFISH, and G&T. We integrate data modalities via theMultiAssayExperimentBioconductor class, document and re-distribute datasets as theSingleCellMultiModalpackage in Bioconductor’s Cloud-basedExperimentHub. The result is single-command actualization of landmark datasets from seven single-cell multimodal data generation technologies, without need for further data processing or wrangling in order to analyze and develop methods within Bioconductor’s ecosystem of hundreds of packages for single-cell and multimodal data.ConclusionsWe provide two examples of integrative analyses that are greatly simplified bySingleCellMultiModal. The package will facilitate development of bioinformatic and statistical methods in Bioconductor to meet the challenges of integrating molecular layers and analyzing phenotypic outputs including cell differentiation, activity, and disease.Author SummaryExperimental data packages that provide landmark datasets have historically played an important role in the development of new statistical methods in Bioconductor by lowering the barrier of access to relevant data, providing a common testing ground for software development and benchmarking, and encouraging interoperability around common data structures. In this manuscript, we review major classes of technologies for collecting multimodal data including genomics, transcriptomics, epigenetics, proteomics, and spatial information at the level of single cells. We present the SingleCellMultiModal R/Bioconductor package that provides single-command access to landmark datasets from seven different technologies, storing datasets using HDF5 and sparse arrays for memory efficiency and integrating data modalities via the MultiAssayExperiment class. We demonstrate two integrative analyses that are greatly simplified by SingleCellMultiModal. The package facilitates development and benchmarking of bioinformatic and statistical methods to integrate molecular layers at the level of single cells with phenotypic outputs including cell differentiation, activity, and disease, within Bioconductor’s ecosystem of hundreds of packages for single-cell and multimodal data.
Qualitative and quantitative top-down proteomics of human colorectal cancer cell lines identified 23000 proteoforms and revealed drastic proteoform-level differences between metastatic and non-metastatic cancer cells
Authors: McCool Elijah N. , Xu Tian , Chen Wenrong , Beller Nicole C. , Nolan Scott M. , Hummon Amanda B. , Liu Xiaowen , Sun Liangliang 
Published: October 2021

AbstractUnderstanding cancer metastasis at the proteoform level is crucial for discovering new protein biomarkers for cancer diagnosis and drug development. Proteins are the primary effectors of function in biology and proteoforms from the same gene can have drastically different biological functions. Here, we present the first qualitative and quantitative top-down proteomics (TDP) study of a pair of isogenic human metastatic and non-metastatic colorectal cancer (CRC) cell lines (SW480 and SW620). This study pursues a global view of human CRC proteome before and after metastasis in a proteoform specific manner. We identified 23,319 proteoforms of 2,297 genes from the CRC cell lines using capillary zone electrophoresis-tandem mass spectrometry (CZE-MS/MS), representing nearly one order of magnitude improvement in the number of proteoform identifications from human cell lines compared to literature data. We identified 111 proteoforms containing single amino acid variants (SAAVs) using a proteogenomic approach and revealed drastic differences between the metastatic and non-metastatic cell lines regarding SAAVs profiles. Quantitative TDP analysis unveiled statistically significant differences in proteoform abundance between the SW480 and SW620 cell lines on a proteome scale for the first time. Ingenuity Pathway Analysis (IPA) disclosed that many differentially expressed genes at the proteoform level had diversified functions and were closely related to cancer. Our study represents a milestone in TDP towards the definition of human proteome in a proteoform specific manner, which will transform basic and translational biomedical research.For TOC only
Translating outcomes from the clinical setting to preclinical models: chronic pain and functionality in chronic musculoskeletal pain
Authors: Lenert Melissa E. , Gomez Rachelle , Lane Brandon T. , Dailey Dana L. , Vance Carol G.T. , Rakel Barbara A. , Crofford Leslie J. , Sluka Kathleen A. , Merriwether Ericka N. , Burton Michael D. 
Published: October 2021

