bluuebunny/crossref_metadata_2025_split huggingface dataset:
Virgin Birth: A genetic basis for facultative parthenogenesis
Authors: Braun A. L. , Fabian D. K. , Garrison E. , Glover D. M. 
Published: March 2022

AbstractSexual reproduction evolved 1-2 billion years ago and underlies the biodiversity of our planet. Nevertheless, devolution of sexual into asexual reproduction can occur across all phyla of the animal kingdom. The genetic basis for how parthenogenesis can arise is completely unknown. To understand the mechanism and benefits of parthenogenesis, we have sequenced the genome of the facultative parthenogen, Drosophila mercatorum, and compared its organisation and expression pattern during parthenogenetic or sexual reproduction. We identified three genes, desat2, Myc, and polo in parthenogenetic D. mercatorum that when mis-regulated in a non-parthenogenetic species, D. melanogaster, enable facultative parthenogenetic reproduction. This simple genetic switch leads us to propose that sporadic facultative parthenogenesis could evolve as an ‘escape route’ preserving the genetic lineage in the face of sexual isolation.
EPI-589, a redox-active neuroprotectant, potently protects cultured cells from oxidative stress and alleviates symptomatic and pathological progression of motor neuron disease in the wobbler mouse
Authors: Matsumoto Yuji , Sampei Kazuaki , Nashida Tetsuaki , Fujii Yuta , Tani Naoko , Ishibashi Fumiaki , Yamanaka Mitsugu , Ishiyama Takeo 
Published: March 2022

AbstractOxidative stress is believed to play a significant role in the pathophysiology of amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease. The present study aims to firstly investigate the antioxidant activities of EPI-589, a small-molecule quinone derivative, under cell-free or cell culture conditions, and explore the in vivo efficacy of EPI-589 in the wobbler mouse model of human motor neuron disease. The reduced form of EPI-589 showed hydroxyl radical scavenging activities, whereas the oxidized form i.e. EPI-589 did not. In cellular models utilizing ALS patient-derived fibroblasts carrying mutations in the fused in sarcoma (FUS) gene or superoxide dismutase 1 (SOD1) gene, EPI-589 potently protected cells from oxidative stress induced by buthionine sulfoximine and ferric citrate. Protective effect of EPI-589 was also observed in culture of mouse immortalized striatal STHdHQ7/Q7 cells with cystine deprivation. In wobbler mice, oral administration of dietary EPI-589 provided long-lasting amelioration of both of deterioration of the rotarod walking performance and progression of forelimb deformity in wobbler mice throughout the treatment. In separate studies, we found that EPI-589 significantly suppressed changes of pathophysiological markers such as plasma phosphorylated neurofilament heavy chain, urinary 8-hydroxy-2’-deoxyguanosine, and cervical N-acetylaspartate in untreated wobbler mice. Thus, the present study firstly demonstrates that EPI-589 is a highly potent, redox-active neuroprotectant and robustly delays the symptomatic and pathophysiological progression of motor neuron disease in the wobbler mouse, and these findings strongly encourage further exploration of the therapeutic potential of EPI-589 for the treatment of ALS.
Molecular docking between human TMPRSS2 and the serine protease Kunitz-type inhibitor rBmTI-A
Authors: Bomediano Camillo Lívia de Moraes , Sasaki Sergio Daishi 
Published: March 2022

