bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hearing loss genes reveal patterns of adaptive evolution at the coding and non-coding levels in mammals
Authors: Trigila Anabella P. , Pisciottano Francisco , Franchini Lucía F. 
Published: November 2021

AbstractBackgroundMammals possess unique hearing capacities that differ significantly from those of the rest of the amniotes. In order to gain insights into the evolution of the mammalian inner ear, we aim to identify the set of genetic changes and the evolutionary forces that underlie this process. We hypothesize that genes that impair hearing when mutated in humans or in mice (hearing loss (HL) genes) must play important roles in the development and physiology of the inner ear and may have been targets of selective forces across the evolution of mammals. Additionally, we investigated if these HL genes underwent a human-specific evolutionary process that could underlie the evolution of phenotypic traits that characterize human hearing.ResultsWe compiled a dataset of HL genes including non-syndromic deafness genes identified by genetic screenings in humans and mice. We found that many genes including those required for the normal function of the inner ear such asLOXHD1,TMC1,OTOF,CDH23, andPCDH15show strong signatures of positive selection. We also found numerous noncoding accelerated regions in HL genes, and among them, we identified active transcriptional enhancers through functional enhancer assays in transgenic zebrafish.ConclusionsOur results indicate that the key inner ear genes and regulatory regions underwent adaptive evolution in the basal branch of mammals and along the human-specific branch, suggesting that they could have played an important role in the functional remodeling of the cochlea. Altogether, our data suggest that morphological and functional evolution could be attained through molecular changes affecting both coding and noncoding regulatory regions.
Assessment of gentamicin and cisplatin-induced kidney damage mediated via necrotic and apoptosis genes in albino rats
Authors: Abouzed Tarek Kamal , Sherif Eman Abd Elrahman , Barakat Mohamed El Sayed , Sadek Kadry Mohamed , Aldhahrani Adil , Nasr Nasr Elsayed , Eldomany Ehab , Khailo Khaled , Dorghamm Doaa Abdallha 
Published: November 2021

Abstract
Background
Gentamicin (GM) is a low-cost, low-resistance antibiotic commonly used to treat gram-negative bacterial diseases. Cisplatin (Csp) is a platinum-derived anti-neoplastic agent. This experiment aimed to identify the early signs of gentamicin and cisplatin-induced nephrotoxicity in rats. Thirty Wistar rats were divided into three groups of 10: a control group, which received no treatment; a gentamicin group administered by a dose of (100 mg/kg, IP) for 7 consecutive days, and a cisplatin group was administered intraperitoneal in a dose of (1.5 mg/kg body weight) repeated twice a week for 3 weeks.

Results
Both experimental groups exhibited increased levels of creatinine, urea, and uric acid, with the cisplatin-treated group showing higher levels than the gentamicin group. Experimental groups also exhibited significantly increased Malondialdehyde (MDA), reduced glutathione (GSH), and glutathione peroxidase (GSH-Px) with more pronounced effects in the cisplatin-treated group. Further, both experimental groups exhibited significant up-regulation of Tumor Necrosis Factor α (TNF-α), caspase-3, and Bax and down regulation of Bcl-2.

Conclusion
These findings confirm the use of necrotic, apoptotic genes as early biomarkers in the detection of tubular kidney damage. Further, cisplatin was shown to have a greater nephrotoxic effect than gentamicin; therefore, its use should be constrained accordingly when co-administered with gentamicin.
Estradiol increases risk of topoisomerase IIβ-mediated DNA strand breaks to initiate Xp11.2 translocation renal cell carcinoma
Authors: Shi Qiancheng , Liu Ning , Yang Lei , Chen Yi , Lu Yanwen , Guo Hongqian , Han Xiaodong , Li Dongmei , Gan Weidong 
Published: November 2021

Abstract
Background
Xp11.2 translocation renal cell carcinoma (tRCC) is defined by translocation of the transcription factor E3 (TFE3) gene located on chromosome Xp11.2. Due to the high incidence in women, 17β-estradiol (E2) may be a factor influencing TFE3 breaks, and the topoisomerase II (TOP2) poison is considered one of the important risk factors in mediating DNA breaks. In this study, we investigated the potential pathogenesis of Xp11.2 tRCC using the renal epithelial cell line HK-2.

Methods
Immunofluorescence assay was performed to analyze DNA breaks by quantifying phosphorylation of H2AX (γH2AX), and the micronuclei (MN) assay was designed for monitoring chromosome breaks. The chromatin immunoprecipitation (CHIP) was used to detect whether proteins bound to specific DNA site, and the co-immunoprecipitation (Co-IP) was used to confirm whether proteins bound to other proteins. In some experiments, siRNA and shRNA were transfected to knockdown target genes.

