Stressful Life Events, Unhealthy Eating Behaviors and Obesity among Chinese Government Employees: A Follow-Up Study.

Background: The underlying mechanisms of the relationship between stressful life events and obesity among Chinese workers are unclear. Objective: This study aimed to understand the processes and mechanisms involved in stressful life events, unhealthy eating behavior, and obesity among Chinese workers. Methods: From January 2018 to December 2019, a total of 15,921 government employees were included at baseline and they were followed-up until May 2021. Stressful life events were assessed using the Life Events Scale, and unhealthy eating behavior was assessed using four items. BMI was calculated as weight (kg) divided by height (m2) using physically measured data. Results: Overeating at each mealtime (OR = 2.21, 95%CI: 1.78-2.71) at baseline led to reports of higher risk of obesity at follow up. Eating before going to bed at night sometimes (OR = 1.51, 95%CI: 1.31-1.73) or often (OR = 3.04, 95%CI: 2.28-4.05) at baseline led to reports of higher risk of obesity at follow-up. Eating out sometimes (OR = 1.74, 95%CI: 1.47-2.07) or often (OR = 1.59, 95%CI: 1.07-2.36) at baseline led to reports of higher risk of obesity at follow-up. Stressful life events were not directly associated with obesity, but unhealthy eating behaviors, including overeating at each mealtime (ß = 0.010, 95%CI: 0.007-0.014; ß = 0.002, 95%CI: 0.001-0.004, respectively) and irregular meal timing (ß = -0.011, 95%CI: -0.015--0.008; ß = -0.004, 95%CI: -0.006--0.001, respectively), significantly mediated the associations between stressful life events at baseline and obesity at both baseline and follow-up. Conclusions: Unhealthy eating behaviors mediated the relationship between stressful life events and obesity. Interventions should be provided to workers who have experienced stressful life events and unhealthy eating behaviors.

Balloon Dilation Eustachian Tuboplasty for Dilatory Dysfunction With and Without Effusion: A Comprehensive Outcome Analysis.

OBJECTIVE: This study aimed (1) to demonstrate the efficacy of balloon dilation Eustachian tuboplasty (BDET) for dilatory Eustachian tube dysfunction (ETD) and (2) to determine whether adjunctive ventilation tube insertion (VTI) is superior to myringotomy in relieving symptoms for patients with ETD and concurrent middle ear effusion (MEE) treated with BDET. STUDY DESIGN: A retrospective cohort study. SETTING: Tertiary care academic center. METHODS: Patients with dilatory ETD undergoing BDET with a ≥6-month follow-up period were enrolled and evaluated mainly using Eustachian tube function (ETF) tests and Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7). Participants with concurrent MEE were further classified into 2 subgroups, BDET with VTI and BDET with myringotomy. An intergroup comparison and comprehensive outcome evaluation were performed. RESULTS: In total, 35 patients with 50 symptomatic ears were enrolled. According to ETF test results, the normalized ETF rate was 94% on the last visit. The mean ETDQ-7 scores decreased significantly from 3.7 ± 1.4 to 2.0 ± 0.9 after interventions, with the most improvement in symptoms occurring for "ear fullness" and "muffled hearing." For the final visit, strong correlations among ETF tests, tympanometry, and Valsalva results were noted. The aforementioned assessment results did not significantly differ between (1) the patients with MEE and patients without MEE and (2) "BDET with VTI" subgroup and "BDET with myringotomy" subgroup. CONCLUSION: BDET was effective for dilatory ETD, even in cases with concurrent MEE. For patients with ETD and MEE, further research is required to evaluate the benefits of adjunctive myringotomy with or without VTI.

Trends in mortality and causes of death among Chinese adolescents aged 10-19 years from 1990 to 2019.

