Adipose tissue senescence: Biological changes, hallmarks and therapeutic approaches.

Adipose tissue (AT), the largest energy storage reservoir and endocrine organ, plays a crucial role in regulating systemic energy metabolism. As one of the most vulnerable tissues during aging, the plasticity of AT is impaired. With age, AT undergoes redistribution, characterized by expansion of visceral adipose tissue (VAT) and reduction of peripheral subcutaneous adipose tissue (SAT). Additionally, age-related changes in AT include reduced adipogenesis of white adipocytes, decreased proliferation and differentiation capacity of mesenchymal stromal/stem cells (MSCs), diminished thermogenic capacity in brown/beige adipocytes, and dysregulation of immune cells. Specific and sensitive hallmarks enable the monitoring and evaluation of the biological changes associated with aging. In this study, we have innovatively proposed seven characteristic hallmarks of AT senescence, including telomere attrition, epigenetic alterations, genomic instability, mitochondrial dysfunction, disabled macroautophagy, cellular senescence, and chronic inflammation, which are intricately interconnected and mutually regulated. Finally, we discussed anti-aging strategies targeting AT, offering insights into mitigating or delaying metabolic disturbances caused by AT senescence.

Integrated test system for interfacial strength and morphology of multi-type hydrate-bearing sediments.

Predicting the strength parameters of multi-type sediments containing hydrates is the basis and precondition for the safe and efficient development of natural gas hydrates. However, studies on the shear mechanical behavior and morphology of multi-type hydrate-bearing sediments (HBS) are still insufficient. Herein, this study presents an integrated test system that can be used to measure the interfacial strength and morphology of multi-type sediments containing hydrates. This device integrates specimen preparation, shear test, morphology observation, and data analysis, which is helpful to comprehensively evaluate interfacial strength, roughness, and morphology. The propagation and development characteristics of microfractures of HBS during shearing can be obtained, which is favorable for identifying the damage and failure modes. Preliminary validation experiments have been conducted on massive pure hydrate, hydrate-sediment interface, and homogenous HBS to verify the applicability of the device for multi-type HBS. The device and corresponding analysis method are expected to support the evaluation of interfacial strength and morphology, thereby promoting a deeper understanding of hydrate-sediment interactions and failure mechanisms of hydrate reservoirs.

CST3 alleviates retinal vascular leakage by regulating the Rap1 signaling pathway.

Retinal vascular leakage is a major event in several retinal diseases, including diabetic retinopathy (DR). In a previous study, we demonstrated that the aqueous humor concentration of Cystatin C (CST3), a physiological inhibitor of cysteine protease, is negatively correlated with the severity of diabetic macular edema. However, its function in the retina has not been clearly elucidated. In this study, we found a significant decrease in the aqueous humor concentration of CST3 with DR progression. Furthermore, we found that CST3 was expressed in retinal endothelial cells and that its expression was significantly downregulated in high glucose-treated human retinal microvascular endothelial cells (HRMECs) and the retinal vessels of oxygen-induced retinopathy (OIR) mice. Silencing CST3 expression resulted in decreased HRMEC migration and tubule formation ability. Exogenous addition of the CST3 protein significantly improved HRMEC migration and tubular formation. In-vivo experiments demonstrated that CST3 silencing induced retinal vascular leakage in WT mice, while its intravitreal injection significantly reduced retinal leakage in OIR mice. Mechanistically, CST3 promoted the expression of the downstream adhesion molecules, claudin5, VE-cadherin, and ZO-1, in retinal vascular cells by regulating the Rap1 signaling pathway. Therefore, this study revealed a novel mechanism by which CST3 improves retinal vascular function and provided evidence that it is a potential therapeutic target for retinal vascular leakage.

A novel compound heterozygous PCDH15 variants is associated with arRP in a Chinese pedigree.