AbstractSARS-CoV-2 entrance into host cells is dependent of ACE2 receptor and viral protein S initiation by serine protease TMPRSS2. Cleavage of coronavirus protein S at the junctions Arg685/Ser686 and Arg815/Ser816 leads to the production of the S1/S2 and S2’ fragments needed for the fusion of viral and cell membranes. Studying and identifying serine protease inhibitors is an important step towards the development of candidate drugs to prevent SARS-CoV-2 infection. It has already been stablished that camostat mesylate, a serine protease inhibitor, is capable of blocking TMPRSS2 activity and prevent SARS-CoV-2 entrance into host cells. In this work, the interaction between the two domains of Kunitz-type serine protease inhibitor rBmTI-A and TMPRSS2 was studied through molecular docking. rBmTI-A domain 2 (P1 site Leu84) had the best complex results with predicted binding affinity of -12 Kcal.mol-1 and predicted dissociation constant at 25°C of 1.6 nM. The results suggest that rBmTI-A is capable of binding TMPRSS2 cleavage site at the junction Arg815/Ser816 using essentially the same residues that camostat mesylate.
Mid-term subclinical myocardial injury detection in patients recovered from COVID-19 according pulmonary lesion severity
Authors: Chamtouri Ikram , Kaddoussi Rania , Abroug Hela , Hafsa Mariem , Abdeleli Mabrouk , Fahem Nessrine , Lassoued Taha , Abdallah Asma Ben , Achour Asma , Migaou Asma , Cheikhm’hamed Sawssen , Jomaa Walid , Sriha Asma , Hamda Khaldoun Ben , Maatouk Faouzi 
Published: March 2022

AbstractBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV 2) may cause damage of the cardiovascular system during the acute phase of infection. However, Recent studies described a mid and long-term subtle cardiac injuries after recovery from acute Coronavirus disease 19 (COVID-19).The aim of this study was to determine the relationship between the severity of chest computed tomography (CT) lesions and the persistence of subtle myocardial injuries at mid-term follow-up of patients recovered from COVID-19 infection.MethodsAll COVID-19 patients were enrolled prospectively in this study. Sensitive troponin T (hsTnT) and chest CT scan was performed in all patients at the acute phase of Covid-19 infection. At the mid-term follow up, conventional transthoracic echocardiograph and global longitudinal strain (GLS) of left and right ventricles (LV and RV) were determined and compared between patients with chest CT scan lesions less than 50% (Group 1) and those with severe chest CT scan greater or equal to 50% (Group 2).ResultsThe mean age was 55 more or less than 14 years. Both LV GLS and RV GLS were significantly decreased in the group 2 (p=0.013 and p=0.011, respectively). LV GLS value more than -18% was noted in 43% of all the patients and RV GLS value more than -20% was observed in 48% of them. The group with severe chest CT scan lesions included more patients with reduced LV GLS and reduced RV GLS than the group with mild chest CT scan lesions (G1:29% vs. G2:57%, p=0.002) and (G1:36% vs. G2:60 %, p=0.009) respectively).ConclusionPatients with severe chest CT scan lesions are more likely to develop subclinical myocardial damage. TTE could be recommended in patients recovering from COVID-19 to detect subtle LV and RV lesions.Trial registrationThe cohort of patients is a part of the research protocol (IORG 00093738 N°102/OMB 0990-0279) approved by the Hospital Ethics Committee.
Glucose and lipid profiles in men with non-obstructive azoospermia
Authors: Birowo Ponco , Prasetyo Dimas Tri , Pujianto Dwi Ari , Atmoko Widi , Rasyid Nur 
Published: March 2022