Objective: Promoting adolescent health is essential to achieving the goals of the Healthy China 2030 (HC 2030) initiative. As socioeconomic conditions improve and medical practices and disease patterns evolve, adolescent mortality rates and causes of death vary considerably. This study provides up-to-date data on adolescent mortality and causes of death in China, highlighting key areas of focus for investment in adolescent health. Methods: Data regarding mortality and causes of death in Chinese adolescents aged 10-19 years were extracted from the Global Burden of Disease study from 1990 to 2019. The data variables were examined according to year, sex, and age. The autoregressive integrated moving average model was used to predict non-communicable disease (NCD) mortality rates and rank changes in the leading causes of death until 2030. Results: The all-cause mortality rate (per 100,000 population) of Chinese adolescents aged 10-19 years steadily declined from 1990 (72.6/100,000) to 2019 (28.8). Male adolescents had a higher mortality (37.5/100,000 vs. 18.6 in 2019) and a slower decline rate (percent: -58.7 vs. -65.0) than female adolescents. Regarding age, compared with those aged 10-14 years, the mortality rate of adolescents aged 15-19 years had a higher mortality (35.9/100,000 vs. 21.2 in 2019) and a slower decrease rate (percent: -57.6 vs. -63.2). From 1990 to 2019, the rates of communicable, maternal, and nutritional diseases declined the most (percent: -80.0), while injury and NCDs mortality rates were relatively slow (percent: -50.0 and -60.0). In 2019, the five leading causes of death were road injuries (6.1/100,000), drowning (4.5), self-harm (1.9), leukemia (1.9), and congenital birth defects (1.3). Furthermore, NCDs' mortality rate decreased by -46.6% and -45.4% between 2015-2030 and 2016-2030, respectively. Conclusion: A notable decline was observed in all-cause mortality rates among Chinese adolescents aged 10-19 years. In addition, the mortality rates of NCDs are projected to meet the target from the Global Strategy for Women's, Children's, and Adolescents' Health (2016-2030) and HC2030 reduction indicators by 2030. However, it should be noted that injury is the leading cause of death, with sexual and age disparities remaining consistent.

TTYH3 is a prognostic biomarker and associates with immune cell infiltrations of lung adenocarcinoma / TTYH3 es un biomarcador pronóstico y se asocia con infiltraciones de células inmunitarias del adenocarcinoma de pulmón

SUMMARY: We investigated Tweety Family Member 3 (TTYH3) level in lung adenocarcinoma (LUAD) and its relationship with immune infiltration in tumors by bioinformatics. Differential expressions of TTYH3 in lung cancer were analyzed with Oncomine, TIMER, GEO, UALCAN and HPA. Relationship of TTYH3 mRNA/protein levels with clinical parameters was analyzed by UALCAN. Co-expressed genes of TTYH3 in LUAD were analyzed using Cbioportal. Its relationship with LUAD prognosis was analyzed by Kaplan-Meier plotter. GO and KEGG analysis were performed. Correlation between TTYH3 and tumor immune infiltration were tested by TIMER, TISIDB and GEPIA. We found that TTYH3 was significantly increased in LUAD tissues. TTYH3 high expression was closely related to poor overall survival, post progression survival and first progression in LUAD patients. TTYH3 mRNA/protein levels were significantly associated with multiple pathways. Specifically, TTYH3 up-regulation was mostly related to biological regulation, metabolic process, protein blinding, extracellular matrix organization and pathways in cancer. Moreover, TTYH3 was positively associated with immune cell infiltration in LUAD. Finally, TTYH3 was highly expressed in LUAD as revealed by meta-analysis. TTYH3 is closely related to the prognosis of LUAD and immune cell infiltration, and it can be used as a prognostic biomarker for LUAD and immune infiltration.