BACKGROUND: Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases. However, it is still not well understand about the relationship between PCDH15 variants and RP. METHODS: In this study, we enrolled a Chinese autosomal recessive retinitis pigmentosa (arRP) pedigree and identified the causative gene in the proband by targeted whole exome sequencing (WES). The variants were validated in the family members by Sanger sequencing and co-segregation analysis. RESULTS: Novel compound heterozygous, Frame shift variants of the PCDH15 gene, NM_001384140.1:c.4368 - 2147_4368-2131del and NM_001384140.1:c exon19:c.2505del: p. T836Lfs*6 were identified in the arRP pedigree, which co-segregated with the clinical RP phenotypes. The PCDH15 protein is highly conserved among species. CONCLUSION: This is the first study to identify novel compound heterozygous variants c.4368 - 2147_4368-2131del and c.2505del(p.T836Lfs*6) in the PCDH15 gene which might be disease-causing variants, and extending the variant spectra. All above findings may be contribute to genetic counseling, molecular diagnosis and clinical management of arRP disease.

Construction of a nomogram model based on biomarkers for liver metastasis in non-small cell lung cancer.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) with liver metastasis have a poor prognosis, and there are no reliable biomarkers for predicting disease progression. Currently, no recognized and reliable prediction model exists to anticipate liver metastasis in NSCLC, nor have the risk factors influencing its onset time been thoroughly explored. METHODS: This study conducted a retrospective analysis of 434 NSCLC patients from two hospitals to assess the association between the risk and timing of liver metastasis, as well as several variables. RESULTS: The patients were divided into two groups: those without liver metastasis and those with liver metastasis. We constructed a nomogram model for predicting liver metastasis in NSCLC, incorporating elements such as T stage, N stage, M stage, lack of past radical lung cancer surgery, and programmed death ligand 1 (PD-L1) levels. Furthermore, NSCLC patients with wild-type EGFR, no prior therapy with tyrosine kinase inhibitors (TKIs), and no prior radical lung cancer surgery showed an elevated risk of early liver metastasis. CONCLUSION: In conclusion, the nomogram model developed in this study has the potential to become a simple, intuitive, and customizable clinical tool for assessing the risk of liver metastasis in NSCLC patients following validation. Furthermore, it provides a framework for investigating the timing of metachronous liver metastasis.

One Stone, Three Birds: Feasible Tuning of Barrier Heights Induced by Hybridized Interface in Free-Standing PEDOT@Bi2Te3 Thermoelectric Films.

Converting low-grade thermal energy into electrical energy is crucial for the development of modern smart wearable energy technologies. The free-standing films of PEDOT@Bi2Te3 prepared by tape-casting hold promise for flexible thermoelectric technology in self-powered sensing applications. Bi2Te3 nanosheets fabricated by the solvothermal method are tightly connected with flat-arranged PEODT molecules, forming an S-Bi bonded interface in the composite materials, and the bandgap is reduced to 1.63 eV. Compared with the PEDOT film, the mobility and carrier concentration of the composite are significantly increased at room temperature, and the conductivity reaches 684 S/cm. Meanwhile, the carrier concentration decreased sharply at 360 K indicating the creation of defect energy levels during the interfacial reaction of the composites, which increased the Seebeck coefficient. The power factor was improved by 68.9% compared to PEDOT. In addition, the introduction of Bi2Te3 nanosheets generated defects and multidimensional interfaces in the composite film, which resulted in weak phonon scattering in the conducting polymer with interfacial scattering. The thermal conductivity of the film is decreased and the ZT value reaches 0.1. The composite film undergoes 1500 bending cycles with a 14% decrease in conductivity and has good flexibility. This self-supporting flexible thermoelectric composite film has provided a research basis for low-grade thermal energy applications.

Lactiplantibacillus plantarum Regulates Intestinal Physiology and Enteric Neurons in IBS through Microbial Tryptophan Metabolites.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by visceral pain and gut dysmotility. However, the specific mechanisms by which Lactobacillus strains relieve IBS remain unclear. Here, we screened Lactobacillus strains from traditional Chinese fermented foods with potential IBS-alleviating properties through in vitro and in vivo experiments. We demonstrated that Lactiplantibacillus plantarum D266 (Lp D266) administration effectively modulates intestinal peristalsis, enteric neurons, visceral hypersensitivity, colonic inflammation, gut barrier function, and mast cell activation. Additionally, Lp D266 shapes gut microbiota and enhances tryptophan (Trp) metabolism, thus activating the aryl hydrocarbon receptor (AhR) and subsequently enhancing IL-22 production to maintain gut homeostasis. Mechanistically, Lp D266 potentially modulates colonic physiology and enteric neurons by microbial tryptophan metabolites. Further, our study indicates that combining Lp D266 with Trp synergistically ameliorates IBS symptoms. Together, our experiments identify the therapeutic efficacy of tryptophan-catabolizing Lp D266 in regulating gut physiology and enteric neurons, providing new insights into the development of probiotic-mediated nutritional intervention for IBS management.

