Research progress in the central nervous system mechanism of dexmedetomidine

Dexmedetomidine, which is an α2 adrenergic receptor agonist with sedative, analgesic, anxiolytic and anti-sympathetic effects, has become a widely used drug in clinical anesthesia and intensive care unit (ICU). Compared with other drugs in the department of anesthesiology, dexmedetomidine has no obvious respiratory depression and no obvious hemodynamic changes, and can significantly reduce the dosage of sedative and analgesic drugs when combined with other anesthetics. In clinical applications, dexmedetomidine has been found to induce a sedative response that is associated with rapid arousal. Dexmedetomidine is traditionally thought to act through α2 adrenergic receptors to lower blood pressure, dilate blood vessels and lower heart rate, but it is unclear how it affects neural circuits in the brain. In recent years, there has been an increasing number of studies on the mechanism of action of dexmedetomidine, which has confirmed that the ventrolateral preoptic nucleus (VLPO), locus coeruleus (LC) and ventral tegmental area (VTA) of the hypothalamus are involved in the sedation mediated by dexmedetomidine, the dorsal root ganglion (DRG) and superior cervical ganglion (SCG) are involved in dexmedetomidine-mediated analgesia, and the hypothalamic preoptic area (PO) and hypothalamic paraventricular nucleus (PVN) are involved in the changes in body temperature and water-electrolyte balance mediated by dexmedetomidine, providing a new direction for understanding the mechanism of dexmedetomidine in the central nervous system

Role and research progress of transient receptor potential vanilloid-1 in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a severe critical respiratory disease characterized by refractory hypoxemia, which is caused by intrapulmonary and extrapulmonary factors. It has a rapid onset, and high morbidity and mortality. With the global prevalence and mutation of respiratory viruses, the diagnosis and treatment of ARDS have become more complicated, requiring exploration into the molecular mechanisms and effective therapeutic methods of the occurrence and development of ARDS in clinical practice. Researchers have found that the pathogenesis of ARDS involves the interaction of multiple factors, including imbalances in inflammatory responses and redox reactions, dysregulation of endothelial cells, disruption of alveolar-capillary barrier and abnormalities in coagulation function. Although advancements in molecular biology techniques such as genomics and proteomics have provided new insights into the pathogenesis of ARDS, there is still a lack of early diagnostic biomarker and effective drugs targeted for ARDS. At present, more comprehensive and in-depth basic and clinical research is still needed. Increasing evidence suggests that transient receptor potential vanilloid-1 (TRPV1), also known as the capsaicin receptor, plays a crucial role in respiratory system diseases. TRPV1 is widely distributed in the upper respiratory tract, airway smooth muscle, alveoli and pulmonary blood vessels, participating in mediating airway dilation and constriction, cough reflex, and release of inflammatory mediators related to inflammation and pain, as well as sensing and transmitting various biological signals related to temperature, chemical substances and mechanical stress stimuli in the respiratory system. The widespread distribution and diverse physiological functions of TRPV1 make it a research hotspot in the occurrence and development of respiratory system diseases such as pneumonia, pulmonary edema, cough, asthma and acute lung injury. This article reviews the correlation and molecular mechanisms between ARDS caused by sepsis, traumatic brain injury and respiratory viruses with TRPV1, aiming to summarize the positive effects of regulating TRPV1 expression on the pathogenesis of ARDS and provide reference for strengthening early diagnosis and effective intervention measures for ARDS

Electroacupuncture pretreatment attenuates cerebral ischemic injury through α7 nicotinic acetylcholine receptor-mediated inhibition of high-mobility group box 1 release in rats

