Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront against S. aureus.

Limitations in the clinical treatment of Staphylococcus aureus (S. aureus) infections have arisen due to the advent of antibiotic-resistant strains. Given the immense potential of therapeutic strategies targeting bacterial virulence, the role of MgrA as a pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets-becomes indispensable. In this investigation, leveraging advanced virtual screening and fluorescence anisotropy assays, we discerned methylophiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the MgrA-DNA interaction nexus. Subsequent analysis revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the deleterious effects inflicted by S. aureus USA300 on A549 cells. Furthermore, our data indicate that Mo-A downregulates the transcription of genes associated with immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemotaxis. Upon application in an in vivo setting, Mo-A assumes a protective persona in a murine model of S. aureus USA300-induced pneumonia and demonstrates efficacy in the Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was synergistically enhanced when used in combination with vancomycin. Our findings add substantive weight to the expanding field of virulence-targeted therapeutic strategies and set the stage for more comprehensive exploration of Mo-A potential in combating antibiotic-resistant S. aureus.

Sleep at high altitude: A bibliometric study and visualization analysis from 1992 to 2022.

Background: As an important monitoring index for adaptation to hypoxia, sleep may reflect the adaptive state of the body at high altitudes. The literature has shown a link between altitude and sleep problems, and sleep changes have become a common problem for individuals at high altitudes, negatively impacting their physical and mental health. As research on high-altitude sleep has gained attention in recent years, the publishing volume has increased worldwide, necessitating a more comprehensive understanding of this field. This manuscript evaluates the key themes and emerging trends in high-altitude sleep over the past few decades and predicts future research directions. Methods: Articles related to high-altitude sleep published from 1992 to 2022 were retrieved from the Web of Science Core Collection, and the relevant literature characteristics were extracted after the screening. Then, bibliometric analyses and visualizations were performed using Microsoft Excel, CiteSpace, VOSviewer, and an online analysis platform (http://bibliometric.com). Results: A total of 1151 articles were retrieved, of which 368 were included in the analysis, indicating a gradually increasing trend. The United States, Switzerland, and China have made significant contributions in this field. Bloch KE from the University of Zurich was determined to be the most productive and academically influential author in this field. The highest-yielding journal was High Altitude Medicine & Biology. Initially, altitude training was the primary research topic. Currently, research focuses on sleep disorders and sleep apnea. In the coming years, keywords such as "sleep quality," "prevalence," and "obstructive sleep apnea" will attract more attention. Conclusion: Our findings will assist scholars to better understand the intellectual structure and emerging trends in this field. Future developments in high-altitude sleep research are highly anticipated, particularly in terms of sleep quality at high altitudes and its associated prevalence. This research is also crucial for the improvement and treatment of symptoms during nocturnal sleep in patients with chronic hypoxia due to cardiopulmonary diseases at high altitudes.

A distinction between Fritillaria Cirrhosa Bulbus and Fritillaria Pallidiflora Bulbus via LC-MS/MS in conjunction with principal component analysis and hierarchical cluster analysis.

Fritillaria Cirrhosa Bulbus (known as chuanbeimu in Chinese, FCB) is one of the most used Chinese medicines for lung disease. However, a variety of substitutes have entered the market, with Fritillaria Pallidiflora Bulbus (FPB) being the most common. Due to their similarity in appearance, morphology, and chemical composition but a large price difference, the FCB has frequently been adulterated with the FPB, posing a serious challenge to the distinction and quality of the FCB. Therefore, we aimed to distinguish FCB and FPB based on their main nine isosteroidal alkaloid contents and test the potential of chemometrics as a discrimination approach for evaluating quality. The nine major isosteroidal alkaloids were measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach in 41 batches of FCB and 17 batches of FPB. Additionally, they were categorized and distinguished using the methods of hierarchical cluster analysis (HCA) and principal component analysis (PCA). Quantitative analysis revealed that the nine alkaloids were present in different amounts in the two types of Fritillariae bulbus. In FCB, the highest amount was peimisine (17.92-123.53 µg/g) and the lowest was delavine (0.42-29.18 µg/g), while in FPB, imperialine was higher (78.05-344.09 µg/g), but verticinone and verticine were less than the other seven alkaloids. The FCB and FPB were successfully classified and distinguished by the HCA and PCA. Taken together, the method has a good linear relationship (R2 > 0.9975). The LOD and LOQ of the nine alkaloids were in the range of 0.0651-0.6510 and 0.1953-1.9531 ng/mL, respectively. The intra- and inter-day precision were shown to be excellent, with relative standard deviations (RSDs) below 1.63% and 2.39%, respectively. The LC-MS/MS method in conjunction with HCA and PCA can effectively differentiate FCB and FPB. It may be a promising strategy for quality evaluation and control at the FCB.