Investigamos por bioinformática el nivel de Tweety Family Member 3 (TTYH3) con adenocarcinoma de pulmón (LUAD) y su relación con la infiltración inmune en tumores. Las expresiones diferenciales de TTYH3 en cáncer de pulmón se analizaron con Oncomine, TIMER, GEO, UALCAN y HPA. Con UALCAN se analizó la relación de los niveles de ARNm/proteína de TTYH3 con los parámetros clínicos. Los genes coexpresados de TTYH3 en LUAD se analizaron utilizando Cbioportal. Su relación con el pronóstico LUAD se analizó mediante plotter de Kaplan- Meier. Se realizaron análisis GO y KEGG. TIMER, TISIDB y GEPIA probaron la correlación entre TTYH3 y la infiltración inmune tumoral. Encontramos que TTYH3 aumentó significativamente en los tejidos LUAD. La alta expresión de TTYH3 estuvo estrechamente relacionada con una supervivencia general deficiente, supervivencia posterior a la progresión y primera progresión en pacientes con LUAD. Los niveles de ARNm/ proteína de TTYH3 se asociaron significativamente con múltiples vías. Específicamente, la regulación positiva de TTYH3 se relacionó principalmente con la regulación biológica, el proceso metabólico, el cegamiento de proteínas, la organización de la matriz extracelular y las vías en el cáncer. Además, TTYH3 se asoció positivamente con la infiltración de células inmunitarias en LUAD. Finalmente, TTYH3 se expresó altamente en LUAD como lo reveló el metanálisis. TTYH3 está estrechamente relacionado con el pronóstico de LUAD y la infiltración de células inmunitarias, y se puede utilizar como biomarcador pronóstico para LUAD y la infiltración de células inmunitarias.

The immunomodulatory effects of mesenchymal stem cell-derived extracellular vesicles in Alzheimer's disease.

Neuroinflammation has been identified as another significant pathogenic factor in Alzheimer's disease following Aß amyloid deposition and tau protein hyperphosphorylation, activated in the central nervous system by glial cells in response to injury-related and pathogen-related molecular patterns. Moderate glial cell activity can be neuroprotective; however, excessive glial cell activation advances the pathology of Alzheimer's disease and is accompanied by structural changes in the brain interface, with peripheral immune cells entering the brain through the blood-brain barrier, creating a vicious circle. The immunomodulatory properties of mesenchymal stem cells (MSCs) are primarily conveyed through extracellular vesicles (EVs). MSC-EVs participate in chronic inflammatory and immune processes by transferring nucleic acids, proteins and lipids from the parent cell to the recipient cell, thus MSC-EVs retain their immunomodulatory capacity while avoiding the safety issues associated with living cell therapy, making them a promising focus for immunomodulatory therapy. In this review, we discuss the modulatory effects of MSC-EVs on Alzheimer's disease-associated immune cells and the mechanisms involved in their treatment of the condition. We have found a clinical trial of MSC-EVs in Alzheimer's disease treatment and outlined the challenges of this approach. Overall, MSC-EVs have the potential to provide a safe and effective treatment option for Alzheimer's disease by targeting neuroinflammation.

Investigating cognitive flexibility deficit in schizophrenia using task-based whole-brain functional connectivity.

Background: Cognitive flexibility is a core cognitive control function supported by the brain networks of the whole-brain. Schizophrenic patients show deficits in cognitive flexibility in conditions such as task-switching. A large number of neuroimaging studies have revealed abnormalities in local brain activations associated with deficits in cognitive flexibility in schizophrenia, but the relationship between impaired cognitive flexibility and the whole-brain functional connectivity (FC) pattern is unclear. Method: We investigated the task-based functional connectivity of the whole-brain in patients with schizophrenia and healthy controls during task-switching. Multivariate pattern analysis (MVPA) was utilized to investigate whether the FC pattern can be used as a feature to discriminate schizophrenia patients from healthy controls. Graph theory analysis was further used to quantify the degrees of integration and segregation in the whole-brain networks to interpret the different reconfiguration patterns of brain networks in schizophrenia patients and healthy controls. Results: The results showed that the FC pattern classified schizophrenia patients and healthy controls with significant accuracy. Moreover, the altered whole-brain functional connectivity pattern was driven by a lower degree of network integration and segregation in schizophrenia, indicating that both global and local information transfers at the entire-network level were less efficient in schizophrenia patients than in healthy controls during task-switching processing. Conclusion: These results investigated the group differences in FC profiles during task-switching and not only elucidated that FC patterns are changed in schizophrenic patients, suggesting that task-based FC could be used as a potential neuromarker to discriminate schizophrenia patients from healthy controls in cognitive flexibility but also provide increased insight into the brain network organization that may contribute to impaired cognitive flexibility.

