Causal effects of gut microbiota on sepsis and sepsis-related death: insights from genome-wide Mendelian randomization, single-cell RNA, bulk RNA sequencing, and network pharmacology.

BACKGROUND: Gut microbiota alterations have been implicated in sepsis and related infectious diseases, but the causal relationship and underlying mechanisms remain unclear. METHODS: We evaluated the association between gut microbiota composition and sepsis using two-sample Mendelian randomization (MR) analysis based on published genome-wide association study (GWAS) summary statistics. Sensitivity analyses were conducted to validate the robustness of the results. Reverse MR analysis and integration of GWAS and expression quantitative trait loci (eQTL) data were performed to identify potential genes and therapeutic targets. RESULTS: Our analysis identified 11 causal bacterial taxa associated with sepsis, with increased abundance of six taxa showing positive causal relationships. Ten taxa had causal effects on the 28-day survival outcome of septic patients, with increased abundance of six taxa showing positive associations. Sensitivity analyses confirmed the robustness of these associations. Reverse MR analysis did not provide evidence of reverse causality. Integration of GWAS and eQTL data revealed 76 genes passing the summary data-based Mendelian randomization (SMR) test. Differential expression of these genes was observed between sepsis patients and healthy individuals. These genes represent potential therapeutic targets for sepsis. Molecular docking analysis predicted potential drug-target interactions, further supporting their therapeutic potential. CONCLUSION: Our study provides insights for the development of personalized treatment strategies for sepsis and offers preliminary candidate targets and drugs for future drug development.

The effect of font boldness, noise disturbance and time pressure on human error in the context of cloud change operation.

This study investigated the number of operator errors, task completion time, and workload of subjects at different levels by imposing conditions such as focused text boldness, noise disturbance, and time pressure to simulate a realistic cloud change business process in the laboratory. Results of the study showed that the text bolding of important content reduced the number of errors, whereas noise interference increased the number of errors. Text boldness only reduced the number of corrected errors, and noise interference only increased the number of uncorrected errors. Moreover, bolding was found to have different effects on the number of errors under different noise levels and time pressure levels, with text boldness significantly reducing the number of total errors only in quiet or low time pressure states. Time pressure had no effect on cloud change task error counts, but high time pressure resulted in higher subjective workload.

Operator error is one of the main causes of service failure, and reducing operator error in cloud change operations is of practical importance. In this study, we found focused text boldness could reduce operator errors, while noise could increase the number of errors. High time pressure would lead to a high workload.

Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration.

Accumulation of lipid droplets (LDs) induces cardiac dysfunctions in type 2 diabetes patients. Recent studies have shown that hydrogen sulphide (H2 S) ameliorates cardiac functions in db/db mice, but its regulation on the formation of LDs in cardiac tissues is unclear. Db/db mice were injected with NaHS (40 µmol·kg-1 ) for twelve weeks. H9c2 cells were treated with high glucose (40 mmol/L), oleate (200 µmol/L), palmitate (200 µmol/L) and NaHS (100 µmol/L) for 48 hours. Plasmids for the overexpression of wild-type Hrd1 and Hrd1 mutated at Cys115 were constructed. The interaction between Hrd1 and DGAT1 and DGAT2, the ubiquitylation level of DGAT1 and 2, the S-sulfhydration of Hrd1 were measured. Exogenous H2 S ameliorated the cardiac functions, decreased ER stress and reduced the number of LDs in db/db mice. Exogenous H2 S could elevate the ubiquitination level of DGAT 1 and 2 and increased the expression of Hrd1 in cardiac tissues of db/db mice. The S-sulfhydration of Hrd1 by NaHS enhanced the interaction between Hrd1 and DGAT1 and 2 to inhibit the formation of LD. Our findings suggested that H2 S modified Hrd1 S-sulfhydration at Cys115 to reduce the accumulation of LDs in cardiac tissues of db/db mice.

Hydrogen sulphide ameliorating skeletal muscle atrophy in db/db mice via Muscle RING finger 1 S-sulfhydration.

