bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disparities Exist in Physical Therapy Utilization and Time to Utilization Between Black and White Patients With Musculoskeletal Pain
Authors: Richter Randy R , Chrusciel Timothy , Salsich Gretchen , Austin Tricia , Scherrer Jeffrey F 
Published: July 2022

Abstract

Objective
Black patients are less likely than White patients to receive physical therapy for musculoskeletal pain conditions. Current evidence, however, is limited to self-reported conditions and health services use. The purpose of this study was to use a large electronic health record database to determine whether a race disparity existed in use of physical therapy within 90 days of a new musculoskeletal diagnosis.

Methods
Eligible patients (n = 52,384) were sampled from an Optum deidentified electronic health record database of 5 million adults distributed throughout the United States. In this database, patients were designated as “Black” and “White.” Patients were eligible if they had a new diagnosis for musculoskeletal neck, shoulder, back, or knee pain between January 1, 2012, and December 31, 2017. Logistic regression and Cox proportional hazard models were computed before and after adjusting for covariates to estimate the association between race and receipt of physical therapy services within 90 days of musculoskeletal pain diagnoses.

Results
Patients were on average 47.5 (SD = 14.9) years of age, 12.8% were Black, 87.2% were White, and 52.7% were female. Ten percent of Black patients and 15.5% of White patients received physical therapy services within 90 days of musculoskeletal pain diagnoses. After adjusting for covariates, White patients were 57% more likely (odds ratio = 1.57; 95% CI = 1.44–1.71) to receive physical therapy compared with Black patients and had significantly shorter time to physical therapy than Black patients (hazard ratio = 1.53; 95% CI = 1.42–1.66).

Conclusions
In a nationally distributed cohort, Black patients were less likely than White patients to utilize physical therapy and had a longer time to utilization of physical therapy for musculoskeletal pain.

Impact
These findings highlight the need to determine the mechanisms underlying the observed disparities and how these disparities influence health outcomes.
Sex-dimorphic and age-dependent organization of 24 hour gene expression rhythms in human
Authors: Talamanca Lorenzo , Gobet Cédric , Naef Felix 
Published: July 2022

AbstractThe circadian clock modulates most of human physiology. However, the organization of tissue-specific gene expression rhythms is still poorly known, as well as age and sex dependencies. We leveraged the Genotype-Tissue Expression project (GTEx) using a novel algorithm to assign a unique circadian phase to 914 individuals and transfer time information from stronger to weaker clocks. These donor internal phases allowed us to identify and compare programs of rhythmic gene expression in 46 tissues. Clock transcripts showed highly conserved phase and amplitude relationships across tissues, and were tightly synchronized across the body. Tissue rhythmic gene expression programs differed in breadth, covering global and tissue-specific functions, including metabolic pathways and systemic responses such as heat shock. The circadian clock structure and amplitude was indistinguishable across sexes and age groups. However, overall gene expression rhythms were highly sex-dimorphic and more sustained in females. Moreover, rhythmic programs dampened with age across the body. Together, our stratified analysis unveiled a rich organization of sex- and age-specific circadian gene expression rhythms in humans.One sentence summaryCircadian phase inference of 914 GTEx donors reveals sex- and age-dependent rhythmic gene expression programs across 46 human tissues.
Transferability of cathodal tDCS effects from the primary motor to the dorsolateral prefrontal cortex: a multimodal TMS-EEG study
Authors: Mosayebi-Samani Mohsen , Agboada Desmond , Mutanen Tuomas P. , Haueisen Jens , Kuo Min-Fang , Nitsche Michael A. 
Published: July 2022