Neoantigen-specific TCR-T cell-based immunotherapy for acute myeloid leukemia.

Neoantigens derived from non-synonymous somatic mutations are restricted to malignant cells and are thus considered ideal targets for T cell receptor (TCR)-based immunotherapy. Adoptive transfer of T cells bearing neoantigen-specific TCRs exhibits the ability to preferentially target tumor cells while remaining harmless to normal cells. High-avidity TCRs specific for neoantigens expressed on AML cells have been identified in vitro and verified using xenograft mouse models. Preclinical studies of these neoantigen-specific TCR-T cells are underway and offer great promise as safe and effective therapies. Additionally, TCR-based immunotherapies targeting tumor-associated antigens are used in early-phase clinical trials for the treatment of AML and show encouraging anti-leukemic effects. These clinical experiences support the application of TCR-T cells that are specifically designed to recognize neoantigens. In this review, we will provide a detailed profile of verified neoantigens in AML, describe the strategies to identify neoantigen-specific TCRs, and discuss the potential of neoantigen-specific T-cell-based immunotherapy in AML.

Post-remission measurable residual disease directs treatment choice and improves outcomes for patients with intermediate-risk acute myeloid leukemia in CR1.

OBJECTIVES: This study retrospectively investigated in which cycle measurable residual disease (MRD) is associated with prognosis in patients in first complete remission (CR1) of intermediate-risk acute myeloid leukemia (AML). METHODS: The study enrolled 235 younger patients with intermediate-risk AML. MRD was evaluated by multiparameter flow cytometry after the 1st, 2nd, and 3rd chemotherapy cycles (MRD1-3, respectively). RESULTS: No significant association was detected after the 1st and 2nd cycles. However, the 5-year incidence of relapse was higher in the MRD3-positive group (n = 99) than in the negative group (n = 136) (48.7% vs. 13.7%, P = 0.005), while 5-year disease-free survival (DFS) and overall survival (OS) were lower in the MRD3-positive group than in the negative group (43.2% vs. 81.0% and 45.4% vs. 84.1%; P = 0.003 and 0.005, respectively). Allogeneic hematopoietic stem cell transplantation led to a lower 5-year relapse, and higher DFS and OS rates than chemotherapy in the MRD3-positive group (22.3% vs. 71.5%, 65.9% vs. 23.0%, and 67.1% vs. 23.9%; P < 0.001, 0.002, and 0.022, respectively), but did not affect the MRD-negative group. CONCLUSIONS: MRD3 could serve as an indicator for post-remission treatment choice and help improve outcomes for intermediate-risk AML in CR1.

Stressful Life Events and Chronic Fatigue Among Chinese Government Employees: A Population-Based Cohort Study.

Background: Currently, evidence on the role of stressful life events in fatigue among the Chinese working adults is lacking. This study aimed at exploring the prospective associations between stressful life events and chronic fatigue among Chinese government employees. Methods: From January 2018 to December 2019, a total of 16206 government employees were included at baseline and they were followed-up until May 2021. A digital self-reported questionnaire platform was established to collect information on participants' health and covariates. Life events were assessed by the Life Events Scale (LES), fatigue was assessed by using a single item, measuring the frequency of its occurrence. Binary logistic regression analysis was used for the data analysis. Results: Of the included 16206 Chinese government employees at baseline, 60.45% reported that they experienced negative stressful life events and 43.87% reported that they experienced positive stressful life events over the past year. Fatigue was reported by 7.74% of the sample at baseline and 8.19% at follow-up. Cumulative number of life events at baseline, and cumulative life events severity score at baseline were positively associated with self-reported fatigue at follow up, respectively. After adjusting sociodemographic factors, occupational factors and health behavior related factors, negative life events at baseline (OR: 2.06, 95% CI: 1.69-2.51) were significantly associated with self-reported fatigue at follow-up. Some specific life events including events related to work and events related to economic problems were significantly associated with self-reported fatigue. Specifically, work stress (OR = 1.76, 95%CI: 1.45-2.13), as well as not satisfied with the current job (OR = 1.95, 95%CI: 1.58-2.40), in debt (OR = 1.75, 95%CI: 1.40-2.17) were significantly associated with self-reported fatigue. The economic situation has improved significantly (OR = 0.62, 95%CI: 0.46-0.85) at baseline was significantly associated with lower incidence of self-reported fatigue. Conclusion: Negative stressful life events were associated with fatigue among Chinese government employees. Effective interventions should be provided to employees who have experienced negative stressful life events.