Muscle atrophy occurs in many pathological states, including cancer, diabetes and sepsis, whose results primarily from accelerated protein degradation and activation of the ubiquitin-proteasome pathway. Expression of Muscle RING finger 1 (MuRF1), an E3 ubiquitin ligase, was increased to induce the loss of muscle mass in diabetic condition. However, hydrogen sulphide (H2 S) plays a crucial role in the variety of physiological functions, including antihypertension, antiproliferation and antioxidant. In this study, db/db mice and C2C12 myoblasts treated by high glucose and palmitate and oleate were chose as animal and cellular models. We explored how exogenous H2 S attenuated the degradation of skeletal muscle via the modification of MuRF1 S-sulfhydration in db/db mice. Our results show cystathionine-r-lyase expression, and H2 S level in skeletal muscle of db/db mice was reduced. Simultaneously, exogenous H2 S could alleviate ROS production and reverse expression of ER stress protein markers. Exogenous H2 S could decrease the ubiquitination level of MYOM1 and MYH4 in db/db mice. In addition, exogenous H2 S reduced the interaction between MuRF1 with MYOM1 and MYH4 via MuRF1 S-sulfhydration. Based on these results, we establish that H2 S prevented the degradation of skeletal muscle via MuRF1 S-sulfhydration at the site of Cys44 in db/db mice.

CircPOSTN/miR-361-5p/TPX2 axis regulates cell growth, apoptosis and aerobic glycolysis in glioma cells.

BACKGROUND: Glioma is the most primary central nervous system tumor in adults. The 5 year survival rate for glioma patients remains poor, although treatment strategies had improved in the past few decades. The cumulative studies have shown that circular RNA (circRNA) is associated with glioma process, so the purpose of this study is to clarify the function of circPOSTN in glioma. METHODS: The expression levels of circPOSTN, miR-361-5p, and targeting protein for Xenopus kinesin-like protein 2 (TPX2) were assessed with real-time quantitative polymerase chain reaction (RT-qPCR). The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) and flow cytometry assays were executed to examine proliferation and apoptosis of glioma cells, respectively. Western blot was applied to assess protein expression. The glucose metabolism of glioma cells was analyzed by testing the glucose consumption, lactate production, ATP level, reactive oxygen species (ROS) accumulation and performing Seahorse XF assay. The interaction relationship between miR-361-5p and circPOSTN or TPX2 was analyzed by bioinformatics database and dual-luciferase reporter assay. The influences of circPOSTN silencing in vivo were observed by a xenograft experiment. RESULTS: CircPOSTN was overexpressed in glioma tissues and cells. Absence of circPOSTN in glioma cells promoted apoptosis while impeded proliferation and aerobic glycolysis, which were mitigated by silencing miR-361-5p. What's more, loss-of-functional experiment suggested that knockdown of TPX2 repressed proliferation and aerobic glycolysis, while induced apoptosis in glioma cells. In addition, circPOSTN targetedly regulated TPX2 expression in glioma cells via sponging miR-361-5p. In vivo study revealed that deficiency of circPOSTN restrained tumor growth. CONCLUSION: Mechanistically, circPOSTN regulated cell growth, apoptosis, and aerobic glycolysis in glioma through miR-361-5p/TPX2 axis.

Exogenous H2S reduces the acetylation levels of mitochondrial respiratory enzymes via regulating the NAD+-SIRT3 pathway in cardiac tissues of db/db mice.