Hibifolin, a Natural Sortase A Inhibitor, Attenuates the Pathogenicity of Staphylococcus aureus and Enhances the Antibacterial Activity of Cefotaxime.

This study aimed to identify hibifolin as a sortase A (SrtA) inhibitor and to determine whether it could attenuate the virulence of methicillin-resistant Staphylococcus aureus (MRSA). We employed a fluorescence resonance energy transfer (FRET) assay to screen a library of natural molecules to identify compounds that inhibit SrtA activity. Fluorescence quenching assay and molecular docking were performed to verify the direct binding interaction between SrtA and hibifolin. The pneumonia model was established using C57BL/6J mice by MRAS nasal administration for evaluating the effect of hibifolin on the pathogenicity of MRSA. Herein, we found that hibifolin was able to inhibit SrtA activity with an IC50 of 31.20 µg/mL. Further assays showed that the capacity of adhesion of bacteria to the host cells and biofilm formation was decreased in hibifolin-treated USA300. Results obtained from fluorescence quenching assay and molecular docking indicated that hibifolin was capable of targeting SrtA protein directly. This interaction was further confirmed by the finding that the inhibition activities of hibifolin on mutant SrtA were substantially reduced after mutating the binding sites (TRP-194, ALA-104, THR-180, ARG-197, ASN-114). The in vivo study showed that hibifolin in combination with cefotaxime protected mice from USA300 infection-induced pneumonia, which was more potent than cefotaxime alone, and no significant cytotoxicity of hibifolin was observed. Taken together, we identified that hibifolin attenuated the pathogenicity of S. aureus by directly targeting SrtA, which may be utilized in the future as adjuvant therapy for S. aureus infections. IMPORTANCE We identified hibifolin as a sortase A (SrtA) inhibitor by screening the natural compounds library, which effectively inhibited the activity of SrtA with an IC50 value of 31.20 µg/mL. Hibifolin attenuated the pathogenic behavior of Staphylococcus aureus, including adhesion, invasion, and biofilm formation. Binding assays showed that hibifolin bound to SrtA protein directly. Hibifolin improved the survival of pneumonia induced by S. aureus USA300 in mice and alleviated the pathological damage. Moreover, hibifolin showed a synergistic antibacterial effect with cefotaxime in USA300-infected mice.

Complement C3 Aggravates Post-epileptic Neuronal Injury Via Activation of TRPV1 / 神经科学通报·英文版

Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures. Recent studies have shown that complement component 3 (C3) aggravate the neuronal injury in epilepsy. And our previous studies revealed that TRPV1 (transient receptor potential vanilloid type 1) is involved in epilepsy. Whether complement C3 regulation of neuronal injury is related to the activation of TRPV1 during epilepsy is not fully understood. We found that in a mouse model of status epilepticus (SE), complement C3 derived from astrocytes was increased and aggravated neuronal injury, and that TRPV1-knockout rescued neurons from the injury induced by complement C3. Circular RNAs are abundant in the brain, and the reduction of circRad52 caused by complement C3 promoted the expression of TRPV1 and exacerbated neuronal injury. Mechanistically, disorders of neuron-glia interaction mediated by the C3-TRPV1 signaling pathway may be important for the induction of neuronal injury. This study provides support for the hypothesis that the C3-TRPV1 pathway is involved in the prevention and treatment of neuronal injury and cognitive disorders.