Activation of A2B adenosine receptor protects against demyelination in a mouse model of schizophrenia.

The purpose of the present study was to explore the effects of A2B adenosine receptor (A2BAR) on learning, memory and demyelination in a dizocilpine maleate (MK-801)-induced mouse model of schizophrenia (SCZ). BAY 60-6583, an agonist of A2BAR, or PSB 603, an antagonist of A2BAR, was used to treat SCZ in this model. The Morris Water Maze (MWM) was utilized to determine changes in cognitive function. Moreover, western blotting, immunohistochemistry and immunofluorescence were conducted to investigate the myelination and oligodendrocyte (OL) alterations at differentiation and maturation stages. The MWM results showed that learning and memory were impaired in SCZ mice, while subsequent treatment with BAY 60-6583 alleviated these impairments. In addition, western blot analysis revealed that myelin basic protein (MBP) and chondroitin sulphate proteoglycan 4 (NG2) expression levels were significantly decreased in MK-801-induced mice, while the expression of G protein-coupled receptor 17 (GPR17) was increased. Additionally, the number of anti-adenomatous polyposis coli clone CC-1/OL transcription factor 2 (CC-1+/Olig2+) cells was also decreased. Notably, BAY 60-6583 administration could reverse these changes, resulting in a significant increase in MBP and NG2 protein expression, and in the number of CC-1+/Olig2+ cells, while GPR17 protein expression levels were decreased. The present study indicated that the selective activation of A2BAR using BAY 60-6583 could improve the impaired learning and memory of SCZ mice, as well as protect the myelin sheath from degeneration by regulating the survival and maturation of OLs.

PSB0788 ameliorates maternal inflammation-induced periventricular leukomalacia-like injury.

Studies have shown that periventricular leukomalacia (PVL) is a distinctive form of cerebral white matter injury that pertains to myelination disturbances. Maternal inflammation is a main cause of white matter injury. Intrauterine inflammation cellular will be propagated to the developing brain by the entire maternal-placental-fetal axis, and triggers neural immune injury. As a low-affinity receptor, adenosine A2B receptor (A2BAR) requires high concentrations of adenosine to be significantly activated in pathological conditions. We hypothesized that in the maternal inflammation-induced PVL model, a selective A2BAR antagonist PSB0788 had the potential to prevent the injury. In this work, a total of 18 SD pregnant rats were divided into three groups, and treated with intraperitoneal injection of phosphate buffered saline (PBS), lipopolysaccharide (LPS), or LPS+PSB0788. Placental infection was determined by H&E staining and the inflammatory condition was determined by ELISA. Change of MBP, NG2 and CC-1 in the brain of the rats' offspring were detected by western blot and immunohistochemistry. Furthermore, LPS-induced maternal inflammation reduced the expression of MBP, which related to the decrease in the numbers of OPCs and mature oligodendrocytes in neonate rats. After treatment with PSB0788, the levels of MBP proteins increased in the rats' offspring, improved the remyelination. In conclusion, our study shows that the selective A2BAR antagonist PSB0788 plays an important role in promoting the normal development of OPCs in vivo by the maternal inflammation-induced PVL model. Future studies will focus on the mechanism of PSB0788 in this model.

Intestinal microbiota score could predict survival following allogeneic hematopoietic stem cell transplantation.