Hydrogen sulfide (H2S), a gaseous molecule, is involved in modulating multiple physiological functions, such as antioxidant, antihypertension, and the production of polysulfide cysteine. H2S may inhibit reactive oxygen species generation and ATP production through modulating respiratory chain enzyme activities; however, the mechanism of this effect remains unclear. In this study, db/db mice, neonatal rat cardiomyocytes, and H9c2 cells treated with high glucose, oleate, and palmitate were used as animal and cellular models of type 2 diabetes. The mitochondrial respiratory rate, respiratory chain complex activities, and ATP production were decreased in db/db mice compared with those in db/db mice treated with exogenous H2S. Liquid chromatography with tandem mass spectrometry analysis showed that the acetylation level of proteins involved in the mitochondrial respiratory chain were increased in the db/db mice hearts compared with those with sodium hydrosulfide (NaHS) treatment. Exogenous H2S restored the ratio of NAD+/NADH, enhanced the expression and activity of sirtuin 3 (SIRT3) and decreased mitochondrial acetylation level in cardiomyocytes under hyperglycemia and hyperlipidemia. As a result of SIRT3 activation, acetylation of the respiratory complexe enzymes NADH dehydrogenase 1 (ND1), ubiquinol cytochrome c reductase core protein 1, and ATP synthase mitochondrial F1 complex assembly factor 1 was reduced, which enhanced the activities of the mitochondrial respiratory chain activity and ATP production. We conclude that exogenous H2S plays a critical role in improving cardiac mitochondrial function in diabetes by upregulating SIRT3.

Canadian national survey of family medicine residents on point-of-care ultrasound training.

OBJECTIVE: To assess the quality of point-of-care ultrasound (POCUS) training in family medicine residency programs and to obtain the opinions of current family medicine residents on the role of ultrasound in primary care. DESIGN: A 23-question online survey conducted using SurveyMonkey between March 15 and June 30, 2017. SETTING: Canada. PARTICIPANTS: All family medicine residents of the 17 Canadian family medicine residency programs were included in the study but all enhanced skills residents were excluded. MAIN OUTCOME MEASURES: The quality and relevance of POCUS to primary care as perceived by residents and reported in the survey. RESULTS: A total of 854 Canadian family medicine residents responded, for a national response rate of 32.3%. Most respondents (94.3%) believe that POCUS training should be included in family medicine residency programs; however, only 18.4% of respondents currently receive formal training within their residency. Among those without POCUS training, 91.7% are interested in receiving formal training and 29.7% resorted to taking external POCUS courses. Most (77.5%) would consider using ultrasound in their future practice if they were competent in POCUS. The most useful applications for family medicine were considered to be the FAST (Focused Assessment with Sonography in Trauma) examination for free fluid and ascites (95.1%), procedural guidance (92.4%), and identifying an intrauterine pregnancy (88.6%). CONCLUSION: This is the largest survey identifying the perceived needs of family medicine residents for POCUS. Very few Canadian family medicine residents currently receive POCUS training. Consistent with our recent family medicine program director survey, there is overwhelming interest by family medicine residents to begin incorporating POCUS training into the family medicine curriculum.

Canadian national survey of point-of-care ultrasound training in family medicine residency programs.

OBJECTIVE: To assess the current state of point-of-care ultrasound (POCUS) training in Canadian family medicine residency programs. DESIGN: Cross-sectional survey to evaluate POCUS education in accredited Canadian family medicine residency programs; only 1 completed survey was accepted per residency program. SETTING: Seventeen accredited Canadian family medicine residency programs. PARTICIPANTS: Fourteen directors of family medicine programs across Canada. MAIN OUTCOME MEASURES: Opinions of program directors in family medicine education on the relevance of POCUS in family medicine, and the role of POCUS training in family medicine residency programs. RESULTS: The Web-based, anonymous survey, which was completed during the months of March and April 2016, achieved a response rate of 82% (14 out of 17 program directors). About one-fifth (21%) of program directors reported having an established ultrasound curriculum. Almost all directors (93%) believed that POCUS teaching should be integrated into family medicine residency curricula. Barriers to establishing training included the following: lack of adequate equipment (57%), lack of instructors (57%), lack of available time in the curriculum (57%), and lack of funding available to support training (71%). Seventy-one percent of respondents believed that POCUS could be used in outpatient family medicine clinics to alter clinical decision making. Some potential benefits associated with POCUS in primary care include more rapid diagnosis, improved patient outcomes, and potential to reduce health care costs. CONCLUSION: Although only a few Canadian family medicine residency program directors reported actually having an established ultrasound curriculum, most of them believed that POCUS training should be offered to family medicine residents and that its use could positively affect primary care. A growing number of family medicine residency programs are considering incorporating ultrasound training into their curricula, but resource availability remains a considerable barrier to implementation.