Complement C3 Aggravates Post-epileptic Neuronal Injury Via Activation of TRPV1 / 神经科学通报·英文版

Epilepsy is a brain condition characterized by the recurrence of unprovoked seizures. Recent studies have shown that complement component 3 (C3) aggravate the neuronal injury in epilepsy. And our previous studies revealed that TRPV1 (transient receptor potential vanilloid type 1) is involved in epilepsy. Whether complement C3 regulation of neuronal injury is related to the activation of TRPV1 during epilepsy is not fully understood. We found that in a mouse model of status epilepticus (SE), complement C3 derived from astrocytes was increased and aggravated neuronal injury, and that TRPV1-knockout rescued neurons from the injury induced by complement C3. Circular RNAs are abundant in the brain, and the reduction of circRad52 caused by complement C3 promoted the expression of TRPV1 and exacerbated neuronal injury. Mechanistically, disorders of neuron–glia interaction mediated by the C3–TRPV1 signaling pathway may be important for the induction of neuronal injury. This study provides support for the hypothesis that the C3–TRPV1 pathway is involved in the prevention and treatment of neuronal injury and cognitive disorders.

Application effect of MOOC in Physiology teaching / 中华医学教育探索杂志

Objective:To explore the effect of MOOC in Tibetan medical physiology teaching.Methods:According to the different implementation of teaching mode, 65 clinical undergraduate students of Batch 2017 in Medical College of Tibet University were randomly divided into MOOC teaching group (22 students), MOOC PBL teaching group (21 students) and traditional teaching group (22 students). The test scores and teaching evaluation scores of the three groups were compared, and the teaching evaluation scores of MOOC team among the three teaching modes were compared. SPSS 25.0 was used for statistical analysis, and One-Way ANOVA was used to compare the three groups of data.Results:The scores of the main questions and the total scores of the classroom test from high to low were: MOOC PBL teaching group, MOOC teaching group and traditional teaching control group. Except for multiple-choice questions and fill-in-the-blank questions, the scores of other questions and total scores were all statistically significantly different ( P<0.05). The scores of students on interest in learning, learning initiative, knowledge memory, classroom situation, learning efficiency and the total score of teaching evaluation ranked from high to low were: MOOC PBL teaching group, MOOC teaching group and traditional teaching group ( P<0.05). In contrast, the scores of students on teaching interaction and classroom management in traditional teaching group were higher than those in MOOC PBL teaching group and MOOC teaching group ( P<0.05). The scores of MOOC teaching team on saving time, saving materials, teaching efficiency, learning goal achievement, students' acceptance, improving learning interest, learning initiative and total score of teaching effect from high to low were: MOOC PBL teaching group, MOOC teaching group and traditional teaching group ( P<0.05). Conclusion:The application of MOOC can improve the teaching effect and quality of the physiology teaching for medical students in Tibet.

Effects of internet-based quiz on the teaching of Pathophysiology / 中华医学教育探索杂志

Objective To explore the effects of internet-based quiz on pathophysiological teaching.Methods undergraduates from two different classes (41 of batch 2107 from nursing and 49 of batch 2016 from pharmacy) taught by the same teacher were enrolled in the study and randomized into quiz group and control group to compare their teaching effect.Indexes evaluated were scores of midterm exam and final exam,students' teaching evaluation scores and teachers' self-evaluation scores.T test for data analysis was performed by SPSS 20.0.Results the scores of each general question and the total scores of midterm examin the quiz group were higher than those in the control group,with statistically significant differences (P＜0.005),except for the scores of short-answer and discussion questions.The scores of each general question and the total scores of final exams in the quiz group were higher than those in the control group,with statistically significant differences (P＜0.005).Scores of knowledge memory,learning efficiency,learning interest,learning activeness and students' evaluation for the same teacher in the quiz group were significantly higher than those in the control group.There were no significant differences between two groups in the scores of classroom management,teacher's professional ethics,teaching democracy,homework,teaching capacity and teaching interaction.When using these two teaching methods,the scores of teachers for comprehending students' study,motivating students to study,saving working time,saving resources and teachers' self-evaluation in the quiz group were higher than those in the control group,with statistically significant differences (P＜0.05).There were no statistical differences between two groups in the scores of classroom management,teacher's professional ethics,teaching democracy,homework,teaching capacity and teaching interaction.Conclusion Internet-based quiz is an effective way to improve students' study,so as to improve the teaching quality.