<p>Abstract</p> <p>Background</p> <p>We have previously reported that electroacupuncture (EA) pretreatment induced tolerance against cerebral ischemic injury, but the mechanisms underlying this effect of EA are unknown. In this study, we assessed the effect of EA pretreatment on the expression of α7 nicotinic acetylcholine receptors (α7nAChR), using the ischemia-reperfusion model of focal cerebral ischemia in rats. Further, we investigated the role of high mobility group box 1 (HMGB1) in neuroprotection mediated by the α7nAChR and EA.</p> <p>Methods</p> <p>Rats were treated with EA at the acupoint "Baihui (GV 20)" 24 h before focal cerebral ischemia which was induced for 120 min by middle cerebral artery occlusion. Neurobehavioral scores, infarction volumes, neuronal apoptosis, and HMGB1 levels were evaluated after reperfusion. The α7nAChR agonist PHA-543613 and the antagonist α-bungarotoxin (α-BGT) were used to investigate the role of the α7nAChR in mediating neuroprotective effects. The roles of the α7nAChR and HMGB1 release in neuroprotection were further tested in neuronal cultures exposed to oxygen and glucose deprivation (OGD).</p> <p>Results</p> <p>Our results showed that the expression of α7nAChR was significantly decreased after reperfusion. EA pretreatment prevented the reduction in neuronal expression of α7nAChR after reperfusion in the ischemic penumbra. Pretreatment with PHA-543613 afforded neuroprotective effects against ischemic damage. Moreover, EA pretreatment reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis and HMGB1 release following reperfusion, and the beneficial effects were attenuated by α-BGT. The HMGB1 levels in plasma and the penumbral brain tissue were correlated with the number of apoptotic neurons in the ischemic penumbra. Furthermore, OGD in cultured neurons triggered HMGB1 release into the culture medium, and this effect was efficiently suppressed by PHA-543,613. Pretreatment with α-BGT reversed the inhibitory effect of PHA-543,613 on HMGB1 release.</p> <p>Conclusion</p> <p>These data demonstrate that EA pretreatment strongly protects the brain against transient cerebral ischemic injury, and inhibits HMGB1 release through α7nAChR activation in rats. These findings suggest the novel potential for stroke interventions harnessing the anti-inflammatory effects of α7nAChR activation, through acupuncture or pharmacological strategies.</p

Genomic data for 78 chickens from 14 populations

Background: Since the domestication of the red jungle fowls (Gallus gallus; dating back to~10 000 B.P.) in Asia, domestic chickens (Gallus gallus domesticus) have been subjected to the combined effects of natural selection and human-driven artificial selection; this has resulted in marked phenotypic diversity in a number of traits, including behavior, body composition, egg production, and skin color. Population genomic variations through diversifying selection have not been fully investigated. Findings: The whole genomes of 78 domestic chickens were sequenced to an average of 18-fold coverage for each bird. By combining this data with publicly available genomes of five wild red jungle fowls and eight Xishuangbanna game fowls, we conducted a comprehensive comparative genomics analysis of 91 chickens from 17 populations. After aligning ~21.30 gigabases (Gb) of high-quality data from each individual to the reference chicken genome, we identified ~6.44 million (M) single nucleotide polymorphisms (SNPs) for each population. These SNPs included 1.10 M novel SNPs in 17 populations that were absent in the current chicken dbSNP (Build 145) entries. Conclusions: The current data is important for population genetics and further studies in chickens and will serve as a valuable resource for investigating diversifying selection and candidate genes for selective breeding in chickens.Peer reviewedAnimal Scienc

Comparative transcriptomics of 5 high-altitude vertebrates and their low-altitude relatives

Abstract Background: Species living at high altitude are subject to strong selective pressures due to inhospitable environments (e.g., hypoxia, low temperature, high solar radiation, and lack of biological production), making these species valuable models for comparative analyses of local adaptation. Studies that have examined high-altitude adaptation have identified a vast array of rapidly evolving genes that characterize the dramatic phenotypic changes in high-altitude animals. However, how high-altitude environment shapes gene expression programs remains largely unknown. Findings: We generated a total of 910 Gb of high-quality RNA-seq data for 180 samples derived from 6 tissues of 5 agriculturally important high-altitude vertebrates (Tibetan chicken, Tibetan pig, Tibetan sheep, Tibetan goat, and yak) and their cross-fertile relatives living in geographically neighboring low-altitude regions. Of these, ∼75% reads could be aligned to their respective reference genomes, and on average ∼60% of annotated protein coding genes in each organism showed FPKM expression values greater than 0.5. We observed a general concordance in topological relationships between the nucleotide alignments and gene expression–based trees. Tissue and species accounted for markedly more variance than altitude based on either the expression or the alternative splicing patterns. Cross-species clustering analyses showed a tissue-dominated pattern of gene expression and a species-dominated pattern for alternative splicing. We also identified numerous differentially expressed genes that could potentially be involved in phenotypic divergence shaped by high-altitude adaptation. Conclusions: These data serve as a valuable resource for examining the convergence and divergence of gene expression changes between species as they adapt or acclimatize to high-altitude environments