Postoperative Analgesia after Laparoscopic Ovarian Cyst Resection: Double-blind Multicenter Randomized Control Trial Comparing Intraperitoneal Nebulization and Peritoneal Instillation of Ropivacaine.

STUDY OBJECTIVE: To compare the effects of local anesthetic intraperitoneal nebulization with intraperitoneal instillation during laparoscopic ovarian cystectomy on postoperative morphine consumption and pain. DESIGN: Multicenter, randomized, case-control trial. DESIGN CLASSIFICATION: Canadian Task Force Classification I. SETTING: University hospitals in Italy. PATIENTS: One hundred forty patients scheduled for laparoscopic ovarian cystectomy. INTERVENTIONS: Patients were randomized to receive either nebulization of ropivacaine 150 mg before surgery or instillation of ropivacaine 150 mg before surgery. Nebulization was performed using the Aeroneb Pro device (Aerogen, Galway, Ireland). MEASUREMENTS AND MAIN RESULTS: One hundred forty patients were enrolled, and 123 completed the study. There was no difference between the 2 groups in average morphine consumption (7.3 ± 7.5 mg in the nebulization group vs 9.2 ± 7.2 mg in the instillation group; p = .17). Eighty-two percent of patients in the nebulization group required morphine compared with 96% in the instillation group (p < .05). Patients receiving nebulization had a lower dynamic Numeric Ranking Scale compared with those in the instillation group in the postanesthesia care unit postanesthesia care unit and 4 hours after surgery (p < .05). Ten patients (15%) in the nebulization group experienced shivering in the postanesthesia care unit compared with 2 patients (4%) in the instillation group (p = .035). CONCLUSION: Nebulization of ropivacaine prevents the use of morphine in a significant proportion of patients, reduced postoperative pain during the first hours after surgery, and was associated with a higher incidence of postoperative shivering when compared with instillation.

Does near-infrared spectroscopy identify asphyxiated newborns at risk of developing brain injury during hypothermia treatment?

OBJECTIVE: The aim of this article is to assess whether near-infrared spectroscopy (NIRS) identifies, during hypothermia treatment, the asphyxiated newborns who later develop brain injury. STUDY DESIGN: In this study, asphyxiated newborns, for whom later brain injury was defined by brain imaging and/or autopsy results, were monitored by NIRS during therapeutic hypothermia. We compared regional cerebral oxygenation saturation (rSO2) measured by NIRS at key time points for newborns who developed or did not develop later brain injury. RESULTS: A total of 18 asphyxiated newborns treated with hypothermia were enrolled. rSO2 was higher in the asphyxiated newborns who developed later brain injury. Sensitivity within the first 10 hours of hypothermia treatment for an adverse outcome was 100% (95% confidence interval [CI], 70-100%) and specificity was 83% (95% CI, 36-99%). CONCLUSIONS: NIRS appears to identify asphyxiated newborns at risk of developing brain injury as early as the first 10 hours of hypothermia treatment. Thus, NIRS may have an important role as an early outcome predictor in this population.

Unraveling the genetic and molecular landscape of sepsis and acute kidney injury: A comprehensive GWAS and machine learning approach.