Effects of internet-based quiz on the teaching of Pathophysiology / 中华医学教育探索杂志

Objective@#To explore the effects of internet-based quiz on pathophysiological teaching.@*Methods@#undergraduates from two different classes (41 of batch 2107 from nursing and 49 of batch 2016 from pharmacy) taught by the same teacher were enrolled in the study and randomized into quiz group and control group to compare their teaching effect. Indexes evaluated were scores of midterm exam and final exam, students' teaching evaluation scores and teachers' self-evaluation scores. T test for data analysis was performed by SPSS 20.0.@*Results@#the scores of each general question and the total scores of midterm exam in the quiz group were higher than those in the control group, with statistically significant differences (P<0.005), except for the scores of short-answer and discussion questions. The scores of each general question and the total scores of final exams in the quiz group were higher than those in the control group, with statistically significant differences (P<0.005). Scores of knowledge memory, learning efficiency, learning interest, learning activeness and students' evaluation for the same teacher in the quiz group were significantly higher than those in the control group. There were no significant differences between two groups in the scores of classroom management, teacher's professional ethics, teaching democracy, homework, teaching capacity and teaching interaction. When using these two teaching methods, the scores of teachers for comprehending students' study, motivating students to study, saving working time, saving resources and teachers' self-evaluation in the quiz group were higher than those in the control group, with statistically significant differences (P<0.05). There were no statistical differences between two groups in the scores of classroom management, teacher's professional ethics, teaching democracy, homework, teaching capacity and teaching interaction.@*Conclusion@#Internet-based quiz is an effective way to improve students' study, so as to improve the teaching quality.

HIF2A Variants Were Associated with Different Levels of High-Altitude Hypoxia among Native Tibetans.

Hypoxia inducible factors, including HIF1A and HIF2A, play central roles in response to high-altitude hypoxia and genetic variants of HIF1A or HIF2A were associated with high-altitude sickness or adaptation. However, it remains to determine whether they are associated with tolerance to different levels of high-altitude selection pressure among native Tibetans. We recruited 189 Tibetan subjects living at 2,700 meters (Low level of high altitude, LHA), 197 at 3,200 meters (Middle level of high altitude of high altitude, MHA), 249 at 3,700 meters (High level of high altitude, HHA) and 269 at 4,700 meters (Very high level of high altitude, VHA) and performed association analysis of twelve tSNPs (tagging SNPs) in HIF1A and HIF2A with high-altitude. We found (1) a increasing trend of HIF2A rs5621780-C(18.4%, 15.9%, 32.8% and 31.1%, respectively, in LHA, MHA, HHA and VHA)(P = 3.56E-9); (2) increasing trends of HIF2A rs6756667-A(68.7%, 73.4%, 79.9% and 89.6%), rs7589621- G(74.6%, 77.9%, 83.7%, and 92.1%) and rs1868092-A(64.1%, 67.3%, 75.1% and 84.4%) (P = 3.56E-9, 4.68E-16, 1.17E-13 and 7.09E-14, respectively); (3) a increasing trend of haplotype AG (68.7%, 73.1%, 79.9% and 89.6%) (P = 2.22E-7) which was constructed by rs6756667 and rs7589621; (4) a strong linear correlation between major alleles of rs6756667-A (R2 = 0.997, P = 0.002), rs7589621-G (R2 = 0.994, P = 0.003), rs1868092-A (R2 = 0.985, P = 0.008) and altitude by linear correlation test. The associations between HIF2A variants and different level of high altitude support that extremely high-altitude hypoxia challenge imposes selective effects on HIF2A variants among native Tibetans.

Polymorphisms of genes in neurotransmitter systems were associated with alcohol use disorders in a Tibetan population.

