bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity
Authors: Cheers Samuel R. , O’Connor Anne E. , Johnson Travis K. , Merriner D. Jo , O’Bryan Moira K. , Dunleavy Jessica E. M. 
Published: August 2022

AbstractThe development and function of male gametes is critically dependent on a dynamic microtubule network, yet how this is regulated remains poorly understood. We have recently shown that microtubule severing, via the action of the meiotic AAA ATPase protein clade, plays a critical role in this process. Here, we sought to elucidate the roles of spastin, an as yet unexplored member of this clade in spermatogenesis. Using a SpastKO/KO mouse model, we reveal that spastin loss resulted in a complete loss of functional germ cells. Spastin plays a critical role in the assembly and function of the male meiotic spindle, and in its absence, apoptosis is significantly increased. Consistent with meiotic failure, round spermatid nuclei were enlarged, indicating aneuploidy, but were still able to enter spermiogenesis. During spermiogenesis, we observed extreme abnormalities in manchette structure, supernumerary acrosome formation, and commonly, a loss of nuclear integrity. This work defines a novel and essential role for spastin in regulating microtubule dynamics during spermatogenesis and is of potential relevance to patients carrying Spastin variants and to the medically assisted reproductive technology industry.Summary statementWe identify an essential role for the microtubule severing enzyme spastin in the regulation of microtubule dynamics during spermatogenesis.
Indoleamine 2, 3-dioxygenase 1 mediated alterations in the functionality of immune cells, decipher the pregnancy outcomes in crossbred dairy cows
Authors: Mohapatra Sunil Kumar , Chaudhary Dheeraj , Panda Bibhudatta S. K. , Somagond Yallappa M. , Kamboj Aarti , Kapila Rajeev , Dang Ajay Kumar 
Published: August 2022

ABSTRACTPregnancy establishment in bovines requires maternal immune cell modulation. Present study investigated possible role of immunosuppressive indolamine-2, 3-dioxygenase 1 (IDO1) enzyme in the alteration of neutrophil (NEUT) and peripheral blood mononuclear cells (PBMCs) functionality of crossbred cows. Blood was collected from non-pregnant (NP) and pregnant (P) cows, followed by isolation of NEUT and PBMCs. Plasma pro-inflammatory (IFNγ and TNFα) and anti-inflammatory cytokines (IL-4 and IL-10) were estimated by ELISA and analysis of IDO1 gene in NEUT and PBMCs by RT-qPCR. Neutrophil functionality was assessed by chemotaxis, measuring activity of myeloperoxidase and β-D glucuronidase enzyme and evaluating nitric oxide production. Changes in PBMCs functionality was determined by transcriptional expression of pro-inflammatory (IFNγ, TNFα) and anti-inflammatory cytokine (IL-4, IL-10, TGFβ1) genes. Significantly elevated (P < 0.05) anti-inflammatory cytokines, increased IDO1 expression, reduced NEUT velocity, MPO activity and NO production observed only in P cows. Significantly higher (P < 0.05) expression of anti-inflammatory cytokines and TNFα genes were observed in PBMCs. Study highlights possible role of IDO1 in modulating the immune cell and cytokine activity during early pregnancy and may be targeted as early pregnancy biomarkers.
Mercury exposure and health risks associated with use of skin-lightening products: A systematic review
Authors: Bastiansz Ashley , Ewald Jessica , Saldaña Verónica Rodríguez , Santa-Rios Andrea , Basu Niladri 
Published: August 2022

AbstractBackgroundThe Minamata Convention on Mercury (Article 4) prohibits the manufacture, import or export of skin-lightening products containing mercury concentrations above 1 μg/g. However, there is a lack of knowledge surrounding the global prevalence of mercury-added skin-lightening products.ObjectiveThe objective of this study was to increase our understanding of worldwide human mercury exposure and associated health risks from the use of skin-lightening products.MethodsA systematic search of peer-reviewed scientific literature was performed in four databases (PubMed, Web of Science Core Collection, Scopus, and Toxline). The initial search in July of 2018 identified 1,711 unique scientific articles, of which 34 were ultimately deemed eligible for inclusion after iterative screens at the title, abstract, and whole text levels. A second search was performed in November of 2020 using the same methods, of which another 7 scientific articles were included. All papers were organized according to four data groups 1) “Mercury in products”, 2) “Usage of products”, 3) “Human biomarkers of exposure”; and 4) “Health impacts”, prior to data extraction and synthesis.ResultsThis review was based on data contained within 41 peer-reviewed scientific papers from 22 countries worldwide published between 2000 and 2020. In total, we captured mercury concentration values from 787 skin-lightening product samples (overall pooled central median mercury level was 0.49 μg/g, IQR: 0.02 – 5.9) and 1,042 human biomarker measurements from 863 individuals. We also synthesized usage information from 3,898 individuals, and self-reported health impacts associated with using mercury-added products from 832 individuals.DiscussionThis review suggests that mercury widely exists as an active ingredient in many skin-lightening products worldwide, and that users are at risk of variable, and often high exposures. These synthesized findings help increase our understanding of the health risks associated with the use of these products.
Physician Responses to Apple Watch-Detected Irregular Rhythm Alerts: A Case-Based Survey
Authors: Demkowicz Patrick C. , Dhruva Sanket S. , Spatz Erica S. , Beatty Alexis L. , Ross Joseph S. , Khera Rohan 
Published: August 2022

