Structural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing.

Structural variants (SVs), accounting for a larger fraction of the genome than SNPs/InDels, are an important pool of genetic variation, enabling environmental adaptations. Here, we perform long-read sequencing data of 320 Tibetan and Han samples and show that SVs are highly involved in high-altitude adaptation. We expand the landscape of global SVs, apply robust models of selection and population differentiation combining SVs, SNPs and InDels, and use epigenomic analyses to predict enhancers, target genes and biological functions. We reveal diverse Tibetan-specific SVs affecting the regulatory circuitry of biological functions, including the hypoxia response, energy metabolism and pulmonary function. We find a Tibetan-specific deletion disrupts a super-enhancer and downregulates EPAS1 using enhancer reporter, cellular knock-out and DNA pull-down assays. Our study expands the global SV landscape, reveals the role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles of SVs in human biology.

The strategies of exercise intervention for adolescent depression: A meta-analysis of randomized controlled trials.

Purpose: This study aimed to investigate the effect of exercise intervention, and analyze exercise intervention strategies for adolescent depression through a meta-analysis of RCTs. Methods: Accordance to PRISMA guidelines, PubMed, Medline, EBSCO, Web of Science, SPORTDiscus, PsycINFO, ProQuest, and CNKI were searched for eligible records. Peer-reviewed studies were included if they met the following criteria: population (mean age of 10-18 years), intervention (physical activity, sport, or exercise), and outcomes (depression, adherence, ITT, dropout, adverse events, follow-up report). The protocol of this systematic review was registered in PROSPERO (CRD42022321683). Effect sizes calculations and methodological quality of exercise intervention (TESTEX scale) were carried out. The certainty of evidence was assessed by GRADE framework. Results: Thirteen randomized controlled trials were eligible for this review, which comprised a total of 433 adolescents. Compared with the control treatment, the effect of exercise on adolescent depression was moderate (SMD = -0.65, 95%CI: -1.03 to -0.27, p < 0.01). Heterogeneity was substantial (T 2 = 0.30, I 2 = 67%, p < 0.01). The moderating effect analysis showed that exercise intervention characteristics (organization form, exercise frequency, exercise intensity, exercise type, and single exercise session duration) of included studies varied greatly revealing multiple factors that may impact the antidepressant effect of exercise on adolescent depression (I 2 > 50%, p < 0.05). Three studies show that the positive effect of exercise on reducing depression in adolescents remained 40 weeks after the intervention. Moreover, owing to the included studies contained methodological limitations, the certainty of evidence was reduced to moderate level. Conclusion: This study shows that exercise intervention has a moderate and sustained positive effect on adolescent depression. Our results recommended that adolescents with depression undertake moderate to high intensity group mixed exercise for more than 12 weeks, 20 to 60 min/time, more than 3 times/week. Additionally, our study also shows that the antidepressant effects remained for a long time after the end of exercise interventions. However, following the GRADE framework, we rated the certainty of evidence the primary meta-analysis as moderate evidence due to some limitations of included studies. Therefore, rigorous studies are still needed to verify the results. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=321683], identifier [CRD42022321683].

HFIP: an integrated multi-omics data and knowledge platform for the precision medicine of heart failure.

As the terminal clinical phenotype of almost all types of cardiovascular diseases, heart failure (HF) is a complex and heterogeneous syndrome leading to considerable morbidity and mortality. Existing HF-related omics studies mainly focus on case/control comparisons, small cohorts of special subtypes, etc., and a large amount of multi-omics data and knowledge have been generated. However, it is difficult for researchers to obtain biological and clinical insights from these scattered data and knowledge. In this paper, we built the Heart Failure Integrated Platform (HFIP) for data exploration, fusion analysis and visualization by collecting and curating existing multi-omics data and knowledge from various public sources and also provided an auto-updating mechanism for future integration. The developed HFIP contained 253 datasets (7842 samples), multiple analysis flow, and 14 independent tools. In addition, based on the integration of existing databases and literature, a knowledge base for HF was constructed with a scoring system for evaluating the relationship between molecular signals and HF. The knowledge base includes 1956 genes and annotation information. The literature mining module was developed to assist the researcher to overview the hotspots and contexts in basic and clinical research. HFIP can be used as a data-driven and knowledge-guided platform for the basic and clinical research of HF. Database URL: http://heartfailure.medical-bigdata.com.