Studies of linkage and association in various ethnic populations have revealed many predisposing genes of multiple neurotransmitter systems for alcohol use disorders (AUD). However, evidence often is contradictory regarding the contribution of most candidate genes to the susceptibility of AUD. We, therefore, performed a case-control study to investigate the possible associations of genes selected from multiple neurotransmitter systems with AUD in a homogeneous Tibetan community population in China. AUD cases (N = 281) with an alcohol use disorder identification test (AUDIT) score ≥10, as well as healthy controls (N = 277) with an AUDIT score ≤5, were recruited. All participants were genotyped for 366 single nucleotide polymorphisms (SNPs) of 34 genes selected from those involved in neurotransmitter systems. Association analyses were performed using PLINK version 1.07 software. Allelic analyses before adjustment for multiple tests showed that 15 polymorphisms within seven genes were associated with AUD (p<0.05). After adjustment for the number of SNPs genotyped within each gene, only the association of a single marker (rs10044881) in HTR4 remained statistically significant. Haplotype analysis for two SNPs in HTR4 (rs17777298 and rs10044881) showed that the haplotype AG was significantly associated with the protective effect for AUD. In conclusion, the present study discovered that the HTR4 gene may play a marked role in the pathogenesis of AUD. In addition, this Tibetan population sample marginally replicated previous evidence regarding the associations of six genes in AUD.

Gender-specific interactions between alcohol metabolism genes and severity of quantitative alcohol-related-traits in a Tibetan population.

Association between genes influencing alcohol metabolism and alcohol use disorders (AUD) has been extensively studied, but the effect of interactions between these genes and AUD have rarely been tested. Our previous case-control study in a Tibetan population noted that the positive association between c2 allele of cytochrome P4502E1 (CYP2E1) gene and AUD might only exist in males who are homozygotes for 1 alleles of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-1B (ADH1B) genes, but this interaction did not reach statistical significance. Using the same set of data, the present study was aimed at exploring interactions between these genes and quantitative alcohol-related-trait scores (QARTs), and whether these are influenced by gender. The sample included 383 AUD cases with the alcohol use disorders identification test (AUDIT) score ≥10 and 350 normal controls with the AUDIT score ≤5. QARTs were measured using three factors from AUDIT. Possible associations of QARTs with interactions among genotypes of ALDH2 1/ 2, ADH1B1/2 and CYP2E1 c1/c2 and sex were analyzed in AUD cases and normal controls separately. The subjects with 2 alleles of ALDH2 or/and ADH1B had significantly lower scores of alcohol intake among controls but had significantly higher scores of alcohol related problems among cases. The score of alcohol intake in male cases who are homozygous for ALDH2 1 and ADH1B 1 and with CYP2E1 c2 allele was significantly higher than that of other cases. These findings suggest that interactions between genes influencing alcohol metabolism are influenced by gender and might affect QARTs differently between the milder-/non-drinkers and AUD cases.

Interaction among genes influencing ethanol metabolism and sex is association with alcohol use disorders in a Tibet population.

Associations between alcohol use disorders and polymorphisms of genes influencing ethanol metabolism have been widely reported, but gene-gene and gene-sex interaction studies have rarely been examined. Using a set of samples collected during an epidemiological study of alcohol use disorders AUDs in a Tibetan population in China, we performed a case-control study to investigate the relationship between the functional polymorphisms of genes influencing ethanol metabolism and AUDs. The sample included 383 individuals with an AUDIT score >or=10 and 350 control subjects with the AUDIT score

An epidemiological survey of alcohol use disorders in a Tibetan population.

We performed an epidemiological survey in order to detect the prevalence of alcohol use disorders in a sub-group of the population of Tibet. The Alcohol Use Disorders Identification Test (AUDIT) questionnaire, the Severity of Alcohol Dependence Questionnaire (SADQ), and a 12-item version of the General Health Questionnaire (GHQ12) were used to obtain epidemiological data on alcohol use disorders and to assess the severity of 'problem drinking' and general mental health status. The AUDIT is a reliable and valid screening tool for both alcohol abuse and dependence in the Tibetan population to identify individuals with alcohol use problems. The cut-off points were set to be 10 and 13 of the AUDIT scores as a diagnostic discriminator of alcohol abuse and alcohol dependence, respectively, with both sensitivity and specificity>0.84. The prevalence of alcohol abuse, was 2.7% (female: 2.0%; male: 6.2%), alcohol dependence 13.5% (female: 7.6%; male: 25.4%) and alcohol use disorders 16.2% (female: 9.6%; male: 31.6%). Age and sex were the main factors affecting an individual's alcohol use and general mental health status. The epidemiological data on alcohol use disorders documented in this project may be helpful in future work seeking more valid causal inferences or interpretations related to this prevalent health problem in Tibet.