Intestinal microbiota is an important prognostic factor for allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its role in predicting survival has not been determined. Here, stool samples at day 15 ± 1 posttransplant were obtained from 209 patients at two centers. Microbiota was examined using 16S rRNA sequencing. The microbiota diversity and abundance of specific bacteria (including Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae, and Enterobacteriaceae) were assigned a value of 0 or 1 depending on whether they were positive or negative associated with survival, respectively. An accumulated intestinal microbiota (AIM) score was generated, and patients were divided into low- and high-score groups. A low score was associated with a better 3-year cumulative overall survival (OS) as well as lower mortality than a high score (88.5 vs. 43.9% and 7.1 vs. 35.8%, respectively; both P < 0.001). In multivariate analysis, a high score was found to be an independent risk factor for OS and transplant-related mortality (hazard ratio = 5.68 and 3.92, respectively; P < 0.001 and 0.003, respectively). Furthermore, the AIM score could serve as a predictor for survival (area under receiver operating characteristic curve = 0.836, P < 0.001). Therefore, the intestinal microbiota score at neutrophil recovery could predict survival following allo-HSCT.

A2B adenosine receptor inhibition ameliorates hypoxic-ischemic injury in neonatal mice via PKC/Erk/Creb/HIF-1α signaling pathway.

Periventricular leukomalacia (PVL), the dominant cerebral white matter injury disease, is induced by hypoxia-ischemia and inflammation in premature infants. The activation of A2B adenosine receptor (A2BAR) is shown to involve into inflammation, ischemia, and other typical stress reactions, but its exact function in PVL has not been clarified. We gained initial insight from PVL mouse model (P9) by the induction of hypoxia-ischemia with right carotid ligation followed by exposure to hypoxia and intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS). The results showed that treatment of PSB-603, an A2BAR selective antagonist, greatly ameliorated cerebral ischemic injury by increasing bodyweights, reducing infarct volume, brain injury,inflammation andcontributing to long-term learning memory functionalrecoveryof the PVL mice. Meanwhile, PSB-603 treatment suppressed neurons apoptosis as characterized byreducing of Caspase-3 level, inhibited microglia activation and attenuated hypomyelination through promoting MBP expression and oligodendrocytes differentiation. A2BAR inhibition also augmented PKC expression, the activity of PKC downstream signaling molecules were then explored. Erk expression and Creb phosphorylation exhibited upregulation in PSB-603 treatment group compared with the control group. Hypoxia Inducible Factor-1α (HIF-1α), a direct target of hypoxia, which is a key regulator of adenosine signaling by binding to the A2BAR promoter to induce expression of A2BAR, was shown to be decreased by PSB-603. Taken together, A2BAR inhibition can ameliorate hypoxic-ischemic injury in PVL mice maybe through PKC/Erk/Creb/HIF-1α signaling pathway.

Hearing Features and Cochlear Implantation Outcomes in Patients With Pathogenic MYO15A Variants: a Multicenter Observational Study.

OBJECTIVES: Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants. DESIGN: This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes. RESULTS: At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation. CONCLUSIONS: The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention.

Exploring the Molecular Basis of Substrate and Product Selectivities of Nocardicin Bifunctional Thioesterase.

D-amino acid introduction in peptides can enrich their biological activities and pharmacological properties as potential drugs. This achievement of stereochemical inversion usually owes to an epimerase or racemase. Interestingly, a unique bifunctional thioesterase (NocTE), which is incorporated in nonribosomal peptide synthetase (NRPS) NocA-NocB assembly line for the biosynthesis of monocyclic ß-lactam antibiotic nocardicin A, can control the generation of D-products with high stereochemical purity. However, the molecular basis of NocTE selectivity on substrates and products is still unclear. Herein, we constructed a series of systems with different peptides varying in stereochemistry, length, and composition to investigate the substrate selectivity. The studies on binding affinities and loading conformations elucidated the important roles of peptide length and ß-lactam ring in substrate selectivity. Through energy decomposition and interaction analyses, some key residues involved in substrate selectivity were captured. On the other hand, natural product undergoing epimerization was found to be liberated from the active pocket more easily in comparison with its diastereomer (epi-nocardicin G), explaining the superiority of nocardicin G. These results provide detailed molecular insights into the exquisite control of substrate and product scopes for NocTE, and encourage to diversification of substrates and final products for NRPS assembly line. The molecular insights into substrate and product selectivities of unique bifunctional thioesterase NocTE were illustrated via several molecular simulations and free energy calculations, contributing to expanding substrate and product scopes of nonribosomal peptide synthetases.