AbstractNeurophysiological effects of transcranial direct current stimulation (tDCS) have been extensively studied over the primary motor cortex (M1). Much less is however known about its effects over non-motor areas, such as the prefrontal cortex (PFC), which is the neuronal foundation for many high-level cognitive functions and involved in neuropsychiatric disorders. In this study, we, therefore, explored the transferability of cathodal tDCS effects over M1 to the PFC. Eighteen healthy human participants (11 males and 8 females) were involved in eight randomized sessions, in which four cathodal tDCS dosages, low, medium, and high, as well as sham stimulation, were applied over the M1 and PFC. After-effects of tDCS were evaluated via transcranial magnetic stimulation (TMS)-electroencephalography (EEG), and TMS-elicited motor evoked potentials (MEP), for the outcome parameters TMS-evoked potentials (TEP), TMS-evoked oscillations, and MEP amplitude alterations. TEPs were studied both at the regional and global scalp levels. The results indicate a regional dosage-dependent nonlinear neurophysiological effect of M1 tDCS, which is not one-to-one transferable to PFC tDCS. Low and high dosages of M1 tDCS reduced early positive TEP peaks (P30, P60), and MEP amplitudes, while an enhancement was observed for medium dosage M1 tDCS (P30 and MEP amplitudes). In contrast, prefrontal low, medium and high dosage tDCS uniformly reduced the early positive TEP peak amplitudes. Furthermore, for both cortical areas, regional tDCS-induced modulatory effects were not observed for late TEP peaks, nor TMS-evoked oscillations. However, at the global scalp level, widespread effects of tDCS were observed for both, TMS-evoked potentials and oscillations. This study provides the first direct physiological comparison of tDCS effects applied over different brain areas and therefore delivers crucial information for future tDCS applications.SIGNIFICANCE STATEMENTModulatory effects of tDCS over the M1 were largely taken as a template so far for the use of this intervention over non-motor regions. However, the neurophysiological effects of tDCS over non-motor regions, such as the prefrontal cortex (PFC), have been much less explored. In the current study, we, using concurrent transcranial magnetic stimulation- electroencephalography, systematically explored the transferability of cathodal tDCS effects on cortical excitability from M1 to the PFC. The results indicate a dosage-dependent nonlinear neurophysiological effect of motor cortex tDCS, which is not one-to-one transferable to prefrontal tDCS. This study provides the first direct physiological comparison of tDCS effects applied over different brain areas, which will further consolidate the rationale for the extension of tDCS applications at both, basic and clinical levels.
Dose-dependent disruption of hepatic zonation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice: integration of single-nuclei RNA sequencing and spatial transcriptomics
Authors: Nault R. , Saha S. , Bhattacharya S. , Sinha S. , Maiti T. , Zacharewski Tim 
Published: July 2022

ABSTRACT2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dose-dependently induces the development of hepatic fat accumulation and inflammation with fibrosis in mice initially in the portal region. Conversely, differential gene and protein expression is first detected in the central region. To further investigate cell-specific and spatially resolved dose-dependent changes in gene expression elicited by TCDD, single-nuclei RNA sequencing and spatial transcriptomics were used for livers of male mice gavaged with TCDD every 4 days for 28 days. The proportion of 11 cell (sub)types across 131,613 nuclei dose-dependently changed with 68% of all portal and central hepatocyte nuclei in control mice being overtaken by macrophages following TCDD treatment. We identified 368 (portal fibroblasts) to 1,339 (macrophages) differentially expressed genes. Spatial analyses revealed initial loss of portal identity that eventually spanned the entire liver lobule with increasing dose. Induction of R-spondin 3 (Rspo3) and pericentralApc, suggested dysregulation of the Wnt/β-catenin signaling cascade in zonally resolved steatosis. Collectively, the integrated results suggest disruption of zonation contributes to the pattern of TCDD-elicited NAFLD pathologies.SYNOPSISSingle-nuclei RNA sequencing (snRNAseq) and spatial transcriptomics were integrated to investigate cell-specific and spatially resolved dose-dependent changes elicited by TCDD. We show that TCDD causes a loss of zonal characteristics that disrupts spatially defined metabolic functions.- Dose-dependent analyses show higher responsiveness of central hepatocytes despite hepatotoxicity occurring initially in the portal region.- Integration of snRNAseq and spatial transcriptomics demonstrates a loss of hepatocytes with portal characteristics.- TCDD disrupted spatially resolved expression of β-catenin signaling members that are critical in maintaining liver zonation.- Spatial transcriptomics and snRNAseq shows induction of R-spondin3 from nonparenchymal cells which serve as cue for the β-catenin pathway.
Fancm regulates meiotic double-strand break repair pathway choice in mammals
Authors: Tsui Vanessa , Lyu Ruqian , Novakovic Stevan , Stringer Jessica M. , Dunleavy Jessica E. M. , Granger Elissah , Semple Tim , Leichter Anna , Martelotto Luciano G. , Merriner D. Jo , Liu Ruijie , McNeill Lucy , Zerafa Nadeen , Hoffmann Eva , O’Bryan Moira K. , Hutt Karla , Deans Andrew J. , Heierhorst Jörg , McCarthy Davis J. , Crismani Wayne 
Published: July 2022