AbstractFibromyalgia (FM) is a chronic pain disorder characterized by chronic widespread musculoskeletal pain (CWP), tenderness, and fatigue, which interferes with daily functioning and quality of life. In clinical studies, this symptomology is assessed, while preclinical models of CWP are limited to nociceptive assays. The aim of the study was to investigate the human-to-model translatability of clinical behavioral assessments for pain and muscle function in a preclinical model of CWP. We assessed correlations between pain behaviors and muscle function in a preclinical model of CWP and in women with fibromyalgia to examine whether similar relationships between outcomes existed in both settings, for usability of clinical assays in model systems. For preclinical measures, the acidic saline model of FM which induces widespread muscle pain, was used in adult female mice. Two gastrocnemius injections of acidic or physiological pH saline were given following baseline measures, five days apart. An array of adapted pain measures and functional assays were assessed for three weeks. For clinical measures, pain and functional assays were assessed in adult women with FM. For both preclinical and clinical outcomes, movement-evoked pain (MEP) was associated with mechanical pain sensitivity. Mechanical sensitivity was correlated to shifts in weight-bearing preclinically and was predictive of functionality in patients. Preclinically, it is imperative to expand how the field assesses pain behaviors when studying multi- symptom disorders like FM. Targeted pain assessments to match those performed clinically is an important aspect of improving preclinical to clinical translatability of animal models.SummaryPreclinical assessments of chronic musculoskeletal pain recapitulate several outcome measures for clinical assessment of patients with FM, particularly prolonged resting pain, and MEP.
Multi-‘omics of host-microbiome interactions in short- and long-term Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Authors: Xiong Ruoyun , Gunter Courtney , Fleming Elizabeth , Vernon Suzanne D. , Bateman Lucinda , Unutmaz Derya , Oh Julia 
Published: October 2021

AbstractMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system, debilitating disability manifesting as severe fatigue and post-exertional malaise. The chronic dysfunctions in ME/CFS are increasingly recognized as significant health factors with potential parallels with ‘long COVID’. However, the etiology of ME/CFS remains elusive with limited high-resolution human studies. In addition, reliable biomarker-based diagnostics have not been well-established, but may assist in disease classification, particularly during different temporal phases of the disease. Here, we performed deep multi-‘omics (shotgun metagenomics of gut microbiota and plasma metabolomics) and clinical phenotyping of healthy controls (n=79) vs. two cohorts of ME/CFS patients – those with short-term disease (<4 years, n=75), and patients with long-term disease (>10y, n=79). Overall, ME/CFS was characterized by reduced gut microbiome diversity and richness with high heterogeneity, and depletion of sphingomyelins and short-chain fatty acids in the plasma. We found significant differences when stratifying by cohort; short-term ME/CFS was associated with more microbial dysbiosis, but long-term ME/CFS was associated with markedly more severe phenotypic and metabolic abnormalities. We identified a reduction in the gene-coding capacity (and relative abundance of butyrate producers) of microbial butyrate biosynthesis together with a reduction in the plasma concentration of butyrate, especially in the short-term group. Global co-association and detailed gene pathway correlation analyses linking the microbiome and metabolome identified additional potential biological mechanisms underlying host-microbiome interactions in ME/CFS, including bile acids and benzoate pathways. Finally, we built multiple state-of-the-art classifiers to identify microbes, microbial gene pathways, metabolites, and clinical features that individually or together, were most able to differentiate short or long-term MECFS, or MECFS vs. healthy controls. Taken together, our study presents the highest resolution, multi-cohort and multi-‘omics analysis to date, providing an important resource to facilitate mechanistic hypotheses of host-microbiome interactions in ME/CFS.
FEMA: Fast and efficient mixed-effects algorithm for large sample whole-brain imaging data
Authors: Parekh Pravesh , Fan Chun Chieh , Frei Oleksandr , Palmer Clare E. , Smith Diana M. , Makowski Carolina , Iversen John R. , Pecheva Diliana , Holland Dominic , Loughnan Robert , Nedelec Pierre , Thompson Wesley K. , Hagler Donald J. , Andreassen Ole A. , Jernigan Terry L. , Nichols Thomas E. , Dale Anders M. 
Published: October 2021

AbstractThe linear mixed-effects model (LME) is a versatile approach to account for dependence among observations. Many large-scale neuroimaging datasets with complex designs have increased the need for LME, however LME has seldom been used in whole-brain imaging analyses due to its heavy computational requirements. In this paper, we introduce a fast and efficient mixed-effects algorithm (FEMA) that makes whole-brain vertex-wise, voxel-wise, and connectome-wide LME analyses in large samples possible. We validate FEMA with extensive simulations, showing that the estimates of the fixed effects are equivalent to standard maximum likelihood estimates but obtained with orders of magnitude improvement in computational speed. We demonstrate the applicability of FEMA by studying the cross-sectional and longitudinal effects of age on region-of-interest level and vertex-wise cortical thickness, as well as connectome-wide functional connectivity values derived from resting state functional MRI, using longitudinal imaging data from the Adolescent Brain Cognitive DevelopmentSMStudy release 4.0. Our analyses reveal distinct spatial patterns for the annualized changes in vertex-wise cortical thickness and connectome-wide connectivity values in early adolescence, highlighting a critical time of brain maturation. The simulations and application to real data show that FEMA enables advanced investigation of the relationships between large numbers of neuroimaging metrics and variables of interest while considering complex study designs, including repeated measures and family structures, in a fast and efficient manner. The source code for FEMA is available via:https://github.com/cmig-research-group/cmig_tools/.
Loss-of-Function FLNC Variants are Associated with Arrhythmogenic Cardiomyopathy Phenotypes when Identified through Exome Sequencing of a General Clinical Population
Authors: Carruth Eric D. , Qureshi Maria , Alsaid Amro , Kelly Melissa A. , Calkins Hugh , Murray Brittney , Tichnell Crystal , Sturm Amy C. ,   Regeneron Genetics Center, Baras Aris , Kirchner H. Lester , Fornwalt Brandon K. , James Cynthia A. , Haggerty Christopher M. 
Published: October 2021