Metabolic Crosstalk between Liver and Brain: From Diseases to Mechanisms.

Multiple organs and tissues coordinate to respond to dietary and environmental challenges. It is interorgan crosstalk that contributes to systemic metabolic homeostasis. The liver and brain, as key metabolic organs, have their unique dialogue to transmit metabolic messages. The interconnected pathogenesis of liver and brain is implicated in numerous metabolic and neurodegenerative disorders. Recent insights have positioned the liver not only as a central metabolic hub but also as an endocrine organ, capable of secreting hepatokines that transmit metabolic signals throughout the body via the bloodstream. Metabolites from the liver or gut microbiota also facilitate a complex dialogue between liver and brain. In parallel to humoral factors, the neural pathways, particularly the hypothalamic nuclei and autonomic nervous system, are pivotal in modulating the bilateral metabolic interplay between the cerebral and hepatic compartments. The term "liver-brain axis" vividly portrays this interaction. At the end of this review, we summarize cutting-edge technical advancements that have enabled the observation and manipulation of these signals, including genetic engineering, molecular tracing, and delivery technologies. These innovations are paving the way for a deeper understanding of the liver-brain axis and its role in metabolic homeostasis.

Potential of digital chest radiography-based deep learning in screening and diagnosing pneumoconiosis: An observational study.

The diagnosis of pneumoconiosis is complex and subjective, leading to inevitable variability in readings. This is especially true for inexperienced doctors. To improve accuracy, a computer-assisted diagnosis system is used for more effective pneumoconiosis diagnoses. Three models (Resnet50, Resnet101, and DenseNet) were used for pneumoconiosis classification based on 1250 chest X-ray images. Three experienced and highly qualified physicians read the collected digital radiography images and classified them from category 0 to category III in a double-blinded manner. The results of the 3 physicians in agreement were considered the relative gold standards. Subsequently, 3 models were used to train and test these images and their performance was evaluated using multi-class classification metrics. We used kappa values and accuracy to evaluate the consistency and reliability of the optimal model with clinical typing. The results showed that ResNet101 was the optimal model among the 3 convolutional neural networks. The AUC of ResNet101 was 1.0, 0.9, 0.89, and 0.94 for detecting pneumoconiosis categories 0, I, II, and III, respectively. The micro-average and macro-average mean AUC values were 0.93 and 0.94, respectively. The accuracy and Kappa values of ResNet101 were 0.72 and 0.7111 for quadruple classification and 0.98 and 0.955 for dichotomous classification, respectively, compared with the relative standard classification of the clinic. This study develops a deep learning based model for screening and staging of pneumoconiosis is using chest radiographs. The ResNet101 model performed relatively better in classifying pneumoconiosis than radiologists. The dichotomous classification displayed outstanding performance, thereby indicating the feasibility of deep learning techniques in pneumoconiosis screening.

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB.

BACKGROUND: While de novo cholesterol biosynthesis plays a crucial role in chemotherapy resistance of colorectal cancer (CRC), the underlying molecular mechanism remains poorly understood. METHODS: We conducted cell proliferation assays on CRC cells with or without depletion of squalene epoxidase (SQLE), with or without 5-fluorouracil (5-FU) treatment. Additionally, a xenograft mouse model was utilized to explore the impact of SQLE on the chemosensitivity of CRC to 5-FU. RNA-sequencing analysis and immunoblotting analysis were performed to clarify the mechanism. We further explore the effect of SQLE depletion on the ubiquitin of NF-κB inhibitor alpha (IκBα) and (S)-2,3-epoxysqualene on the binding of IκBα to beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) by using immunoprecipitation assay. In addition, a cohort of 272 CRC patients were selected for our clinical analyses. RESULTS: Mechanistically, (S)-2,3-epoxysqualene promotes IκBα degradation and subsequent NF-κB activation by enhancing the interaction between BTRC and IκBα. Activated NF-κB upregulates the expression of baculoviral IAP repeat containing 3 (BIRC3), sustains tumor cell survival after 5-FU treatment and promotes 5-FU resistance of CRC in vivo. Notably, the treatment of terbinafine, an inhibitor of SQLE commonly used as antifungal drug in clinic, enhances the sensitivity of CRC to 5-FU in vivo. Additionally, the expression of SQLE is associated with the prognosis of human CRC patients with 5-FU-based chemotherapy. CONCLUSIONS: Thus, our finding not only demonstrates a new role of SQLE in chemoresistance of CRC, but also reveals a novel mechanism of (S)-2,3-epoxysqualene-dependent NF-κB activation, implicating the combined potential of terbinafine for 5-FU-based CRC treatment.