AbstractMeiotic crossovers are required for accurate chromosome segregation and to produce new allelic combinations. Meiotic crossover numbers are tightly regulated within a narrow range, despite an excess of initiating DNA double-strand breaks. Here, we describe the tumour suppressor FANCM as a meiotic anti-crossover factor in mammals. Crossover analyses with single-gamete and pedigree datasets both reveal a genome-wide increase in crossover frequencies in Fancm-deficient mice. Gametogenesis is heavily perturbed in Fancm loss of function mice, which is consistent with the reproductive defects reported in humans with biallelic FANCM mutations. A portion of the gametogenesis defects can be attributed to the cGAS-STING pathway. Despite the gametogenesis phenotypes in Fancm mutants both sexes were capable of producing offspring. We propose that the anti-crossover function and role in gametogenesis of Fancm are separable and will inform diagnostic pathways for human genomic instability disorders.
Mcm2 promotes stem cell differentiation via its ability to bind H3-H4
Authors: Xu Xiaowei , Hua Xu , Brown Kyle , Ren Xiaojun , Zhang Zhiguo 
Published: July 2022

AbstractMcm2, a subunit of the Mcm2-7 helicase best known for its role in DNA replication, contains a histone binding motif that facilitates the transfer of parental histones following DNA replication. Here we show that Mcm2 is important for the differentiation of mouse embryonic stem (ES) cells. The Mcm2-2A mutation defective in histone binding impairs differentiation and disrupts the programmatic changes in gene expression and histone modifications during differentiation. Mcm2 localizes at transcription starting sites and the binding of Mcm2 at gene promoters is disrupted in both Mcm2-2A ES cells and neuro-precursor cells (NPCs). Reduced Mcm2 binding at bivalent chromatin domains containing repressive H3K27me3 and active H3K4me3 modifications in Mcm2-2A ES cells correlates with decreased chromatin accessibility at corresponding sites in NPCs. Together, our studies reveal a novel function of Mcm2 in ES cell differentiation, likely through manipulating chromatin landscapes at bivalent chromatin domains.
Complete sequence verification of plasmid DNA using the Oxford Nanopore Technologies’ MinION device
Authors: Brown Scott D. , Dreolini Lisa , Wilson Jessica F. , Balasundaram Miruna , Holt Robert A. 
Published: July 2022

AbstractBackgroundSequence verification is essential for plasmids used as critical reagents or therapeutic products. Typically, high-quality plasmid sequence is achieved through capillary-based Sanger sequencing, requiring customized sets of primers for each plasmid. This process can become expensive, particularly for applications where the validated sequence needs to be produced within a regulated and quality-controlled environment for downstream clinical research applications.ResultsHere, we describe a cost-effective and accurate plasmid sequencing and consensus generation procedure using the Oxford Nanopore Technologies’ MinION device as an alternative to capillary-based plasmid sequencing options. This procedure can verify the identity of a pure population of plasmid, either confirming it matches the known and expected sequence, or identifying mutations present in the plasmid if any exist. We use a full MinION flow cell per plasmid, maximizing available data and allowing for stringent quality filters. Pseudopairing reads for consensus base calling reduces read error rates from 5.3 % to 0.53 %, and our pileup consensus approach provides per-base counts and confidence scores, allowing for interpretation of the certainty of the resulting consensus sequences. For pure plasmid samples, we demonstrate 100 % accuracy in the resulting consensus sequence, and the sensitivity to detect small mutations such as insertions, deletions, and single nucleotide variants. In test cases where the sequenced pool of plasmids contains subclonal templates, detection sensitivity is similar to that of traditional capillary sequencing.ConclusionsOur pipeline can provide significant cost savings compared to outsourcing clinical-grade sequencing of plasmids, making generation of high-quality plasmid sequence for clinical sequence verification more accessible. While other long-read-based methods offer higher-throughput and less cost, our pipeline produces complete and accurate sequence verification for cases where absolute sequence accuracy is required.
Diverse Monogenic Subforms of Human Spermatogenic Failure
Authors: Nagirnaja Liina , Lopes Alexandra M. , Charng Wu-Lin , Miller Brian , Stakaitis Rytis , Golubickaite Ieva , Stendahl Alexandra , Luan Tianpengcheng , Friedrich Corinna , Mahyari Eisa , Fadial Eloise , Kasak Laura , Vigh-Conrad Katinka , Oud Manon S. , Xavier Miguel J. , Cheers Samuel R. , James Emma R. , Guo Jingtao , Jenkins Timothy G , Riera-Escamilla Antoni , Barros Alberto , Carvalho Filipa , Fernandes Susana , Gonçalves João , Gurnett Christina A. , Jørgensen Niels , Jezek Davor , Jungheim Emily S , Kliesch Sabine , McLachlan Robert I. , Omurtag Kenan R , Pilatz Adrian , Sandlow Jay , Smith James , Eisenberg Michael L. , Hotaling James M , Jarvi Keith A. , Punab Margus , Rajpert-De Meyts Ewa , Carrell Douglas T. , Krausz Csilla , Laan Maris , O’Bryan Moira K. , Schlegel Peter N. , Tüttelmann Frank , Veltman Joris A. , Almstrup Kristian , Aston Kenneth I. , Conrad Donald F. 
Published: July 2022