AbstractThe impact of a low testosterone level among men with non-obstructive azoospermia with various testicular histopathological patterns on the regulation of glucose and lipid metabolism is less well known than among the general population. The aim of this retrospective study was to examine the association between testicular histopathology and components of the metabolic profile among men with non-obstructive azoospermia. Participants were divided into two groups: men with non-obstructive azoospermia and men with obstructive azoospermia. Testicular biopsies were performed among those with non-obstructive azoospermia. We included 115 patients in this study: 83 (72.2%) had non-obstructive azoospermia and 32 (27.8%) had obstructive azoospermia. The plasma glucose concentration, glycated hemoglobin level, and lipid profile were similar between patients with non-obstructive azoospermia and those with obstructive azoospermia. Upon subgroup analysis of patients with non-obstructive azoospermia, those with Sertoli-cell-only syndrome had the lowest testosterone (431 ± 238 ng/dL;P=0.039) and highest follicle-stimulating hormone (23.4 ± 18.2 mIU/mL;P=0.002) concentrations. They also had the highest triglyceride concentration (163 ± 114 mg/dL;P=0.001). Interestingly, patients with Sertoli-cell-only syndrome had a lower fasting plasma glucose concentration (92 ± 11 mg/dL;P<0.001) and glycated hemoglobin level (5.9 ± 0.8%;P=0.022) than those with histopathological patterns of maturation arrest and hypospermatogenesis. In conclusion, differences in glucose and lipid metabolism are evident between men with non-obstructive azoospermia with different spermatogenesis patterns.
Genetic mapping of multiple metabolic traits identifies novel genes for adiposity, lipids and insulin secretory capacity in outbred rats
Authors: Le Thu H , Crouse Wesley L , Keele Gregory R , Holl Katie , Seshie Osborne , Tschannen Michael , Craddock Ann , Das Swapan K. , McDonald Bailey , Sharma Neeraj K , Key Chia-Chi Chuang , Hawkins Gregory , Valdar William , Mott Richard , Woods Leah C Solberg 
Published: March 2022

AbstractDespite the successes of human genome-wide association studies, the causal genes underlying most metabolic traits remain unclear. We used outbred heterogeneous stock (HS) rats, coupled with expression data and mediation analysis, to identify quantitative trait loci (QTLs) and candidate gene mediators for adiposity, glucose tolerance, serum lipids and other metabolic traits. Physiological traits were measured in 1519 male HS rats, with liver and adipose transcriptomes measured in over 410 rats. Genotypes were imputed from low coverage whole genome sequence. Linear mixed models were used to detect physiological and expression QTLs (pQTLs and eQTLs, respectively), employing both SNP- and haplotype-based models for pQTL mapping. Genes with cis-eQTLs that overlapped pQTLs were assessed as causal candidates through mediation analysis. We identified 15 SNP-based pQTLs and 19 haplotype-based pQTLs, of which 11 were in common. Using mediation, we identified the following genes as candidate mediators of pQTLs: Grk5 for a fat pad weight pQTL on Chr1, Krtcap3 for fat pad weight and serum lipids pQTLs on Chr6, Ilrun for a fat pad weight pQTL on Chr20 and Rfx6 for a whole pancreatic insulin content pQTL on Chr20. Furthermore, we verified Grk5 and Ktrcap3 using gene knock-down/out models, thereby shedding light on novel regulators of obesity.
Intratumor Childhood Vaccine-Specific CD4+T cell Recall Coordinates Antitumor CD8+T cells and Eosinophils
Authors: Brown Michael C. , McKay Zachary P. , Yang Yuanfan , Beasley Georgia M. , Ashley David M. , Bigner Darell D. , Nair Smita K. , Gromeier Matthias 
Published: March 2022

ABSTRACTBackgroundCD4+T cells are key contributors to cancer immune surveillance. However, means to effectively harness CD4+T cell help for cancer immunotherapy are lacking, and antitumor mechanisms of CD4+T cells remain crudely defined.MethodsThe impact of polio immunization on polio virotherapy was tested in syngeneic murine melanoma and breast cancer models. Antitumor effects of polio and tetanus toxoid antigens were assessed in polio and tetanus immunized mice. T and B cell knockout mice, CD4+T cell adoptive transfer, and eosinophil depletion demonstrated cell-type specific contributions to the antitumor efficacy of polio recall. Phenotyping of adoptively transferred OT-I (OVA-specific) T cells in B16-OVA tumor bearing mice, as well as adoptive transfer of T cells to naïve tumor-bearing recipients, measured the impact of intratumor polio/tetanus recall on antitumor T cell immunity. Pan-cancer human transcriptome data sets were queried to test associations between eosinophils and Tregs; cytokine profiles of polio and tetanus recall were defined in human peripheral blood of healthy donors and cancer patients; CD40L blockade was used to determine dependency of recall antigen therapy on CD40:CD40L signaling.ResultsPrior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth in a manner complemented by pattern recognition receptor agonist therapy and PD1 blockade. Intratumor recall antigens augmented antitumor T cell function, and caused marked tumor infiltration of type 2 innate lymphoid cells (ILC2s) and eosinophils, coinciding with decreased proportions of intratumor Tregs. Antitumor effects of recall antigens were mediated by CD4+T cells, independent of CD40L signaling, and were dependent on both eosinophils and CD8+T cells. Human PBMCs mounted diverse cytokine/chemokine responses, which were not impaired in patients with advanced cancer, and an inverse relationship between eosinophil and Treg signatures was observed across TCGA cancer types.ConclusionThis work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+T cell help for antitumor CD8+T cells, and implicates eosinophils as antitumor effectors of CD4+T cells.
Revealing the microbial heritage of traditional Brazilian cheeses through metagenomics
Authors: Kothe Caroline Isabel , Mohellibi Nacer , Renault Pierre 
Published: March 2022