Revisiting Assessment of Computational Methods for Hi-C Data Analysis

The performances of algorithms for Hi-C data preprocessing, the identification of topologically associating domains, and the detection of chromatin interactions and promoter–enhancer interactions have been mostly evaluated using semi-quantitative or synthetic data approaches, without utilizing the most recent methods, since 2017. In this study, we comprehensively evaluated 24 popular state-of-the-art methods for the complete end-to-end pipeline of Hi-C data analysis, using manually curated or experimentally validated benchmark datasets, including a CRISPR dataset for promoter–enhancer interaction validation. Our results indicate that, although no single method exhibited superior performance in all situations, HiC-Pro, DomainCaller, and Fit-Hi-C2 showed relatively balanced performances of most evaluation metrics for preprocessing, topologically associating domain identification, and chromatin interaction/promoter–enhancer interaction detection, respectively. The comprehensive comparison presented in this manuscript provides a reference for researchers to choose Hi-C analysis tools that best suit their needs

Sevoflurane preconditioning induces tolerance to brain ischemia partially via inhibiting thioredoxin-1 nitration

Abstract Background Sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly elucidated. Nitration is an important form of post-translational modification in pathological signaling. This study was to investigate the role of thioredoxin-1 (Trx-1) nitration in neuroprotection effect induced by sevoflurane preconditioning in a transient stroke model in rats. Methods Adult male Sprague–Dawley rats were preconditioned with 2% sevoflurane or vehicle oxygen exposure, 1 h per day, for 5 consecutive days. At 24 h after the last exposure, rats were subjected to focal brain ischemia induced by middle cerebral artery occlusion (MCAO) for 90 min, followed by 72-h reperfusion. Trx-1 expression and activity, as well as the content of nitrotyrosine at penumbra were detected at 24 h after preconditioning and 2, 8, 24, 72 h after MCAO. Nitrated Trx-1 was examined by immunoprecipitation at 8 h after MCAO. The role of Trx-1 nitration in ischemic tolerance was assessed by administration of nitrated human-Trx-1 prior to MCAO. Neurological scores, brain infarct volumes and TUNEL staining were evaluated at 24 h after reperfusion. Results Ischemic stroke decreased Trx-1 activity but not the expression in penumbra tissue. The content of nitrotyrosine was elevated after MCAO. Preconditioning with sevoflurane increased Trx-1 activity and reduced its nitration at 8 h after MCAO in comparison with vehicle preconditioning. The decrement of Trx-1 activity was correlated with its nitration level. Exogenous administration of nitrated human-Trx-1 reversed the brain ischemic tolerance of sevoflurane preconditioning, exacerbating brain infarct volume, neurobehavioral defects and apoptosis, while administration of human-Trx-1 had no effect on the sevoflurane preconditioning-induced neuroprotection. Conclusion Ischemic stroke reduces Trx-1 activity via post-translational nitrative modulation in rats. Sevoflurane preconditioning induces brain ischemic tolerance and anti-apoptosis by partially preserving Trx-1 activity via inhibiting nitration

Reversing relaxation-induced embrittlement by high-temperature thermal cyclic annealing in Zr-based metallic glass

Annealing usually induces structural relaxation and reduction of liquid-like regions, leading to embrittlement in bulk metallic glasses (BMGs). Here, we find that the short-term high-temperature thermal cycling (HTC) annealed Zr41.2Ti13.8Cu12.5Ni10Be22.5 (Vit1) BMG shows an improved plasticity without sacrificing their yield strength. And only relaxation behavior with increased hardness is observed after HTC, which is different from the rejuvenation effect usually observed in cryogenic thermal cycling (CTC). We revealed that this embrittlement reversal is attributed to enhanced fluctuations of full width at half maximum (FWHM) of the hardness’ distribution at micrometer and larger scales induced by short-term HTC. The enhanced fluctuations of mechanical heterogeneities across the diameter on a cross-section of the short-term HTC sample may increase the number and decrease the size of shear transformation zones (STZs) activated at high stress and promote the deflection of shear bands (SBs) during their propagation to form multiple SBs. The enhanced plasticity after HTC induced relaxation contradicts the common sense that relaxation accompanying with annihilation of free volume or liquid-like region usually causes embrittlement. Present results indicate that short-term HTC could be a powerful mean to tune the mechanical performance, shedding new lights on the interplay among relaxation, mechanical/structural heterogeneity, and plasticity of MGs