OBJECTIVES: This study aimed to explore the underlying mechanisms of sepsis and acute kidney injury (AKI), including sepsis-associated AKI (SA-AKI), a frequent complication in critically ill sepsis patients. METHODS: GWAS data was analyzed for genetic association between AKI and sepsis. Then, we systematically applied three distinct machine learning algorithms (LASSO, SVM-RFE, RF) to rigorously identify and validate signature genes of SA-AKI, assessing their diagnostic and prognostic value through ROC curves and survival analysis. The study also examined the functional and immunological aspects of these genes, potential drug targets, and ceRNA networks. A mouse model of sepsis was created to test the reliability of these signature genes. RESULTS: LDSC confirmed a positive genetic correlation between AKI and sepsis, although no significant shared loci were found. Bidirectional MR analysis indicated mutual increased risks of AKI and sepsis. Then, 311 key genes common to sepsis and AKI were identified, with 42 significantly linked to sepsis prognosis. Six genes, selected through LASSO, SVM-RFE, and RF algorithms, showed excellent predictive performance for sepsis, AKI, and SA-AKI. The models demonstrated near-perfect AUCs in both training and testing datasets, and a perfect AUC in a sepsis mouse model. Significant differences in immune cells, immune-related pathways, HLA, and checkpoint genes were found between high- and low-risk groups. The study identified 62 potential drug treatments for sepsis and AKI and constructed a ceRNA network. CONCLUSIONS: The identified signature genes hold potential clinical applications, including prognostic evaluation and targeted therapeutic strategies for sepsis and AKI. However, further research is needed to confirm these findings.

Pan-cancer analysis revealed prognosis value and immunological relevance of RAMPs.

Whether receptor activity-modifying proteins (RAMPs) play a key role in human cancer prognosis and immunity remains unknown. We used data from the public databases, The Cancer Genome Atlas, Therapeutically Applicable Research to Generate Effective Treatments, and the Genotype-Tissue Expression project. We utilized bioinformatics methods, R software, and a variety of online databases to analyze RAMPs. In general, RAMPs were significantly and differentially expressed in multiple tumors, and RAMP expression was closely associated with prognosis, immune checkpoints, RNA-editing genes, tumor mutational burden, microsatellite instability, ploidy, and stemness indices. In addition, the expression of RAMPs is strongly correlated with tumor-infiltrating lymphocytes in human cancers. Moreover, the RAMP co-expression network is largely involved in many immune-related biological processes. Quantitative reverse transcription polymerase chain reaction and Western blot proved that RAMP3 was highly expressed in glioma, and RAMP3 promoted tumor proliferation and migration. RAMPs exhibit potential as prognostic and immune-related biomarkers in human cancers. Moreover, RAMPs can be potentially developed as therapeutic targets or used to enhance the efficacy of immunotherapy.

Classification of high-grade glioblastoma and single brain metastases using a new SCAT-inception model trained with MRI images.

Background and objectives: Glioblastoma (GBM) and brain metastasis (MET) are the two most common intracranial tumors. However, the different pathogenesis of the two tumors leads to completely different treatment options. In terms of magnetic resonance imaging (MRI), GBM and MET are extremely similar, which makes differentiation by imaging extremely challenging. Therefore, this study explores an improved deep learning algorithm to assist in the differentiation of GBM and MET. Materials and methods: For this study, axial contrast-enhanced T1 weight (ceT1W) MRI images from 321 cases of high-grade gliomas and solitary brain metastasis were collected. Among these, 251 out of 270 cases were selected for the experimental dataset (127 glioblastomas and 124 metastases), 207 cases were chosen as the training dataset, and 44 cases as the testing dataset. We designed a new deep learning algorithm called SCAT-inception (Spatial Convolutional Attention inception) and used five-fold cross-validation to verify the results. Results: By employing the newly designed SCAT-inception model to predict glioblastomas and brain metastasis, the prediction accuracy reached 92.3%, and the sensitivity and specificity reached 93.5 and 91.1%, respectively. On the external testing dataset, our model achieved an accuracy of 91.5%, which surpasses other model performances such as VGG, UNet, and GoogLeNet. Conclusion: This study demonstrated that the SCAT-inception architecture could extract more subtle features from ceT1W images, provide state-of-the-art performance in the differentiation of GBM and MET, and surpass most existing approaches.

Psychometric properties of the Chinese version of Sport Anxiety Scale-2.