Nonconformist tendencies related to risky choices in female methamphetamine abstainers.

Background: Many experimental studies and theoretical models have tried to explain the multifaceted formation of drug addiction. In most addiction models, social factors are an important component; however, few empirical studies have investigated the social influences on the safe or risky choices of drug-addicted individuals during the abstinence stage. Objectives: To investigate the behavioral patterns of female methamphetamine abstainers under social influence. Methods: Thirty-seven female methamphetamine abstainers (average abstinence time: 8.61 ± 4.75 months) and 40 matched controls performed a gambling task in the presence of peers' choices. We applied both model-free and computational model-based analysis to examine how the decision patterns differed with social influence between the two groups. Results: 1) the choice data from the two groups showed a social influence effect such that participants made more risky choices when others made risky choices; 2) overall, the female methamphetamine abstainers made more risky choices in the social influence task; and 3) in the computational model parameters, the female methamphetamine abstainers exhibited more nonconforming attitudes (with negative other-conferred utility) with respect to peer influence, whereas controls showed higher conformity to peers. Conclusion: Our findings provide the first objective evidence that female methamphetamine abstainers show peer nonconformity. This nonconformist tendency may be a potential behavioral marker to track drug addiction and help to elucidate the mechanisms of decisions made by female methamphetamine abstainers.

Enhanced neural responses to monetary rewards in methamphetamine use disordered individuals compared to healthy controls.

Converging evidence supports that addiction involves the pathological usurpation of normal reward processes. However, the nature and direction of reward processing dysfunction in substance abusers remain unclear. The current study explored the electrophysiological responses associated with different stages of reward processing in methamphetamine (MA) use disordered individuals. Electroencephalography recording was used to compare responses of 21 MA use disordered individuals and 22 healthy controls (HC) while participants engaged in a simple gambling task. Compared to HC, MA use disordered individuals made more risky choices following a loss outcome on a previous trial. During the reward anticipatory stage, MA use disordered individuals showed an enhanced stimulus-preceding negativity (SPN), as compared to HC. During the reward outcome stage, MA use disordered individuals showed an enhanced feedback-related negativity (FRN) for the losses versus gains as compared to HC. Furthermore, an enhanced P300 was observed under the gain condition, but not under the loss condition, in MA use disordered individuals as compared to HC. These findings provide further evidence that MA use disordered individuals have a sensitized neural response to non-drug rewards and support the impulsivity and incentive sensitization theories in MA use disordered individuals. The current study helps to elucidate the neural mechanisms of reward processing in MA use disordered individuals.

[Effect of Huperzine A on neural lesion of acute organophosphate poisoning in mice].

OBJECTIVE: Effects of neurophathologic changes and expression of Glu and 60 nNOS were observed in acute isocarbophos and phoxim poisoning in mice. METHODS: KM male mice were randomly divided into three groups, which were control, non-treated and Huperzine A (HupA)-treated groups. The control group was given tween-80. Nontreated group was given isocarbophos (14.7 mg/kg) or phoxim (1702 mg/kg). HupA-treated group was given HupA 2h before phoxim or isocarbophos. Twenty-four hours after exposure, the whole brain was removed and adjacent coronal sections was obtained. One part of sections were stained with toluidine blue. The part of sections were used to assessed the expression of Glu and nNOS in the cortex and hippocampal of brain by immunohistochemistry. RESULTS: Compared to control group, non-treated group was observed nissal body nembers reduced and dyeing light. The animals of HupA protective group were observed nissal body nembers reduced, but the lesional degree was lighter obviously than non-treated group. The statistically reduced of the expression of Glu (P<0.01), the elevation of nNOS (P<0.01), after Isocarbophos intoxication were observed. Compared to non-treated group, the significant elevation of Glu (P<0.01) and reduced of nNOS (P<0.01) was observed on HupA-treated groups. Whereas for phoxim treatment, no changes were observed. CONCLUSION: HupA have protective effect against glutamatergic systems disorder caused by Isocarbophos poisoning. Administration of HupA have no effects of the neurotransmitter changes induces by acute poisoning of phoxim. It is different for the toxic effect mechanism of the two organophosphate.