AbstractNon-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable with current medicine. Due to the biological complexity of sperm production, defining the genetic basis of NOA has proven challenging, and to date, the most advanced classification of NOA subforms is based on simple description of testis histology. In this study, we exome-sequenced over 1,000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. Population-based testing against fertile controls identified 27 genes as significantly associated with azoospermia. The disrupted genes are primarily on the autosomes, enriched for undescribed human “knockouts”, and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing of adult testes shows that, rather than affecting a single cell type or pathway, azoospermia genes can be grouped into molecular subforms with highly synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed specifically in mitotic divisions of type B spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may serve as a basis for disease classification more advanced than histology.
A Randomised -Controlled Phase 2 trial of Molnupiravir in Unvaccinated and Vaccinated Individuals with Early SARS-CoV-2
Authors: Khoo Saye H , FitzGerald Richard , Saunders Geoffrey , Middleton Calley , Ahmad Shazaad , Edwards Christopher J , Hadjiyiannakis Dennis , Walker Lauren , Lyon Rebecca , Shaw Victoria , Mozgunov Pavel , Periselneris Jimstan , Woods Christie , Bullock Katie , Hale Colin , Reynolds Helen , Downs Nichola , Ewings Sean , Buadi Amanda , Cameron David , Edwards Thomas , Knox Emma , Donovan-Banfield I’ah , Greenhalf William , Chiong Justin , Lavelle-Langham Lara , Jacobs Michael , Painter Wendy , Holman Wayne , Lalloo David G , Tetlow Michelle , Hiscox Julian A , Jaki Thomas , Fletcher Thomas , Griffiths Gareth 
Published: July 2022

SummaryBackgroundMolnupiravir was licensed for treating high-risk patients with COVID-19 based on data from unvaccinated adults. AGILE CST-2 (NCT04746183) Phase II reports safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals.MethodsAdult out-patients with PCR-confirmed SARS-CoV-2 infection within five days of symptom onset were randomly assigned 1:1 to receive molnupiravir (800mg twice daily for five days) or placebo. The primary outcome was time to swab PCR-negativity, compared using a Bayesian model for estimating the probability of a superior virological response (Hazard Ratio>1) for molnupiravir over placebo. Secondary outcomes included change in viral titre at day 5, safety and tolerability, clinical progression and patient reported outcome measures. We analysed outcomes after the last participant reached day 29.FindingsOf 180 participants randomised (90 molnupiravir, 90 placebo), 50% were vaccinated. Infections with SARS-CoV-2 variants Delta (40%), Alpha (21%), Omicron (21%) and EU1 (16%) were represented. The median time to negative-PCR was 8 versus 11 days for molnupiravir and placebo (HR=1·30, 95% CrI 0·92-1·71, p=0·07 by Logrank and p=0·03 by Breslow-Gehan tests). Although small numbers precluded subgroup analysis, no obvious differences were observed between vaccinated and unvaccinated participants. Using a two-point prior the probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was just below our defined threshold of 80% for establishing superiority. Using an uninformative continuous prior, the probability of HR>1 was 94·7%. As an exploratory analysis, the change in viral titre on day 5 (end of treatment) was significantly greater with molnupiravir compared with placebo. A total of 4 participants reported severe adverse events (grade 3+), 3 of whom were in the placebo arm.InterpretationWe found molnupiravir to be well-tolerated, with evidence for high probability of antiviral efficacy in a population of vaccinated and unvaccinated individuals infected with a broad range of viral variants.FundingFunded by Ridgeback Biotherapeutics and UK National Institute for Health and Care Research infrastructure funding. The AGILE platform infrastructure is supported by the Medical Research Council (grant number MR/V028391/1) and the Wellcome Trust (grant number 221590/Z/20/Z).
Structural basis of transcriptional activation by the OmpR/PhoB-family response regulator PmrA
Authors: Lou Yuan-Chou , Huang Hsuan-Yu , Yeh Hsin-Hong , Chiang Wei-Hung , Chen Chinpan , Wu Kuen-Phon 
Published: July 2022