Dynamic changes in body composition during XELOX/SOX chemotherapy in patients with gastric cancer.

Objectives: In this study, we compared the dynamic changes in body composition during XELOX/SOX chemotherapy in patients with gastric cancer. Furthermore, we investigated the potential impact of these changes on the occurrence of toxic side effects. Methods: Patients with gastric cancer who received adjuvant or first-line XELOX/SOX chemotherapy between January 2020 and June 2023 were enrolled. The Brief Conghua Scale was used to assess energy intake, and nutritional management was carried out with reference to the Chinese Guidelines for Nutritional Therapy of Cancer 2020. The NRS 2002 Nutritional Risk Screening Scale, PG-SGA scale, bioelectrical impedance analysis, and dynamic changes in lumbar 3 vertebral skeletal muscle index were compared between baseline and post-chemotherapy in the study. The neutropenia was evaluated using the Common Terminology Criteria for Adverse Events V.5.0, developed by the National Institutes of Health. Results: Dynamic follow-up was completed in 39 cases, with a mean follow-up time of 117.62 ± 43.38 days. The incidence of sarcopenia increased significantly after chemotherapy, escalating from 46.2% to 51.3%. After chemotherapy, the mean L3SMI decreased from 36.00 cm2/m2 to 34.99 cm2/m2. Furthermore, when compared to pre-chemotherapy values, the body composition indexes body mass index (BMI), SL3, fat mass free index (FFMI), lean body mass (LBM), and body surface area (BSA) were significantly reduced after chemotherapy. Regardless of baseline or post-chemotherapy status, the incidence of grade ≥ 3 neutropenia was significantly higher in the sarcopenia group than in the non-sarcopenia group. Furthermore, when the skeletal muscle index decreased during chemotherapy, the incidence of grade ≥ 3 neutropenia was significantly higher in both the sarcopenia and non-sarcopenia groups compared to baseline. When the incidence of grade ≥ 3 neutropenia in the post-chemotherapy sarcopenia group was compared to baseline status, the increase was significantly higher in the sarcopenia group than in the maintenance/increase group. Conclusions: Skeletal muscle mass decreased progressively during XELOX/SOX chemotherapy in gastric cancer patients, followed by a higher incidence of grade ≥ 3 neutropenia.

Benralizumab efficacy and safety in severe asthma: A randomized trial in Asia.

BACKGROUND: Benralizumab is indicated as add-on therapy in patients with uncontrolled, severe eosinophilic asthma; it has not yet been evaluated in a large Asian population with asthma in a clinical trial. OBJECTIVE: To evaluate the efficacy and safety of benralizumab in patients with severe asthma in Asia. METHODS: MIRACLE (NCT03186209) was a randomized, Phase 3 study in China, South Korea, and the Philippines. Patients aged 12-75 years with severe asthma receiving medium-to-high-dose inhaled corticosteroid/long-acting ß2-agonists, stratified (2:1) by baseline blood eosinophil count (bEOS) (≥300/µL; <300/µL), were randomized (1:1) to benralizumab 30 mg or placebo. Endpoints included annual asthma exacerbation rate (AAER; primary endpoint), change from baseline at Week 48 in pre-bronchodilator (BD) forced expiratory volume in 1 second (pre-BD FEV1) and total asthma symptom score (TASS). Safety was evaluated ≤ Week 56. RESULTS: Of 695 patients randomized, 473 had baseline bEOS ≥300/µL (benralizumab n = 236; placebo n = 237). In this population, benralizumab significantly reduced AAER by 74% (rate ratio 0.26 [95% CI 0.19, 0.36], p < 0.0001) and significantly improved pre-BD FEV1 (least squares difference [LSD] 0.25 L [95% CI 0.17, 0.34], p < 0.0001) and TASS (LSD -0.25 [-0.45, -0.05], p = 0.0126) versus placebo. In patients with baseline bEOS <300/µL, there were numerical improvements in AAER, pre-BD FEV1, and TASS with benralizumab versus placebo. The frequency of adverse events was similar for benralizumab (76%) and placebo (80%) in the overall population. CONCLUSIONS: MIRACLE data reinforces the efficacy and safety of benralizumab for severe eosinophilic asthma in an Asian population, consistent with the global Phase 3 results.