A Transcanal Endoscopic Approach for Management of Pulsatile Tinnitus due to High-Riding Dehiscent Jugular Bulb.

Pulsatile tinnitus (PT) caused by a high-riding dehiscence jugular bulb (HDJB) is a rare but treatable otology disease. There are several managements include transcatheter endovascular coil embolization, transvenous stent-assisted coil embolization, or resurfacing the dehiscent bony wall of high jugular bulb under the use of microscope. Among those options, surgical resurfacing of HDJB might be an effective and safe choice with less destruction. However, previous studies approached middle ear cavity via microscope can only provide a lateral, indirect view, while resurfacing the vessel through a transcanal endoscopic ear surgery (TEES) approach may give surgeon a direct and easy way to manage HDJB. In this report, we presented a case of 40-year-old woman with HDJB and shared our clinical consideration and reasoning of the surgical management of PT via a transtympanic approach by TEES rather than a transmastoid approach.

Sociodemographic disparity in health-related behaviours and dietary habits among public workers in China: a cross-sectional study.

OBJECTIVE: We aimed to estimate the distribution of health-related behaviours and dietary habits by sociodemographics among public workers in China. DESIGN: Cross-sectional study. SETTING: A representative sample was obtained from 10 government-run institutions in Hunan province of China. PARTICIPANTS: A total of 5029 public workers were included in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence on their sociodemographic characteristics, health-related behaviours and dietary habits. Socioeconomic status (SES) scores were calculated by multiplying ordinal numerical values assigned to consecutive categories of education level and annual household income. Multivariate logistic regression analysis and categorical principal component analysis were used to estimate differences in health-related behaviours and dietary habits by sociodemographics. RESULTS: The distribution of health-related behaviours and dietary habits was varied by sociodemographic groups. Middle-aged groups (41-60 years) were more likely to smoke (for men, 34.5%), use alcohol (for men, 22.5%), and have short sleep duration (for men, 36.3%; for women, 39.6%). Young participants (≤30 years) were more likely to have multiple unhealthy behaviours and dietary habits. Those in low-SES have a significant higher rate of smoking (ORadj=1.46, 95% CI: 1.15 to 1.85) and leisure-time physical inactivity (ORadj=1.18, 95% CI: 1.02 to 1.37), but a lower rate of late sleeping (ORadj=0.69, 95% CI: 0.57 to 0.83) than those in high-SES. Notably, older men (≥51 years) with low-SES preferred the 'smoked and pickled foods and dessert' and 'fish and nut' pattern. In high-SES groups, 41-50 year old people preferred the 'traditional foods' and 'cereals and dairy product' pattern. No difference in dietary patterns by sociodemographics was found among women (p<0.05). CONCLUSIONS: Our findings of the disparity distribution of health-related behaviours and dietary habits by specific gender, age and SES among Chinese public workers have important policy implications for developing targeted health interventions to facilitate health-related behaviours and dietary habits in this population.

Protective effects of Lycium barbarum polysaccharide on ovariectomy­induced cognition reduction in aging mice.