ABSTRACTPmrA, an OmpR/PhoB-family response regulator, activates gene transcription responsible for polymyxin resistance in bacteria by recognizing promoters in which the canonical -35 element is replaced by the pmra-box, representing the PmrA recognition sequence. Here, we report a cryo-electron microscopy-derived structure of a bacterial PmrA-dependent transcription activation complex (TAC) containing a PmrA dimer, an RNA polymerase σ70-holoenzyme (RNAPH), and the pbgP promoter DNA. Our structure reveals that the RNAPH mainly contacts the PmrA C-terminal DNA binding domain (DBD) via electrostatic interactions and reorients the DBD three base pairs upstream of the pmra-box, resulting in a dynamic TAC conformation. In vivo assays show that substitution of PmrA DNA-recognition residues eliminated its transcriptional activity, but variants with altered RNAPH-interacting residues exhibited elevated transcriptional activity. Our study indicates that both PmrA recognition-induced DNA distortion and PmrA promoter escape play important roles in its transcriptional activation.
SP1 affects the migration and invasion of laryngeal cancer cells by regulating methylation of claudin 4 promoter region through the p-JNK pathway
Authors: Ni Jinsong , Shi Hailian , Peng Kaiyue , Liu Ya , Liu Yafang 
Published: July 2022

AbstractClaudin 4 (CLDN4) is abnormally expressed in various tumors, but the mechanisms controlling CLDN4 expression in laryngeal cancer are poorly understood. Here, we describe hypermethylation of the promoter region of the CLDN4 gene and a positive correlation between the expression of CLDN4 and transcription factor Sp1 in laryngeal carcinoma. Specifically, CLDN4 expression was downregulated when laryngeal cancer cells were treated with Sp1 transcription factor inhibitor MTM. Immunohistochemical staining showed that while the expression of CLDN4 and p-JNK was negatively correlated, p-JNK positively correlated with MMP-2 and MMP-9 expression. The expressions of p-JNK, MMP-2, and MMP-9 were significantly downregulated in HEp-2 cells transfected with CLDN4, decreasing migration and invasiveness of HEp-2 cells. Thus, we show that SP1-mediated hypermethylation of the CLDN4 promoter region may activate the JNK signaling pathway and increase MMP-2/MMP-9 expression, which can then affect the migration and invasiveness of laryngeal cancer cells. These results contribute to our understanding of the regulatory mechanisms of CLDN4 in laryngeal cancer and identify the Sp1-CLDN4-jnk signaling pathway-MMP-2/MMP-9 axis as a potential target for the treatment of laryngeal cancer.
Experimental determination and mathematical modeling of standard shapes of forming autophagosomes
Authors: Sakai Yuji , Takahashi Satoru , Koyama-Honda Ikuko , Saito Chieko , Mizushima Noboru 
Published: July 2022

AbstractThe formation of autophagosomes involves dynamic morphological changes of a phagophore from a disk-shaped membrane cisterna into a cup-shaped intermediate and a spherical autophagosome. However, the physical mechanism behind these morphological changes remains elusive. Here, we determined the average shapes of phagophores by statistically investigating three-dimensional electron micrographs of more than 100 phagophores. The results showed that the cup-shaped structures adopted a characteristic morphology; they were longitudinally elongated, and the rim was catenoidal with an outwardly recurved shape. To understand these characteristic shapes, we established a theoretical model of the shape of entire phagophores. The model quantitatively reproduced the average morphology and revealed that the characteristic shape of phagophores (i.e., an elongated shape with a catenoidal rim) was primarily determined by the relative size of the open rim to the total surface area. These results suggest that autophagosomal membranes are highly flexible and that the morphological changes during autophagosome formation follow a stable path determined by elastic bending energy minimization.SummaryThe formation of autophagosomes involves dynamic morphological changes of membrane cisternae. Sakai et al. determined the average shapes of forming autophagosomes by statistically investigating three-dimensional electron micrographs and established a theoretical model that quantitatively reproduces the phagophore shapes.