AbstractBrazilian artisanal cheeses date from the first Portuguese settlers and evolved via local factors, resulting in unique products that are now part of the patrimony and identity of different Brazilian regions. In this study, we combined several culture-independent approaches, including 16S/ITS metagenetics, assembly- and deep profiling-metagenomics to characterize the originality of the microbiota of five varieties of Brazilian artisanal cheeses from the South and Southeast regions of Brazil. Their core microbiota contained mainly lactic acid bacteria (LAB), of which Lactococcus lactis subsp. lactis was the most frequent, followed by Streptococcus thermophilus in the South region. Moreover, several samples from the Southeast region contained, as dominant LAB, two other food Streptococci belonging to a new species of the salivarius group and S. infantarius. Rinds of samples from the Southeast region were dominated by the halotolerant bacterium Corynebacterium variabile and the yeasts Diutina catenulata and, to a lesser extent, by Debaryomyces hansenii and Kodamaea ohmeri. Rinds from the South region contained mainly LAB due to their short ripening time, and the predominant yeast was D. hansenii. Phylogenomic analysis based on L. lactis metagenome-assembled genomes (MAGs) showed that most Brazilian strains are closely related and form a different clade from those whose genomes are available at this time, indicating that they belong to a specific group. Lastly, functional analysis showed that S. infantarius acquired a ∼26 kb DNA fragment from S. thermophilus starter strains that carry the LacSZ system, allowing fast lactose assimilation, an adaptation advantage for growth in milk. Finally, our study identified several areas of concern, such as the presence of somatic cell DNA and high levels of antibiotic resistance genes in several cheese microbiota, implying that the milk used was from diseased herds. Overall, the data from this study highlight the potential value of the traditional and artisanal cheese production network in Brazil, and provide a metagenomic-based scheme to help manage this resource safely.
Deterioration of the human transcriptome with age due to increasing intron retention and spurious splicing
Authors: Mariotti Marco , Kerepesi Csaba , Oliveros Winona , Mele Marta , Gladyshev Vadim N. 
Published: March 2022

AbstractAdult aging is characterized by a progressive deterioration of biological functions at physiological, cellular and molecular levels, but its damaging effects on the transcriptome are not well characterized. Here, by analyzing splicing patterns in ∼1,000 human subjects sampled across multiple tissues, we found that splicing fidelity declines with age. Most prominently, genuine introns fail to be spliced out, manifesting as a broad surge in intron retention, and this is exacerbated by the increase in diverse spurious exon-exon junctions with age. Both of these effects are prominently detected in the majority of human tissues. Collectively, they result in the progressive deterioration of the active transcriptome, wherein functional mRNAs are increasingly diluted with non-functional splicing isoforms. We discuss the concept of “splicing damage” and formulate methods to quantify it. Using these tools, we show that splicing damage increases both with age and with the incidence of diseases. Altogether, this work uncovers transcriptome damage as a critical molecular indicator of human aging and healthspan.
An integrated single-cell atlas of the limb skeleton from development through adulthood
Authors: Herpelinck Tim , Ory Liesbeth , Verbraeken Tom , Nasello Gabriele , Barzegari Mojtaba , Bolander Johanna , Luyten Frank P. , Tylzanowski Przemko , Geris Liesbet 
Published: March 2022