Women experience cognitive decline as they age due to the decrease in estrogen levels following menopause. Currently, effective pharmaceutical treatments for age­related cognitive decline are lacking; however, several Traditional Chinese medicines have shown promising effects. Lycium barbarum polysaccharides (LBPs) were found to exert a wide variety of biological activities, including anti­inflammatory, antioxidant and anti­aging effects. However, to the best of our knowledge, the neuroprotective actions of LBP on cognitive impairment induced by decreased levels of estrogen have not yet been determined. To evaluate the effects of LBP on learning and memory impairment in an animal model of menopause, 45 female ICR mice were randomly divided into the following three groups: i) Sham; ii) ovariectomy (OVX); and iii) OVX + LBP treatment. The results of open­field and novel object recognition tests revealed that mice in the OVX group had learning and memory impairments, and lacked the ability to recognize and remember new objects. Notably, these deficits were attenuated following LBP treatment. Immunohistochemical staining confirmed the protective effects of LBP on hippocampal neurons following OVX. To further investigate the underlying mechanism of OVX in mice, mRNA sequencing of the hippocampal tissue was performed, which revealed that the Toll­like receptor 4 (TLR4) inflammatory signaling pathway was significantly upregulated in the OVX group. Moreover, reverse transcription­quantitative PCR and immunohistochemical staining demonstrated that OVX induced hippocampal injury, upregulated the expression levels of TLR4, myeloid differentiation factor 88 and NF­κB, and increased the expression of TNF­α, IL­6 and IL­1ß inflammatory factors. Conversely, LBP treatment downregulated the expression levels of mRNAs and proteins associated with the TLR4/NF­κB signaling pathway, decreased the inflammatory response and reduced neuronal injury in mice that underwent OVX. In conclusion, the findings of the present study indicated that oral LBP treatment may alleviate OVX­induced cognitive impairments by downregulating the expression levels of mRNAs and proteins associated with the TLR4/NF­κB signaling pathway, thereby reducing neuroinflammation and damage to the hippocampal neurons. Thus, LBP may represent a potential agent for the prevention of learning and memory impairments in patients with accelerated aging caused by estrogen deficiency.

Gene modification strategies for next-generation CAR T cells against solid cancers.

Immunotherapies have become the backbone of cancer treatment. Among them, chimeric antigen receptor (CAR) T cells have demonstrated great success in the treatment of hematological malignancies. However, CAR T therapy against solid tumors is less effective. Antigen targeting; an immunosuppressive tumor microenvironment (TME); and the infiltration, proliferation, and persistence of CAR T cells are the predominant barriers preventing the extension of CAR T therapy to solid tumors. To circumvent these obstacles, the next-generation CAR T cells will require more potent antitumor properties, which can be achieved by gene-editing technology. In this review, we summarize innovative strategies to enhance CAR T cell function by improving target identification, persistence, trafficking, and overcoming the suppressive TME. The construction of multi-target CAR T cells improves antigen recognition and reduces immune escape. Enhancing CAR T cell proliferation and persistence can be achieved by optimizing costimulatory signals and overexpressing cytokines. CAR T cells equipped with chemokines or chemokine receptors help overcome their poor homing to tumor sites. Strategies like knocking out immune checkpoint molecules, incorporating dominant negative receptors, and chimeric switch receptors can favor the depletion or reversal of negative T cell regulators in the TME.

Increased biomass and reduced tissue cadmium accumulation in rice via indigenous Citrobacter sp. XT1-2-2 and its mechanisms.

Microbial remediation is a promising technique to remediate heavy metals contaminated soils. In this study, the cadmium (Cd)- resistant Citrobacter sp. XT1-2-2, isolated from heavy metals contaminated paddy soils, was investigated to evaluate the effect of this strain on soil Cd speciation, cellular Cd distribution, tissue Cd accumulation and rice biomass. The percentage of Cd2+ removal by Citrobacter sp. XT1-2-2 was up to 82.3 ± 2.1% within 240 min in the solution. The average content of soil soluble plus exchangeable and carbonate-bound fractions of Cd decreased, whereas Fe/Mn oxide-bound, organic matter-bound and residual fractions increased with bacteria inoculation. For the paddy soil inoculated with the XT1-2-2 strain, Cd concentrations of roots, culms, leaves and grains were significantly reduced by 24.1%, 46.9%, 41.5% and 66.7%, respectively. In addition, inoculation bacteria significantly increased the biomass of the roots, above-ground tissues and the rice grains. All results indicated that the XT1-2-2 strain had the ability to immobilize soil Cd and decrease Cd accumulation in rice grains. Therefore, the XT1-2-2 strain has potential for application to remediate Cd-contaminated paddy soils. It is possible to exploit a new bacterial-assisted technique for the remediation in Cd-contaminated paddy soils.