ABSTRACTBackgroundThe FLNC gene has recently garnered attention as a likely cause of arrhythmogenic cardiomyopathy (ACM), which is considered an actionable genetic condition. However, the association with disease in an unselected clinical population is unknown. We hypothesized that individuals with loss-of-function variants in FLNC (FLNCLOF) would have increased odds for ACM-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort.MethodsWe identified rare, putative FLNCLOF among 171,948 individuals with exome sequencing linked to health records. Associations with ACM phenotypes from available diagnoses and cardiac evaluations were investigated.ResultsSixty individuals (0.03%; median age 58 years [47–70 IQR], 43% male) harbored 27 unique FLNCLOF. These individuals had significantly increased odds ratios (OR) for dilated cardiomyopathy (OR:4.9, [95% confidence interval: 2.6–7.6]; p<0.001), supraventricular tachycardia (OR:3.2, [1.1–5.6]; p=0.01), defibrillator implantation (OR:4.6, [1.9–8.4]; p<0.001), and left-dominant ACM (OR:4.2, [1.4–7.9]; p=0.003). Echocardiography revealed reduced left ventricular ejection fraction (52±13% vs. 57±9%; p=0.001) associated with FLNCLOF. Overall, at least 9% of FLNCLOF carriers demonstrated evidence of penetrant disease.ConclusionsFLNCLOF variants are associated with increased odds of ventricular arrhythmia and dysfunction in an unselected clinical population. These findings support genomic screening of FLNC for actionable secondary findings.
Prostate-specific membrane antigen is a biomarker for residual disease following neoadjuvant intense androgen deprivation therapy in prostate cancer
Authors: Bright John R. , Lis Rosina T. , Ku Anson T. , Terrigino Nicholas T. , Trostel Shana Y. , Carrabba Nicole V. , Harmon Stephanie A. , Turkbey Baris , Wilkinson Scott , Sowalsky Adam G. 
Published: October 2021

ABSTRACTNeoadjuvant intense androgen deprivation therapy can exert a wide range of histologic responses, which in turn are reflected in the final prostatectomy specimen. Accurate identification and measurement of residual tumor volumes are critical for tracking and stratifying patient outcomes. The goal of this current study was to evaluate the ability of antibodies against prostate-specific membrane antigen (PSMA) to detect residual tumor in a cohort of 35 patients treated with androgen deprivation therapy plus enzalutamide for six months prior to radical prostatectomy. Residual carcinoma was detected in 31 patients, and PSMA reacted positively with tumor in all cases. PSMA staining was 95.5% sensitive for tumor, with approximately 81.6% of benign regions showing no reactivity. By contrast, PSMA positively reacted with 72.2% of benign regions in a control cohort of 37 untreated cases, resulting in 27.8% specificity for tumor. PSMA further identified highly dedifferentiated prostate carcinomas including tumors with evidence of neuroendocrine differentiation. We propose that anti-PSMA immunostaining be a standardized marker for identifying residual cancer in the setting of neoadjuvant intense androgen deprivation therapy.
Altered Neurotransmitter Ratio in the Prefrontal Cortex is Associated with Pain in Fibromyalgia Syndrome
Authors: Bishop James H. , Faerman Afik , Geoly Andrew , Khan Naushaba , Tischler Claudia , Amin Heer , Maron-Katz Adi , Azeez Azeezat , Yeomans David C. , Hurd Ralph , Gu Meng , Baltusis Laima , Spielman Daniel , Sacchet Matthew D. , Spiegel David , Williams Nolan 
Published: October 2021