Network analysis of depressive and anxiety symptoms in older Chinese adults with diabetes mellitus.

Background: The move away from investigating mental disorders as whole using sum scores to the analysis of symptom-level interactions using network analysis has provided new insights into comorbidities. The current study explored the dynamic interactions between depressive and anxiety symptoms in older Chinese adults with diabetes mellitus (DM) and identified central and bridge symptoms in the depression-anxiety network to provide potential targets for prevention and intervention for depression and anxiety. Methods: This study used a cross-sectional design with data from the 2017-2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). A regularized partial correlation network for depressive and anxiety symptoms was estimated based on self-reported scales completed by 1685 older adults with DM aged 65 years or older. Depressive and anxiety symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) and the Seven-Item Generalized Anxiety Disorder Scale (GAD-7), respectively. Expected influence (EI) and bridge expected influence (BEI) indices were calculated for each symptom. Results: According to cutoff scores indicating the presence of depression and anxiety, the prevalences of depression and anxiety in our sample were 52.9% and 12.8%, respectively. The comorbidity rate of depression and anxiety was 11.5%. The six edges with the strongest regularized partial correlations were between symptoms from the same disorder. "Feeling blue/depressed", "Nervousness or anxiety", "Uncontrollable worry", "Trouble relaxing", and "Worry too much" had the highest EI values. "Nervousness or anxiety" and "Everything was an effort" exhibited the highest BEI values. Conclusion: Central and bridge symptoms were highlighted in this study. Targeting these symptoms may be effective in preventing the comorbidity of depressive and anxiety symptoms and facilitate interventions in older Chinese adults with DM who are at risk for or currently have depressive and anxiety symptoms.

Causal association between genetically predicted circulating immune cell counts and frailty: a two-sample Mendelian randomization study.

Background: Despite the recognized link between immune responses and frailty, the association between immune cell counts and frailty based on previous observational studies remains disputed, with uncertain causal nexus. This study aimed to elucidate causal association between genetically predicted circulating immune cell counts and frailty. Methods: We conducted the two-sample Mendelian randomization (MR) study with independent genetic variants associated with six immune cell subtype counts from genome-wide association studies in 563,946 European individuals. Frailty summary data, assessed via frailty index (FI), was obtained from study comprising 175,226 subjects. Univariate MR, reverse MR and multivariate MR were conducted to comprehensive investigate the association between immune cell counts and FI, with two-step MR analysis for mediation analysis. Results: Univariate MR evidence indicated that among six leukocyte subtype counts, only elevated eosinophil count was significantly correlated with higher FI (ß = 0.059, 95% confidence interval [CI], 0.042-0.078, P=5.63E-11), with no reverse causal relationship identified in reverse MR. In multivariate MR, the causal effect of eosinophil count retained statistical significance (ß = 0.063, 95% CI, 0.021-0.104, P = 0.003). Ultimately, the two-step MR analysis demonstrated two mediators in this causal pathway: asthma (ß= 0.019, 95% CI, 0.013-0.025, P = 35.84E-10, mediated proportion, 31.732%) and rheumatoid arthritis (ß= 0.004, 95% CI, 0.001-0.006, P=1.75E-03, mediated proportion, 6.411%). Conclusions: Within immune cell subtypes, MR evidence indicated only genetically predicted circulating eosinophil count had irreversible and independent causal effect on frailty, with asthma and rheumatoid arthritis possibly serving as partial mediators. The finding stressed the need for further exploring physiological functions of eosinophils in order to develop effective strategies against frailty.

Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression.

Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 (CDH2) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of CDH2 promoter.

Review of lipocalin-2-mediated effects in diabetic retinopathy.

BACKGROUND: Studies have uncovered LCN2 as a marker of inflammation strongly related to obesity, insulin resistance, and abnormal glucose metabolism in humans, and is involved in vascular diseases, inflammatory diseases, and neurological diseases. In recent years, studies have shown that elevated levels of LCN2 have a strong association with diabetic retinopathy (DR), but the pathogenesis is unknown. Here, we reviewed the relevant literature and compiled the pathogenesis associated with LCN2-induced DR. METHODS: We searched PubMed and Web of Science electronic databases using "lipocalin-2, diabetic retinopathy, retinal degeneration, diabetic microangiopathies, diabetic neuropathy and inflammation" as subject terms. RESULTS: In diabetic retinal neuropathy, LCN2 causes impaired retinal photoreceptor function and retinal neurons; in retinal microangiopathy, LCN2 induces apoptosis of retinal vascular endothelial cells and promotes angiogenesis; in retinal inflammation, increased secretion of LCN2 recruits inflammatory cells and induces pro-inflammatory cytokines. Moreover, LCN2 has the potential as a biomarker for DR. Recent studies have shown that retinal damage can be attenuated by silencing LCN2, which may be associated with the inhibition of caspase-1-mediated pyroptosis, and LCN2 may be a new target for the treatment of DR. CONCLUSIONS: In conclusion, LCN2, involved in the development of diabetic retinopathy, is a key factor in diabetic retinal microangiopathy, neurodegeneration, and retinal inflammation. LCN2 is likely to be a novel molecular target leading to DR, and a more in-depth study of the pathogenesis of DR caused by LCN2 may provide considerable benefits for clinical research and potential drug development.

A new perspective for evaluating the efficacy of tACS and tDCS in improving executive functions: A combined tES and fNIRS study.

BACKGROUND: Executive function enhancement is considered necessary for improving the quality of life of patients with neurological or psychiatric disorders, such as attention-deficit/hyperactivity disorder, obsessive-compulsive disorder and Alzheimer's disease. Transcranial electrical stimulation (tES) has been shown to have some beneficial effects on executive functioning, but the quantification of these improvements remains controversial. We aimed to explore the potential beneficial effects on executive functioning induced by the use of transcranial alternating current stimulation (tACS)/transcranial direct current stimulation (tDCS) on the right inferior frontal gyrus (IFG) and the accompanying brain function variations in the resting state. METHODS: We recruited 229 healthy adults to participate in Experiments 1 (105 participants) and 2 (124 participants). The participants in each experiment were randomly divided into tACS, tDCS, and sham groups. The participants completed cognitive tasks to assess behavior related to three core components of executive functions. Functional near-infrared spectroscopy (fNIRS) was used to monitor the hemodynamic changes in crucial cortical regions in the resting state. RESULTS: Inhibition and cognitive flexibility (excluding working memory) were significantly increased after tACS/tDCS, but there were no significant behavioral differences between the tACS and tDCS groups. fNIRS revealed that tDCS induced decreases in the functional connectivity (increased neural efficiency) of the relevant cortices. CONCLUSIONS: Enhancement of executive function was observed after tES, and the beneficial effects of tACS/tDCS may need to be precisely evaluated via brain imaging indicators at rest. tDCS revealed better neural benefits than tACS during the stimulation phase. These findings might provide new insights for selecting intervention methods in future studies and for evaluating the clinical efficacy of tES.

Association between ambient temperature, PM2.5 and tuberculosis in Northwest China.

Existing evidence suggested that the risk of tuberculosis (TB) infection was associated to the variations in temperature and PM2.5. A total of 9,111 cases of TB were reported in Ningxia Hui Autonomous Region, China from 2013 to 2015 on a daily basis, and 57.2% of them were male. The TB risk was more prominent for a lower temperature in males (RR of 1.724, 95% CI: 1.241, 2.394), the aged over 64 years (RR of 2.241, 95% CI: 1.554, 3.231), and the high mobility occupation subpopulation (RR of 2.758, 95% CI: 1.745, 4.359). High concentration of PM2.5 showed a short-term effect and was only associated with an increased risk in the early stages of exposure for the female, and aged 36-64 years group. There were 15.06% (1370 cases) of cases of TB may be attributable to the temperature, and 2.94% (268 cases) may be attributable to the increase of PM2.5 exposures. Low temperatures may be associated with significantly increase in the risk of TB, and high PM2.5 concentrations have a short-term association on increasing the risk of TB. Strengthening the monitoring and regular prevention and control of high risk groups will provide scientific guidance to reduce the incidence of TB.