[Chromosome damage of human bronchial epithelial cells induced by glycidyl methacrylate].

OBJECTIVE: To observed the chromosome damage of human bronchial epithelial cells induced by glycidyl methacrylate (GMA). METHODS: Chromosome aberration analysis of human bronchial epithelial cells treated with GMA at different dosages (4, 8, 12, 16 and 20 microg/ml), times (1, 2 and 3 times), and phases (10th, 30th genetation) was detected. RESULTS: In the dosages range from 4 to 20 microg/ml, the aberration rates (3%, 6%, 7%, 11% and 14%) were demonstrated increasingly with the increase of exposure doses, and dose-effect relationship was found. Significant differences were observed when treated with GMA three times (6%, 7% and 10%). Structure aberrations were found in the transformed 10th-generation cells, while number aberrations were mainly manifested in the transformed 30th-generation cells. CONCLUSION: The chromosome aberration can be induced by GMA in the human bronchial epithelial cells, from the structure aberration at the beginning to the lack of normal nuclear style.

[Changes of pathologic feature and microtubulin associated protein 2 in nervous system of hens with organophosphate-induced delayed neuropathy induced by 2,4,6-trimethylbenzoyl phenylphosphonate].

OBJECTIVE: To develop the organophosphate-induced delayed neuropathy (OPIDN) hen model with 2,4,6-trimethylbenzoyl phenylphosphonate (TOCP), and observe the change of pathology and investigate the alterations of microtubulin associated protein 2 (MAP2). METHODS: 48 adult hens were randomly divided into four groups, including three experimental groups and control group (n = 12 each group). The hens in three experimental groups were treated with TOCP by gavage at single dosages of 250, 500 and 750 mg/kg respectively while the control hens received an equivalent volume of corn oil by gavage. All hens were sacrificed after 21 days of treatment. Half hens in each group were dissected for HE examination and myelin straining of brain, spinal cord and sciatic nerve while brains of another half hens were dissected for the determination of MAP2 by western blotting. RESULTS: The delayed neurotoxicity symptoms of hens both in 500 and 750 mg/kg groups were consistently observed. The pathological changes of brain, spinal cord and sciatic nerve in 500 and 750 mg/kg groups showed nerve cells difference necrosis, increased cytoplasm basophilia, microglia proliferation, mono-nuclear and lymphocyte infiltration, myelin sheath extensive up to part of them disaggregation deletion. Compared with the control group, at 500 and 750 mg/kg respectively the increase of MAP2 was 25% and 23% (P < 0.01 and P < 0.05). CONCLUSIONS: The histopathologic changes of OPIDN caused by TOCP have dose-response relationship. The changes of MAP2 in nervous system may contribute to the occurrence and development of TOCP induced delayed neurotoxicity.

[Study on malignant transformation of human bronchial epithelial cells induced by glycidyl methacrylate].

OBJECTIVE: To study the malignant transformation of human bronchial epithelial cells induced by glycidyl methacrylate (GMA). METHODS: 16HBE cells were treated multiple times with GMA at concentrations of 1, 2, 4 and 8 microg/ml. Cellular biological characteristics of malignant transformation were identified by the tests of conA, colony forming frequency on soft agar, scanning electron microscope and tumorigenesis in nude mice. Test of immunocytochemical detection was also applied to confirm the derivation of cell and tumor. Groups of solvent control (DMSO) and positive control (MCA) were also performed at the same time. RESULTS: Transformed foci could be observed after the cells were treated by GMA at concentrations from 1 to 8 microg/ml. The number of transformation foci increased with the concentration of GMA. Transforming rate in 8 microg/ml group (8.48 x 10(-6)) was significantly higher (P < 0.01) than that of solvent control group (4.5 x 10(-7)). The transformed cells lost contact inhibition and exhibited a crossover growth in culture dish. They also could grow in semi-solid agar and showed dose-reaction relations with the concentration of GMA. The colony forming frequency in 2, 4 and 8 microg/ml group was 1.20 per thousand, 2.35 per thousand and 5.70 per thousand respectively, which were higher than that of solvent control group (P < 0.01). The transformed cells could be agglutinated by low concentration of conA. Microvilli on the surface of transformed cells increased and became strong and long under scanning electron microscope. The transformed cells could form subcutaneous tumor in nude mice which was diagnosed as squamous cell carcinoma in morphology. Expression of cytokeratin (CK) was detected in both 16HBE cells and tumor formed in nude mice. CONCLUSION: GMA could induce the malignant transformation of 16HBE cells. This research system might provide a potential tool and lay a foundation for the study of the molecular mechanism of carcinogenesis induced by GMA.