Introduction: The Sport Anxiety Scale-2 (SAS-2) is a validated measure of sports trait anxiety, with promising psychometric properties. However, its cross-cultural applicability in Chinese samples remains unexplored. Thus, the primary objectives of this study were twofold: to translate the SAS-2 into Chinese and assess the psychometric properties of the Chinese version. Methods: In Study 1, we initiated the translation of the SAS-2 into Chinese. This assessment involved bilingual Chinese students proficient in both English and Chinese. Additionally, we conducted a cross-linguistic measurement invariance analysis. In Study 2, we delved into the psychometric properties of the Chinese SAS-2 using a sample of Chinese student athletes. This examination encompassed an evaluation of its factor structure, convergent and discriminant validity, and measurement invariance across genders. Results: Our findings in Study 1 indicated no significant differences in item scores between the Chinese SAS-2 and the English version, and measurement invariance across languages. In Study 2, we uncovered that the Chinese SAS-2 and its factors exhibited excellent reliability, with Cronbach's alpha values exceeding 0.80. Confirmatory factor analyses upheld the original three-factor model, demonstrating acceptable model fit indices (CFI = 0.96, TLI = 0.93, RMSEA = 0.08). Furthermore, all three factors of the Chinese SAS-2 displayed significant and positive correlations with athlete burnout and State-Trait anxiety. Additionally, this study elucidated the mediating role of Concentration Disruption (Somatic anxiety and Concentration Disruption) in the relationship between the Trait (State) anxiety, and athlete burnout. Moreover, we identified measurement invariance of the Chinese version of the SAS-2 across genders. Finally, female college athletes exhibited significantly higher scores in somatic anxiety and worry compared to their male counterparts. Discussion: In sum, our findings affirm that the Chinese version of the SAS-2 demonstrates robust reliability and correlates effectively with related criteria, thus validating its suitability for use in a Chinese context.

Multiomics integration reveals the effect of Orexin A on glioblastoma.

Objectives: This study involved a multi-omics analysis of glioblastoma (GBM) samples to elaborate the potential mechanism of drug treatment. Methods: The GBM cells treated with or without orexin A were acquired from sequencing analysis. Differentially expressed genes/proteins/metabolites (DEGs/ DEPs/ DEMs) were screened. Next, combination analyses were conducted to investigate the common pathways and correlations between the two groups. Lastly, transcriptome-proteome-metabolome association analysis was carried out to determine the common pathways, and the genes in these pathways were analyzed through Kaplan-Meier (K-M) survival analysis in public databases. Cell and animal experiments were performed to investigate the anti-glioma activity of orexin A. Results: A total of 1,527 DEGs, 52 DEPs, and 153 DEMs were found. Moreover, the combination analyses revealed that 6, 4, and 1 common pathways were present in the transcriptome-proteome, proteome-metabolome, and transcriptome-metabolome, respectively. Certain correlations were observed between the two data sets. Finally, 11 common pathways were discovered in association analysis, and 138 common genes were screened out in these common pathways. Six genes showed significant differences in terms of survival in both TCGA and CGGA. In addition, orexin A inhibited the proliferation, migration, and invasion of glioma in vitro and in vivo. Conclusion: Eleven common KEGG pathways with six common genes were found among different omics participations, revealing the underlying mechanisms in different omics and providing theoretical basis and reference for multi-omics research on drug treatment.