Results
Our results demonstrated that DNA double-strand breaks were mediated by TOP2β in HK-2 cells, and this process could be amplified through estrogen receptor α (ERα)-dependent pathway induced by E2. After performing translocation site analysis using target region sequencing data in two Xp11.2 tRCC cell lines and ten Xp11.2 tRCC patients, we confirmed that TOP2β and ERα could both bind to TFE3 translocation sites directly to mediate DNA breaks in a E2-dependent manner. However, TOP2β and ERα were not observed to have direct interaction, indicating that their collaborative may be implemented in other ways. Besides, TFE3 was found to be upregulated through NRF1 with increasing E2 concentration, which could increase the risk of TFE3 breaks.

Conclusion
Our results indicate that E2 amplifies TOP2β-mediated TFE3 breaks by ERα-dependent pathway, and E2 upregulates TFE3 by NRF1 to increase the risk of TFE3 breaks. This suggests that E2 is an important pathogenic factor for Xp11.2 tRCC pathogenesis.
The protective effects of pericyte-derived microvesicles on vascular endothelial functions via CTGF delivery in sepsis
Authors: Zhou Henan , Zheng Danyang , Wang Hongchen , Wu Yue , Peng Xiaoyong , Li Qinghui , Li Tao , Liu Liangming 
Published: November 2021

Abstract
Background
It is well known that sepsis is a prevalent severe disease caused by infection and the treatment strategies are limited. Recently pericyte-derived microvesicles (PMVs) were confirmed to be therapeutic in many diseases, whether PMVs can protect vascular endothelial cell (VEC) injury is unknown.

Methods
Pericytes were extracted from the retina of newly weaned rats, and PMVs were collected after starvation and characterized by flow-cytometry and transmission electron microscopy. First, the effect of PMVs on pulmonary vascular function in septic rats was measured via intravenous administration with HE staining, immunofluorescence, and Elisa analysis. Then, PMVs were co-incubated with VECs in the presence of lipopolysaccharide (LPS), and observed the protective effect of PMVs on VECs. Next, the proteomic analysis and further Gene Ontology (GO) enrichment analysis were performed to analyze the therapeutic mechanism of PMVs, and the angiogenesis-related protein CTGF was highly expressed in PMVs. Finally, by CTGF upregulation and downregulation in PMV, the role of PMV-carried CTGF was investigated.

Results
PMVs restored the proliferation and angiogenesis ability of pulmonary VECs, and alleviated pulmonary vascular leakage in septic rats and LPS-stimulated VECs. Further study showed that PMVs delivered CTGF to VECs, and subsequently activated ERK1/2, and increased the phosphorylation of STAT3, thereby improving the function of VECs. The further study found CD44 mediated the absorption and internalization of PMVs to VECs, the anti-CD44 antibody inhibited the protective effect of PMVs.

Conclusions
PMVs may delivery CTGF to VECs, and promote the proliferation and angiogenesis ability by activating the CTGF-ERK1/2-STAT3 axis, thereby protecting pulmonary vascular function in sepsis. The therapeutic effect of PMVs was highly related to CD44-mediated absorption.
Hydrogen gas with extracorporeal cardiopulmonary resuscitation improves survival after prolonged cardiac arrest in rats
Authors: Yin Tai , Becker Lance B. , Choudhary Rishabh C. , Takegawa Ryosuke , Shoaib Muhammad , Shinozaki Koichiro , Endo Yusuke , Homma Koichiro , Rolston Daniel M. , Eguchi Shuhei , Ariyoshi Tadashi , Matsumoto Asami , Oka Kentaro , Takahashi Motomichi , Aoki Tomoaki , Miyara Santiago J. , Nishikimi Mitsuaki , Sasaki Junichi , Kim Junhwan , Molmenti Ernesto P. , Hayashida Kei 
Published: November 2021

Abstract
Background
Despite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats.

Methods
Rats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated.

Results
The survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan–Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in d-glutamine and d-glutamate metabolism.