[Experimental study on protective effects of HupA in the treatment of isocarbophos poisoning].

OBJECTIVE: To investigate the therapeutic and prophylactic efficiency of HupA in mice with acute isocarbophos poisoning, and the protective effects of the HupA on AChE inhibited by isocarbophos. METHODS: Mice were randomizedly divided into the non-treatment group, the atropine control group, the HupA treatment group and the atropine and HupA combined treatment group. Toxic signs and survival rates were observed and compared among these groups. The AChE activity was monitored in the whole blood, the red cells and brain tissue exposed to isocarbophos in the either treated with HupA or non-treated groups. RESULTS: In HupA treatment group compared with the non-treatment group, toxic signs were significantly decreased and the survival rate was increased. The therapeutic efficiency in the atropine and HupA combined treatment group was better than other groups. After isocarbophos was administered, the AChE activity in the HupA treatment group and the non-treatment group was decreased. However, the AChE activity in the whole blood (1.096 +/- 0.111), (1.262 +/- 0.146), (1.181 +/- 0.353) U/ml, the red cells (0.798 +/- 0.063), (1.000 +/- 0.176), (0.837 +/- 0.331) and the brain tissue (13.739 +/- 2.970), (18.507 +/- 3.466), (10.764 +/- 2.212) U/g in HupA treatment group 0.5, 1 and 2 hours after isocarbophos was administered was significantly higher than those in the non-treatment group (P < 0.05 or P < 0.01). CONCLUSION: HupA has therapeutic effect on mice with acute isocarbophos poisoning. The protective effect of HupA on blood and brain AChE inhibited by isocarbophos may be one of the mechanisms of the therapeutic effect of HupA in acute Isocarbophos poisoning.

[Advances on study of organophosphate poisoning prevented by Huperzine A].

Currently, it is a concerned project in medicine to study the effective methods for treatment of organophosphate (OP) poisoning. Huperzine A is a potent, reversible red cells acetylcholinesterases (AChE) inhibitor, which shows high specificity for AChE preserving scavenger capacity of plasma butyrylcholinesterase (BuChE) for OP agents, and cross the blood-brain barrier smoothly preventing the AChE in CNS, so the CNS damages induced by the acute OP poisoning were prevented. These review summarizes the results of experimental in animals, prevention mechanism, and prevention value of HupA against OP poison.

[Analytical methods used in pharmacokinetics studies for biotechnology drugs].

In order to provide a reference for selecting analytical methods in pharmacokinetics studies for biotechnology drugs such as recombinant proteins, monoclonal antibodies or genetic engineering antibodies and oligonucleotide drugs, the following methods such as radiolabels, immunoassays, bioassays, chromatography and even the novel protein-chip technique are reviewed. Their mechanisms, application fields, and advantages and limitations are also summarized.

[The neuromuscular transmission effects induced by pralidoxine chloride on rats with acute isocarbophos poisoning].

OBJECTIVE: To study the effects of improving the neuromuscular transmission (NMT), "non-AChE-reactivating effects", by oximes in treating acute isocarbophos poisoning. METHODS: The effect of pralidoxime chloride(PAM-Cl) on the neuromuscular transmission(NMT) in rats exposed to isocarbophos was studied by using the stimulation single fiber electromyography (SSFEMG) to determine the single fiber action potential. RESULTS: After the rats exposed to isocarbophos were treated by PAM-Cl, the mean consecutive difference(MCD) value [(25.99 +/- 5.84) microsecond] of single fiber action potential was significantly lower than that before PAM-Cl treatment [(33.21 +/- 4.09) microsecond, (P < 0.01)], but no AChE reactivation in blood and gastrocnemius was observed. CONCLUSION: PAM-Cl has "non-AChE-reactivating effects", it could markedly improve isocarbophos-induced NMT block of gastrocnemius.