Hydrogen sulfide regulates SERCA2a SUMOylation by S-Sulfhydration of SENP1 to ameliorate cardiac systole-diastole function in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus that eventually progresses to heart failure. The sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA2a), an important calcium pump in cardiomyocytes, is closely related to myocardial systolic-diastolic function. In mammalian cells, hydrogen sulfide (H2S), as a second messenger, antioxidant, and sulfurizing agent, is involved in diverse biological processes. Despite the importance of H2S for protection against DCM, the mechanisms remain poorly understood. The aim of the present study was to determine whether H2S regulates intracellular calcium homeostasis by acting on SERCA2a to reduce cardiomyocyte apoptosis during DCM. Db/db mice were injected with NaHS for 18 weeks. Neonatal rat cardiomyocytes (NRCMs) were treated with high glucose, palmitate, oleate, and NaHS for 48 h. Compared to the NaHS-treated groups, in vivo and in vitro type 2 diabetic models both showed reduced intracellular H2S content, reduced cystathionine γ-lyase (CSE) expression, impaired cardiac function, decreased SERCA2a expression and decreased SERCA2a activity, reduced SUMOylation of SERCA2a, increased sentrin-specific protease 1 (SENP1) expression, and disruption of calcium homeostasis leading to activation of the mitochondrial apoptosis pathway. Compared to the NaHS-treated type 2 diabetes cellular model, overexpression of SENP1 C683A reduced the S-sulfhydration of SENP1, reduced the SUMOylation of SERCA2a, reduced the increased expression and activity of SERCA2a, and induced mitochondrial apoptosis in cardiomyocytes. These results suggested that exogenous H2S elevates SENP1 S-sulfhydration to increase SERCA2a SUMOylation, improve myocardial systolic-diastolic function, and decrease cardiomyocyte apoptosis in DCM.

Borane-catalyzed cascade Friedel-Crafts alkylation/[1,5]-hydride transfer/Mannich cyclization to afford tetrahydroquinolines.

An unprecedented redox-neutral annulation reaction of tertiary anilines with electron-deficient alkynes was developed that proceeds through a cascade Friedel-Crafts alkylation/[1,5]-hydride transfer/Mannich cyclization sequence. Under B(C6F5)3 catalysis, a range of functionalized 1,2,3,4-tetrahydroquinolines were facilely constructed in moderate to good yields with exclusive 3,4-anti-stereochemistry. The commercial availability of the catalyst and the high atom and step economy of the procedure, together with metal-free and external oxidant-free conditions, make this an attractive method in organic synthesis.

Relationship between Severity of Disease and Postoperative Neurological Recovery in Patients with Cervical Spondylotic Myelopathy Combined with Developmental Spinal Stenosis.

Objective: The study aimed to investigate the correlation between the severity of disease and postoperative neurological recovery in patients with cervical spondylotic myelopathy (CSM) combined with developmental spinal stenosis. Methods: A retrospective analysis of the clinical data of 114 CSM patients combined with developmental spinal stenosis admitted to our hospital from June 2019 to June 2020 was performed. All of the patients who underwent posterior cervical unidoor vertebroplasty were divided into the mild, moderate, and severe groups according to the Torg-Pavlov ratio. The clinical data including patients' age, course of spinal cord high signal change, and first onset age were collected. The recovery time, preoperative, and postoperative Japanese Orthopaedic Association (JOA) scores of patients in each group were compared with the calculation of the improvement rate. The correlation between the severity of disease and postoperative neurological recovery in CSM patients combined with developmental spinal stenosis was analyzed by Pearson correlation. The factors influencing postoperative neurological recovery were analyzed using multivariate logistic regression analysis. The receiver operating characteristic curve (AUC) was used to evaluate the value of each influencing factor in predicting postoperative recovery. Results: Significant differences were observed in the proportion of linear hyperintensity changes in the spinal cord, the age of first onset, the course of the disease, and the Torg-Pavlov ratio among the mild, moderate, and severe groups (P < 0.05). The postoperative recovery time of the moderate and severe groups was significantly higher than that of the mild group, while the preoperative JOA score was significantly lower than that of the mild group. On the other hand, the postoperative recovery time of the severe group was prominently higher than that of the moderate group, whereas the preoperative JOA score was observably lower than that of the moderate group (P < 0.05). Pearson correlation analysis showed that the postoperative recovery time was significantly negatively correlated with the Torg-Pavlov ratio, age at first onset, and disease course (r = -0.359, -0.502, -0.368, P < 0.05), while it was positively correlated with spinal cord linear high-signal changes (r = 0.641, P < 0.05). Multifactorial logistic regression analysis revealed that the Torg-Pavlov ratio, age at first onset, and disease course were protective factors, while spinal cord linear high-signal alterations were risk factors affecting the recovery time of postoperative neurological function (P < 0.05). The area under the curve (AUC) of the Torg-Pavlov ratio, linear hyperintensity changes in the spinal cord, age at first onset, and disease duration in predicting the postoperative neurological recovery time were 0.794, 0.767, 0.772, and 0.802, respectively. The AUC predicted by the combined detection of each factor was 0.876, which was better than the area under the curve of single prediction. Conclusion: Patients with CSM combined with developmental spinal stenosis were characterized by younger age of onset, a short course of the disease, and linear changes in the spinal cord high signal. The degree of developmental spinal stenosis may affect the postoperative recovery time of neurological function in CSM patients but had little effect on postoperative neurological recovery. The Torg-Pavlov ratio, age of first onset, course of the disease, and changes in the spinal cord linear hyperintensity were the factors that affected postoperative neurological recovery, which may provide a basis for reasonably predicting a postoperative neurological recovery in patients with CSM combined with developmental spinal stenosis.