Conclusions
H2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia–reperfusion injury in critically ill patients who require ECMO support.
COPSOQ III in Germany: validation of a standard instrument to measure psychosocial factors at work
Authors: Lincke Hans-Joachim , Vomstein Martin , Lindner Alexandra , Nolle Inga , Häberle Nicola , Haug Ariane , Nübling Matthias 
Published: November 2021

Abstract
Background
Over the last almost 20 years COPSOQ (Copenhagen Psychosocial Questionnaire) has become a well-established instrument to measure psychosocial stress at work. In Germany, a first validated version of COPSOQ was introduced in 2005. After the COPSOQ international network took over responsibility for the development of COPSOQ, a new version was published in 2019 (COPSOQ III). The German version of this questionnaire is now to be validated.

Methods
Measurement qualities of German COPSOQ III are explored in adherence to the to the usual requirements of a validation study as defined by DIN EN ISO 10075-3. A sample of observations from more than 250,000 participants surveyed with the COPSOQ in Germany is used for univariate and multivariate statistical analysis.

Results
With its 84 items the German COPSOQ III includes all psychosocial work factors that are internationally obligatory and is still compatible with almost 70% of the content in the 2005 German version. Typical psychometric properties of the questionnaire (e. g., validity and reliability) are either good or very good for most of the 84 items and 31 scales. Beyond basic results, congruences with widely used theoretical approaches like the Demand-Control(−Support) model or the Job Demands-Resources model are generally satisfactory.

Conclusions
With the launch of COPSOQ III in Germany, new workplace psychosocial aspects could be explored. Like the preceding version, the questionnaire is a highly useful instrument for research as well as for risk assessment in enterprises. COSPQO III covers a multitude of theoretical approaches and gives comprehensive information on psychosocial working conditions to deduce actions for their improvement.
Italian national consensus statement on management and pharmacological treatment of phenylketonuria
Authors: Burlina Alberto , Biasucci Giacomo , Carbone Maria Teresa , Cazzorla Chiara , Paci Sabrina , Pochiero Francesca , Spada Marco , Tummolo Albina , Zuvadelli Juri , Leuzzi Vincenzo 
Published: November 2021

Abstract
Background
Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by defects in the phenylalanine-hydroxylase gene (PAH), the enzyme catalyzing the conversion of phenylalanine to tyrosine. PAH impairment causes phenylalanine accumulation in the blood and brain, with a broad spectrum of pathophysiological and neurological consequences for patients. Prevalence of disease varies, with peaks in some regions and countries, including Italy. A recent expert survey described the real-life of clinical practice for PKU in Italy, revealing inhomogeneities in disease management, particularly concerning approach to pharmacotherapy with sapropterin hydrochloride, analogous of the natural PAH co-factor, allowing disease control in a subset of patients. Therefore, the purpose of this paper is to continue the work initiated with the expert survey paper, to provide national guidances aiming to harmonize and optimize patient care at a national level.

Participants
The Consensus Group, convened by 10 Steering Committee members, consisted of a multidisciplinary crowd of 46 experts in the management of PKU in Italy.

Consensus process
The Steering Committee met in a series of virtual meeting in order to discuss on clinical focuses to be developed and analyzed in guidance statements, on the basis of expert practice based evidence, large systematic literature review previously performed in the expert survey paper, and evidence based consensus published. Statements were re-discussed and refined during consensus conferences in the widest audience of experts, and finally submitted to the whole consensus group for a modified-Delphi voting.

Results
Seventy three statements, divided in two main clinical areas, PKU management and Pharmacotherapy, achieved large consensus in a multidisciplinary group of expert in different aspects of disease. Importantly, these statements involve guidances for the use of sapropterin dihydrochloride, still not sufficiently implemented in Italy, and a set of good practice to approach the use of novel enzyme replacement treatment pegvaliase.

Conclusions
This evidence-based consensus provides a minimum set of guidances for disease management to be implemented in all PKU centers. Moreover, these guidances represent the first statement for sapropterin dihydrochloride use, implementation and standardization in Italy, and a guide for approaching pegvaliase treatment at a national level on a consistent basis.
Brain substrates for automatic retrieval of value memory in the primate basal ganglia
Authors: Kim Hyoung F. 
Published: November 2021

AbstractOur behavior is often carried out automatically. Automatic behavior can be guided by past experiences, such as learned values associated with objects. Passive-viewing and free-viewing tasks with no immediate outcomes provide a testable condition in which monkeys and humans automatically retrieve value memories and perform habitual searching. Interestingly, in these tasks, caudal regions of the basal ganglia structures are involved in automatic retrieval of learned object values and habitual gaze. In contrast, rostral regions do not participate in these activities but instead monitor the changes in outcomes. These findings indicate that automatic behaviors based on the value memories are processed selectively by the caudal regions of the primate basal ganglia system. Understanding the distinct roles of the caudal basal ganglia may provide insight into finding selective causes of behavioral disorders in basal ganglia disease.
DNA methylation-calling tools for Oxford Nanopore sequencing: a survey and human epigenome-wide evaluation
Authors: Liu Yang , Rosikiewicz Wojciech , Pan Ziwei , Jillette Nathaniel , Wang Ping , Taghbalout Aziz , Foox Jonathan , Mason Christopher , Carroll Martin , Cheng Albert , Li Sheng 
Published: November 2021