ABSTRACTBackgroundWhile the US Food and Drug Administration (FDA) has cleared smart watch software for detecting atrial fibrillation (AF), there is lack of guidance on management by physicians.MethodsWe conducted a case-based survey of physicians in primary care, emergency medicine, and cardiology at Yale and University of California San Francisco from September to December 2021. Cases described asymptomatic patients receiving Apple Watch AF alerts; cases varied in sex, race, medical (diabetes and hypertension) history, and notification frequency. Physicians were asked to select from among prespecified diagnostic testing, referral, and treatment options.ResultsWe emailed 636 physicians, of whom 95 (14.9%) filled out the survey, including 39 primary care, 25 emergency medicine, and 31 cardiology physicians. Among a total of 192 cases (16 unique scenarios), physicians selected at least one diagnostic test in 191 (99.5%) cases and medications in 48 (25.0%). Rates of patient referral (14%, 30%, and 16%, respectively; P=.048), rhythm monitoring (84%, 46%, and 94%, respectively; P<.001), measurement of BNP (8%, 20%, and 2%; P=.003), and use of antiarrhythmics (16%, 4%, and 23%; P=.023) varied among primary care, emergency medicine, and cardiology, respectively. Management was largely consistent across case characteristics (race, sex, medical history, and alert frequency).ConclusionIn hypothetical cases of patients presenting without clinical symptoms, physicians opted for further diagnostic testing and often to medical intervention based on Apple Watch irregular rhythm notifications. There was also considerable variation across physician specialties, suggesting a need for uniform clinical practice guidelines.
Plasma cell-free DNA methylome profiling in pre- and post-surgery oral cavity squamous cell carcinoma
Authors: Patel Krupal B , Padhya Tapan A , Huang Jinyong , Wang Liang , Wang Xuefeng 
Published: August 2022

ABSTRACTPurposeHead and neck squamous cell carcinoma cancer (HNSCC), a highly heterogeneous disease that involves multiple anatomic sites, is a leading cause of cancer-related mortality worldwide. Although the utility of noninvasive biomarkers based on circulating cell-free DNA (cfDNA) methylation profiling has been widely recognized, limited studies have been reported so far regarding the dynamics of cfDNA methylome in oral cavity squamous cell carcinoma (OCSCC). It is hypothesized in this study that comparison of methylation profiles in pre- and post-surgery plasma samples will reveal OCSCC-specific prognostic and diagnostic biomarkers.Materials and methodsMatched plasma samples from eight patients with OCSCC were collected at Moffitt Cancer Center before and after surgical resection. Plasma-derived cfDNA was analyzed by cfMBD-seq, which is a high-sensitive methylation profiling assay. Differential methylation analysis was then performed based on the matched samples profiled. As a strategy to further prioritize tumor-specific targets, top differential methylated regions (DMRs) were called by reanalyzing methylation data from paired tumor and normal tissue collected in the TCGA head and neck cancer cohort.ResultsIn the top 200 HNSCC-specific DMRs detected based on the TCGA dataset, a total of 23 regions reached significance in the plasma-based DMR test. The top five validated DMR regions (ranked by the significance in the plasma study) are located in the promoter regions of genes PENK, NXPH1, ZIK1, TBXT and CDO1, respectively. The genome-wide cfDNA DMR analysis further highlighted candidate biomarkers located in genes SFRP4, SOX1, IRF4 and PCDH17. The prognostic relevance of candidate genes was confirmed by survival analysis using the TCGA data.ConclusionThis study supports the utility of cfDNA-based methylome profiling as a promising noninvasive biomarker source for OCSCC and HNSCC.
MULTI-OMICS TEMPORAL PROFILING OF AXIAL SPONDYLOARTHRITIS PATIENTS REVEALS AN ASSOCIATION OF THERAPEUTIC RESPONSE TO ADALIMUMAB WITH DISEASE ACTIVITY AND INNATE / ADAPTIVE IMMUNITY
Authors: Sobral Daniel , Fernandes Ana F , Sardoo Atlas , Bernardes Miguel , Pinto Patrícia , Santos Helena , Lagoas-Gomes João , Tavares-Costa José , AP Silva José , Dias João M , Bernardo Alexandra , Gaillard Jean-Charles , Armengaud Jean , Benes Vladimir , Domingues Lúcia , Gouveia Nélia , Maia Sara , Branco Jaime C , Coelho Ana V , Pimentel-Santos Fernando M 
Published: August 2022