ABSTRACTThe central mechanisms underlying fibromyalgia syndrome (FMS) remain undetermined. The dorsolateral prefrontal cortex (DLPFC) is particularly relevant to FMS because it is implicated in cognitive, affective, and top-down pain regulation. Imbalances in excitatory (Glutamate) and inhibitory (Gamma aminobutyric acid; GABA) neurochemicals may play a critical role in the pathophysiology of the condition and more generally in homeostatic function within cortical circuits. Although the balance of excitation and inhibition are intrinsically linked no investigations to date have investigated the E/I ratio in FMS. Thus, the primary objective of this study was to determine whether the E/I ratio in the DLPFC is altered in participants with FMS compared to healthy controls using magnetic resonance spectroscopy. Additionally, we examined the relationship between E/I ratio and pain metrics. We hypothesized that the E/I ratio within the DLPFC would be altered in participants with FMS compared to controls and, secondly, that E/I ratio would be associated with both clinical pain and thermal pain sensitivity. The Brief Pain Inventory (BPI) self-assessment was used to evaluate pain severity and impact on physical functioning and acute pain sensitivity was determined via quantitative sensory testing to define thermal (heat) pain threshold and tolerance. Our results revealed an elevation in the E/I ratio in FMS compared to controls. A positive relationship between E/I ratio and thermal pain sensitivity measures was identified in the FMS cohort. Collapsing across groups, there was a positive relationship between E/I ratio and BPI score. These findings suggest that dysfunction in the balance between excitation and inhibition within cognitive brain circuitry may play a role in pain processing in FMS.
Disordered yet functional atrial t-tubules on recovery from heart failure
Authors: Caldwell Jessica L. , Clarke Jessica D. , Smith Charlotte E.R. , Pinali Christian , Quinn Callum J. , Pearman Charles M. , Adomaviciene Aiste , Radcliffe Emma J. , Watkins Amy E. , Horn Margaux A , Bode Elizabeth F. , Eisner Mark , Eisner David A. , Trafford Andrew W. , Dibb Katharine M. 
Published: October 2021

AbstractTransverse (t)-tubules drive the rapid and synchronous Ca2+ rise in cardiac myocytes. The virtual complete loss of atrial t-tubules in heart failure (HF) decreases Ca2+ release. It is unknown if or how atrial t-tubules can be restored and if restored t-tubules are functional.Sheep were tachypaced to induce HF and recovered when pacing was stopped. Serial block face Scanning Electron Microscopy and confocal imaging were used to understand t-tubule ultrastructure and function. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and causality determined using expression studies.Sheep atrial t-tubules reappeared following recovery from HF. Despite being disordered (branched, longer and longitudinally arranged) recovered t-tubules triggered Ca2+ release and were associated with restoration of systolic Ca2+. Telethonin and myotubularin abundance correlated with t-tubule density and altered the density and structure of BIN1-driven tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria.Recovery from HF restores atrial t-tubules and systolic Ca2+ and myotubularin facilitates this process. Atrial t-tubule restoration could present a new and viable therapeutic strategy.Brief SummaryThe loss of atrial transverse (t)-tubules and the associated dysfunction in heart failure is reversible and the protein myotubularin plays an important role.
Diverse B-cell specific transcriptional contexts of the BCL2 oncogene in mouse models impacts pre-malignant development
Authors: Zawil Lina , Marchiol Tiffany , Brauge Baptiste , Saint-Amand Alexis , Carrion Claire , Dessauge Elise , Oblet Christelle , Le Noir Sandrine , Mourcin Frédéric , Jouan Florence , Brousse Mylène , Derouault Paco , Alizadeh Mehdi , Makhour Yolla El , Monvoisin Céline , Léonard Simon , Durand-Panteix Stéphanie , Tarte Karin , Cogné Michel 
Published: October 2021

AbstractFollicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells. The genetic hallmark that leads to the development of FL is the t(14:18) which occurs early in the bone marrow during B cell development, thereby placing the anti-apoptoticBCL2gene under the direct control of the transcriptional enhancers in 3’ of immunoglobulin heavy chain locus (IgH 3’RR) and leading to the constitutive expression of the BCL2 protein. To assess the impact of the BCL2 deregulation on B-cell fate and try to reproduce FL development in mice, two models were designed: the Igκ-BCL2 (Knock in of the BCL2 in the light chain Ig kappa locus) and the 3’RR-BCL2 (Transgene containing BCL2 and a micro-3’RR), both containing the full BCL2 promoter region.
The return of the rings: evolutionary role of aromatic residues in liquid-liquid phase separation
Authors: Ho Wen-Lin , Huang Jie-rong 
Published: October 2021

AbstractAromatic residues appeared relatively late in the evolution of protein sequences. They stabilize the hydrophobic core of globular proteins and are typically absent from intrinsically disordered regions (IDRs). However, recent advances in protein liquid-liquid phase separation (LLPS) studies have shown that aromatic residues in IDRs often act as important “stickers”, promoting multivalent interactions and the formation of higher-order oligomers. To reconcile this apparent contradiction, we compared levels of sequence disorder in RNA binding proteins and the human proteome and found that aromatic residues appear more frequently than expected in the IDRs of RNA binding proteins, which are often found to undergo LLPS. Phylogenetic analysis shows that aromatic residues are highly conserved among chordates, highlighting their importance in LLPS-driven functional assembly. These results suggest therefore that aromatic residues have contributed twice to evolution: in stabilizing structured proteins and in the assembly of biomolecular condensates.