Comprehensive Analysis of N6-Methyladenosine RNA Methylation Regulators in the Diagnosis and Subtype Classification of Rheumatoid Arthritis.

m6A modification is the most abundant mRNA modifications and plays an integral role in various biological processes in eukaryotes. However, the role of m6A regulators in rheumatoid arthritis remains unknown. To determine the expression of m6A RNA methylation regulators in rheumatoid arthritis and their possible functional and prognostic value. In this study, we performed differential analysis in the comprehensive gene expression database GSE93272 dataset between non-rheumatoid arthritis patients and rheumatoid arthritis patients to obtain 15 important m6A regulators. A random forest model and lasso regression were used to screen the five most important m6A regulators to predict the risk of developing rheumatoid arthritis. After further validation using in vitro qPCR experiments, a nomogram model was developed based on the four most important m6A regulators (ELAVL1, WTAP, YTHDF1, and ALKBH5). Immuno-infiltration analysis and consensus clustering analysis were then performed. An analysis of the decision curve showed that the nomogram model could be beneficial to patients. According to selected important m6A regulators, patients with rheumatoid arthritis were classified into two m6A models (ClusterA and ClusterB) via consensus approach. Activated B cells, CD56dim natural killer cells, immature B cells, monocytes, natural killer T cells, and T lymphocytes were associated with ClusterA in immune infiltration analysis. Importantly, immune infiltration in patients with high ELAVL1 expression was strikingly similar to ClusterA. m6A regulators play a non-negligible role in the development of rheumatoid arthritis. A study of m6A patterns may provide future therapeutic options for rheumatoid arthritis.

Low m6A modification-mediated upregulation of PLAC8 promotes trophoblast cell invasion and migration in preeclampsia.

BACKGROUND: The main symptoms of preeclampsia (PE), a specific ailment that develops during pregnancy, are proteinuria and hypertension. The pathological root of the onset and progression of PE is widely regarded as abnormal placental trophoblast cell function. This study aimed to look into the character and mechanism of Placenta-specific 8 (PLAC8) in trophoblast cell invasion and migration. METHODS: Expressions of PLAC8 and AlkB homologue 5 (ALKBH5) were examined by western blot and quantitative real-time PCR. The m6A level of PLAC8 mRNA was detected by methylated RNA Immunoprecipitation. Using Transwell experiments, cell invasion and migration were examined. The enzyme-linked immunosorbent assay was utilized to analyze the MMP-2 and MMP-9 secretion levels. RNA pull-down and RNA immunoprecipitation were conducted to detect the binding between ALKBH5 and PLAC8. RESULTS: In PE tissue and hypoxia-treated HTR-8/SVneo cells, levels of ALKBH5 and PLAC8 were increased, and PLAC8 m6A methylation levels were decreased. There was a positive correlation between PLAC8 and ALKBH5 expression in clinical tissues. In addition, overexpressing PLAC8 promoted HTR-8/SVneo cell migration and invasion, and so as the levels of MMP-2 and MMP-9; while interference with PLAC8 reduced the migration and invasion of hypoxia-treated HTR-8/SVneo cells, and so as the levels of MMP-2 and MMP-9. Moreover, the PLAC8 mRNA's m6A modification site was GAACU (Position 1449, Site 2). Increased levels of MMP-2 and MMP-9, as well as migration and invasion of HTR-8/SVneo cells exposed to hypoxia, were all facilitated by the m6A Site2 mutation. Furthermore, ALKBH5 could bind to PLAC8, reduce its m6A modification, and promote its expression. CONCLUSION: High-expressed ALKBH5 inhibits the m6A level of PLAC8 mRNA and promotes PLAC8 expression, while PLAC8 overexpression can promote hypoxia-induced invasion and migration of HTR-8/Svneo cells, indicating its potential protective function in PE.