ABSTRACTBackgroundAxial Spondyloarthritis can lead to significant disability and impairment in quality of life. TNF inhibitors are recommended to patients enduring active disease despite conventional treatment. Nonetheless, up to 40% of patients of patients fail to respond to TNF inhibitors. In this context, it is important to identify as early as possible patients highly likely to respond. This study aims at identifying, among axial spondyloarthritis patients undergoing treatment with the TNF inhibitor adalimumab, early molecular biomarkers differentiating good responders from non-responders after 14 weeks of treatment, as measured by ASAS20.MethodsPeripheral blood RNA sequencing and serum proteins measured by mass spectrometry were evaluated in a cohort of biologic naïve axial spondyloarthritis patients (n = 35), before (baseline) and after (3-5 days, 2 weeks and 14 weeks) treatment with adalimumab. Results from differential expression analysis were used in combination with clinical data to build logistic regression models and random forest models to predict response to adalimumab at baseline.ResultsResponders to adalimumab presented higher levels of markers of innate immunity at baseline, mostly related with neutrophils, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP and AFF3, the top differentially expressed gene between responders and non-responders at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC=0.96), with random forest models suggesting 80% predictive accuracy. A treatment-associated signature suggests a reduction in inflammatory activity, with C-reactive protein and Haptoglobin showing strong and early decrease in the serum of axial spondyloarthritis patients, while a cluster of apolipoproteins showed increased expression at week 14.ConclusionsDifferences in disease activity and/or blood innate/adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axial spondyloarthritis, where a model including clinical and blood gene expression variables shows high predictive power. Our results suggest novel molecular biomarkers of response to adalimumab at baseline.Trial registrationAxial spondyloarthritis patients were selected from participants of the Bioefficacy study - Biomarkers Identification of Anti-TNFα Agent’s Efficacy in Ankylosing Spondylitis Patients Using a Transcriptome Analysis and Mass Spectrometry (clinical trials.gov identifier NCT02492217).
Published registered reports are rare, limited to one journal group and inadequate for randomized controlled trials in the clinical field
Authors: Anthony Norah , Tisseaux Antoine , Naudet Florian 
Published: August 2022

AbstractObjectiveRegistered reports relate to a new publication of a peer-review of the protocol before the start of the study, followed by an in-principle acceptance by the journal before the study starts. We aimed to describe randomized controlled trials (RCTs) in the clinical field published as registered reports.Study design and settingThis cross-sectional study (registration:https://osf.io/zf53p/) included registered report results for RCTs, identified on PubMed/Medline and on a list compiled by the Center for Open Science. It explored the proportion of reports that received in-principle acceptance (and/or published a protocol before inclusion of the first patient) and changes in the primary outcome.ResultsA total of 93 RCT publications identified as registered reports were included. All but one were published in the same journal group. The date of the in-principle acceptance was never documented. For most of these reports (79/93, 84.9 %) a protocol was published after the date of inclusion of the first patient. A change in the primary outcome was noted in 40/93 (44%) of these publications. Three out of the 40 (33%) mentioned this change.ConclusionsRandomized controlled trials in the clinical field identified as registered reports were rare, they originated from a single journal group and did not comply with the basic features of this format.Protocol registrationhttps://osf.io/zf53p/What is new ?The registered report format for clinical randomized controlled (RCTs) trials is still marginal and few journals make use of it.The clinical RCTs identified as registered reports were from a single journal group and did not necessarily comply with the basic features of this format, and common biases may thus persist.To improve research trustworthiness, more efforts need to be made by Journal publishers, trial funders, etc. for the implementation of this format for clinical RCTs.
identifying cancer patients from GC-patterned fragment ends of cell-free DNA
Authors: Curtis Samuel D. , Summers Mahmoud , Cohen Joshua D. , Wang Yuxuan , Nehme Nadine , Popoli Maria , Ptak Janine , Sillman Natalie , Dobbyn Lisa , Buchanan Adam , Tie Jeanne , Gibbs Peter , Ho-Pham Lan T. , Tran Bich N. H. , Zhou Shibin , Bettegowda Chetan , Lennon Anne Marie , Hruban Ralph H. , Kinzler Kenneth W. , Papadopoulos Nickolas , Vogelstein Bert , Douville Christopher 
Published: August 2022