The anti-fatigue effect of the Auxis thazard oligopeptide via modulation of the AMPK/PGC-1α pathway in mice.

The Auxis thazard oligopeptide (ATO) was obtained by papain digestion and ultrafiltration membrane separation, and its anti-fatigue effects and mechanisms were evaluated using animal experiments on Kunming mice. Compared with the negative control group, the ATO extended the time to exhaustion in mice in a forced swim test by 0.81-1.62 times. Liver glycogen levels were significantly increased by 0.6-1.63 times and muscle glycogen levels were increased by 9.52-10.02%; the levels of lactic acid (16.46-17.21%) and urea nitrogen (34.88-41.91%) decreased. The ATO also increased antioxidant activity, reduced malondialdehyde levels (18.00-35.79%) in the liver and myocardium, and increased the gene and protein expression of AMPK and PGC-1α in fatigued mice. These results indicate that the ATO exerts an anti-fatigue effect via improving energy metabolism and decreasing oxidative stress.

Hydrogen Sulfide Regulates SERCA2a Ubiquitylation via Muscle RING Finger-1 S-Sulfhydration to Affect Cardiac Contractility in db/db Mice.

Hydrogen sulfide (H2S), as a gasotransmitter, is involved in various pathophysiological processes. Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus (DM), which leads to structural and functional abnormalities of the myocardium and eventually causes heart failure (HF). Systolic and diastolic dysfunction are fundamental features of heart failure. SERCA2a, as a key enzyme for calcium transport in the endoplasmic reticulum (ER), affects the process of myocardial relaxation and contraction. H2S can protect the cardiac function against diabetic hearts, however, its mechanisms are unclear. This study found that exogenous H2S affects cellular calcium transport by regulating the H2S/MuRF1/SERCA2a/cardiac contractile pathway. Our results showed that, compared with the db/db mice, exogenous H2S restored the protein expression levels of CSE and SERCA2a, and the activity of SERCA2a, while reducing cytosolic calcium concentrations and MuRF1 expression. We demonstrated that MuRF1 could interact with SERCA2a via co-immunoprecipitation. Using LC-MS/MS protein ubiquitylation analysis, we identified 147 proteins with increased ubiquitination levels, including SERCA2a, in the cardiac tissues of the db/db mice compared with NaHS-treated db/db mice. Our studies further revealed that NaHS administration modified MuRF1 S-sulfhydration and enhanced the activity and expression of SERCA2a. Under hyperglycemia and hyperlipidemia, overexpression of the MuRF1-Cys44 mutant plasmid reduced the S-sulfhydration level of MuRF1 and decreased the ubiquitination level of SERCA2a and the intracellular Ca2+ concentration. These findings suggested that H2S modulates SERCA2a ubiquitination through MuRF1 S-sulfhydration of Cys44 to prevent decreased myocardial contractility due to increased cytosolic calcium.