Abstract
Background
Nanopore long-read sequencing technology greatly expands the capacity of long-range, single-molecule DNA-modification detection. A growing number of analytical tools have been developed to detect DNA methylation from nanopore sequencing reads. Here, we assess the performance of different methylation-calling tools to provide a systematic evaluation to guide researchers performing human epigenome-wide studies.

Results
We compare seven analytic tools for detecting DNA methylation from nanopore long-read sequencing data generated from human natural DNA at a whole-genome scale. We evaluate the per-read and per-site performance of CpG methylation prediction across different genomic contexts, CpG site coverage, and computational resources consumed by each tool. The seven tools exhibit different performances across the evaluation criteria. We show that the methylation prediction at regions with discordant DNA methylation patterns, intergenic regions, low CG density regions, and repetitive regions show room for improvement across all tools. Furthermore, we demonstrate that 5hmC levels at least partly contribute to the discrepancy between bisulfite and nanopore sequencing. Lastly, we provide an online DNA methylation database (https://nanome.jax.org) to display the DNA methylation levels detected by nanopore sequencing and bisulfite sequencing data across different genomic contexts.

Conclusions
Our study is the first systematic benchmark of computational methods for detection of mammalian whole-genome DNA modifications in nanopore sequencing. We provide a broad foundation for cross-platform standardization and an evaluation of analytical tools designed for genome-scale modified base detection using nanopore sequencing.
Circadian dynamics of the teleost skin immune-microbiome interface
Authors: Ellison Amy R. , Wilcockson David , Cable Jo 
Published: November 2021

AbstractBackgroundCircadian rhythms of host immune activity and their microbiomes are likely pivotal to health and disease resistance. The integration of chronotherapeutic approaches to disease mitigation in managed animals, however, is yet to be realised. In aquaculture, light manipulation is commonly used to enhance growth and control reproduction but may have unknown negative consequences for animal health. Infectious diseases are a major barrier to sustainable aquaculture and understanding the circadian dynamics of fish immunity and crosstalk with the microbiome is urgently needed.ResultsHere, using rainbow trout (Oncorhynchus mykiss) as a model, we combine 16S rRNA metabarcoding, metagenomic sequencing and direct mRNA quantification methods to simultaneously characterise the circadian dynamics of skin clock and immune gene expression, and daily changes of skin microbiota. We demonstrate daily rhythms in fish skin immune expression and microbiomes, which are modulated by photoperiod and parasitic lice infection. We identify putative associations of host clock and immune gene profiles with microbial composition. Our results suggest circadian perturbation, that shifts the magnitude and timing of immune and microbiota activity, is detrimental to fish health.ConclusionsThe substantial circadian dynamics and fish host expression-microbiome relationships we find represent a valuable foundation for investigating the utility of chronotherapies in aquaculture, and more broadly contributes to our understanding of the role of microbiomes in circadian health of vertebrates.
Mania and bipolar depression: complementing not opposing poles—a post-hoc analysis of mixed features in manic and hypomanic episodes
Authors: Born Christoph , Grunze Heinz , Post Robert M. , Altshuler Lori L. , Kupka Ralph , McElroy Susan L. , Frye Mark A. , Suppes Trisha , Keck Paul E. , Nolen Willem A. , Schaerer Lars 
Published: November 2021

Abstract
Background
Depending on the classification system used, 5–40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects.

Methods
Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups.

Results
Mean age of participants was 40 ± 12 years (range 18–81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic < 12, hypomanic < 21, manic < 30. Average IDS-C sum scores in manic or hypomanic states were significantly higher (p < .001) than for non-manic states. (Hypo)manic female patients were likely to show more depressive symptoms than males (p < .001). Similar results were obtained when only the core items of the YMRS or only the number of depressive symptoms were considered. Analyzing the frequency of (hypo)manic mixed states applying a proxy of the DSM-5 mixed features specifier extracted from the IDS-C, we found that almost 50% of the (hypo)manic group visits fulfilled DSM-5 mixed features specifier criteria.

Conclusion
Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other.