ABSTRACTOne of the most intriguing characteristics of cell-free DNA (cfDNA) from plasma is the sequence at the ends of the fragments. Previous studies have shown that these end-sequences are somewhat different in cancer patients than in healthy individuals. While investigating this characteristic, we noticed that the bases at the 5’-ends of a double-stranded fragment were highly correlated with the GC content of that particular fragment. This led us to develop a method, called MendSeqS (Modified End-based sequencing System), that incorporates the correlation between end-motifs and GC content into the analysis of shallow (0.5x) whole genome sequencing (WGS). When applied to plasma samples, MendSeqS was able to classify patients with a sensitivity of 96% at 98% specificity in a cohort comprised of 107 individuals evaluated in our laboratory (43 with cancer and 64 without). In cohorts evaluated in three other laboratories, comprising a total of 401 individuals (193 with cancer and 208 without), MendSeqS achieved a sensitivity of 87% at 98% specificity. MendSeqS could in principle be combined with other methods of cfDNA analysis to enhance cancer detection.
Functional Correlates of Cognitive Performance and Working Memory in Temporal Lobe Epilepsy: Insights from Task-based and Resting-state fMRI
Authors: Fajardo-Valdez Alfonso , Camacho-Téllez Vicente , Rodríguez-Cruces Raúl , García-Gomar María Luisa , Pasaye-Alcaraz Erick H. , Concha Luis 
Published: August 2022

AbstractTemporal lobe epilepsy (TLE) is a common form of medically intractable partial epilepsy. Although seizures originate in mesial temporal structures, there are widespread abnormalities of gray and white matter beyond the temporal lobes that negatively impact on functional networks and cognition. Previous studies have focused either on the global impact on functional networks, or on the functional correlates of specific cognitive abilities. Here, we use a step-wise approach to evaluate the link between whole-brain functional connectivity (FC) anomalies to overall cognitive performance, and how such abnormal connectivity alters the fronto-parietal brain regions involved in working memory (WMem), a cognitive disability often reported by TLE patients. We evaluated 40 TLE patients and 36 healthy subjects through extensive cognitive testing, resting-state functional magnetic resonance imaging (rs-fMRI), and task-based fMRI using Sternberg’s task to evaluate WMem. As a group, TLE patients displayed cognitive abnormalities across different domains, although considerable within-group variability was identified. TLE patients showed disruptions of functional networks between and within the default mode network (DMN) and task-positive networks (TPN) resulting in associations with cognitive performance. Furthermore, during the WMem task, TLE patients showed abnormal activity of fronto-parietal regions that was associated with other forms of memory, and alterations of seed-based connectivity analyses. Our results show that different degrees of abnormal functional brain activity and connectivity are related to the severity of cognitive disabilities across cognitive spheres. Differential activity between patients and healthy subjects suggest potential compensatory mechanisms to preserve adequate cognitive performance.
Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis
Authors: Papadopoulou D. , Roumelioti F. , Tzaferis C. , Chouvardas P. , Pedersen A.K. , Charalampous F. , Christodoulou-Vafeiadou E. , Ntari L. , Karagianni N. , Denis M. , Olsen J.V. , Matralis A.N. , Kollias G. 
Published: August 2022

ABSTRACTSynovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNF-TNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its anti-depressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases.
Non-O ABO blood group genotypes differ in their associations with Plasmodium falciparum rosetting and severe malaria
Authors: Opi D. Herbert , Ndila Carolyne M , Uyoga Sophie , Macharia Alex W , Fennell Clare , Nyutu Gideon , Ojal John , Shebe Mohammed , Awuondo Kennedy O , Mturi Neema , Peshu Norbert , Tsofa Benjamin , Band Gavin , Maitland Kathryn , Kwiatkowski Dominic P , Rockett Kirk A , Williams Thomas N. , Rowe J. Alexandra 
Published: August 2022

AbstractBlood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups. Whether the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria and rosetting is unknown. The A and B antigens are host RBC receptors for rosetting, hence we hypothesized that the higher levels of A and/or B antigen on RBCs from AA, BB and AB genotypes compared to AO/BO genotypes could lead to larger rosettes, increased microvascular obstruction and higher risk of malaria pathology. We used a case-control study of Kenyan children and in vitro adhesion assays to test the hypothesis that “double dose” non-O genotypes (AA, BB, AB) are associated with increased risk of severe malaria and larger rosettes than “single dose” heterozygotes (AO, BO). In the case-control study, compared to OO, the double dose genotypes consistently had higher odds ratios (OR) for severe malaria than single dose genotypes, with AB (OR 1.93) and AO (OR 1.27) showing most marked difference (P=0.02, Wald test). In vitro experiments with blood group A-preferring P. falciparum parasites showed that significantly larger rosettes were formed with AA and AB host RBCs compared to OO, whereas AO genotype rosettes were indistinguishable from OO. Overall, the data show that ABO genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.