AbstractThe recent growth of single-cell transcriptomics has turned single-cell RNA sequencing (scRNA-seq) into a near-routine experiment. Breakthroughs in improving scalability have led to the creation of organism-wide transcriptomic datasets, aiming to comprehensively profile the cell types and states within an organism throughout its lifecycle. To date, however, the skeleton remains a majorly underrepresented organ system in organism-wide atlases. Considering how the skeleton not only serves as the central framework of the vertebrate body but is also the home of the hematopoietic niche and a central player in major metabolic and homeostatic processes, this presents a major deficit in current reference atlas projects. To address this issue, we integrated ten separate scRNA-seq datasets containing limb skeletal cells and their developmental precursors, generating an atlas of 133 332 cells. This limb skeletal cell atlas describes cells across the mesenchymal lineage from the induction of the limb to the adult bone and encompasses 39 different cell states. Furthermore, expanding the repertoire of available time points and cell types within a single dataset allowed for more complete analyses of cell-cell communication orin silicoperturbation studies. Taken together, we present a missing piece in the current atlas mapping efforts, which will be of value to researchers in the fields of skeletal biology, hematopoiesis, metabolism and regenerative medicine.
Patterns of rates of mortality in the Clinical Practice Research Datalink
Authors: Schmidt James C. F. , Lambert Paul C. , Gillies Clare , Sweeting Michael J. 
Published: March 2022

AbstractThe Clinical Practice Research Datalink (CPRD) is a widely used data resource, representative in demographic profile, with accurate death recordings but it is unclear if mortality rates within CPRD are similar to rates in the general population. Rates may additionally be affected by selection bias caused by the requirement that a cohort have a minimum lookback window, i.e. observation time prior to start of at-risk follow-up.Standardised Mortality Ratios (SMRs) were calculated incorporating published population reference rates from the Office for National Statistics (ONS), using Poisson regression with rates in CPRD contrasted to ONS rates, stratified by age, calendar year and sex. An overall SMR was estimated along with SMRs presented for cohorts with different lookback windows (1, 2, 5, 10 years). SMRs were stratified by calendar year, length of follow-up and age group. Mortality rates in a random sample of 1 million CPRD GOLD patients were slightly lower than the national population [SMR=0.980 95% confidence interval (CI) (0.973, 0.987)]. Cohorts with observational lookback had SMRs below one [1 year of lookback; SMR=0.905 (0.898, 0.912), 2 years; SMR=0.881 (0.874, 0.888), 5 years; SMR=0.849 (0.841, 0.857), 10 years; SMR=0.837 (0.827, 0.847)]. Mortality rates in the first two years after patient entry into CPRD were higher than the general population, while SMRs dropped below one thereafter.Mortality rates in CPRD, using simple entry requirements, are similar to rates seen in the English population. The requirement of at least a single year of lookback results in lower mortality rates compared to national estimates.
Vascular dysregulation following SARS-CoV-2 infection involves integrin signalling through a VE-Cadherin mediated pathway
Authors: Nader Danielle , Kerrigan Steve 
Published: March 2022

AbstractThe vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins have emerged as possible receptor candidates for SARS-CoV-2, and their complex intracellular signalling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation through hijacking integrin αVβ3. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein – through its RGD motif – binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.
Omicron variant of SARS-COV-2 gains new mutations in New Zealand and Hong Kong
Authors: Yang Xiang-Jiao 
Published: March 2022

Disclaimer statementThe authors have withdrawn this manuscript because an issue was raised about the SARS- COV-2 genome sequence data used in the study. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.