A cohort study on IVF outcomes in infertile endometriosis patients: the effects of rapamycin treatment.

RESEARCH QUESTION: Can rapamycin, used as an anti-senescence drug before IVF cycles, improve the IVF outcomes of women with endometriosis by reducing oxidative stress and senescence? DESIGN: This retrospective analysis involved 168 endometriosis patients undergoing two successive IVF cycles. The treatment group (n = 80) received 3 months of rapamycin before the second IVF cycle, while the non-treatment group (n = 88) had no adjuvant treatment. The first and second IVF cycles were compared between and within groups. Follicular fluid from both IVF cycles (treatment group n = 28, non-treatment group n = 32) were tested for senescence-associated and oxidative stress-related markers. RESULTS: Comparing the follicular fluid from the second cycles, the rapamycin treatment group showed decreased markers of oxidative stress (8-hydroxydesoxyguanosine, malondialdehyde) and increased antioxidant markers (superoxidase dismutase, glutathione peroxidase) (all P < 0.001); the expression of senescence-related markers p16 and p21 was also significantly lower in the treatment group than in the non-treatment group (P < 0.001). Comparing the second IVF cycles, the treatment group needed fewer days of ovarian stimulation, with increased numbers of oocytes obtained and mature oocytes compared with the non-treatment group (all P < 0.001). Furthermore, rates of fertilization, implantation and clinical pregnancy were significantly higher in the treatment group (P = 0.008, 0.034 and 0.038 respectively), as was the live birth rate (P = 0.003). No structural abnormalities were seen in fetuses born to women treated with rapamycin. CONCLUSIONS: This study suggested an association between short-term rapamycin treatment and improved pregnancy outcomes via IVF. This result needs to be further investigated in prospective randomized controlled clinical trials.

The regulatory role of autophagy between TAMs and tumor cells.

Cancer has become a global public health problem and its harmful effects have received widespread attention. Conventional treatments such as surgical resection, radiotherapy and other techniques are applicable to clinical practice, but new drugs are constantly being developed and other therapeutic approaches, such as immunotherapy are being applied. In addition to studying the effects on individual tumor cells, it is important to explore the role of tumor microenvironment on tumor cell development since tumor cells do not exist alone but in the tumor microenvironment. In the tumor microenvironment, tumor cells are interconnected with other stromal cells and influence each other, among which tumor-associated macrophages (TAMs) are the most numerous immune cells. At the same time, it was found that cancer cells have different levels of autophagy from normal cells. In cancer therapy, the occurrence of autophagy plays an important role in promoting tumor cell death or inhibiting tumor cell death, and is closely related to the environment. Therefore, elucidating the regulatory role of autophagy between TAMs and tumor cells may be an important breakthrough, providing new perspectives for further research on antitumor immune mechanisms and improving the efficacy of cancer immunotherapy.

Offspring of women with hyperemesis gravidarum are more likely to have cardiovascular abnormalities.

BACKGROUND: Hyperemesis gravidarum (HG) is a severe form of pregnancy-related nausea and vomiting affecting 0.3-2.3% of pregnancies, which can lead to fluid, electrolyte, and acid-base imbalances, nutritional deficiencies, and weight loss, and is usually severe enough to require hospitalization. Abnormally elevated urinary ketones are commonly seen in patients with HG, and ketone bodies are free to pass through the placenta, and maternal hyperketonemia, with or without acidosis, is associated with an increased rate of stillbirth, an increased incidence of congenital anomalies, and impaired neurophysiologic development of the infant. This study investigates the obstetric outcomes of patients with HG and whether HG increases the incidence of cardiovascular disease in the offspring. METHODS: This study included 1020 pregnant women who were hospitalized in our hospital for HG and ultimately delivered in our hospital as well as pregnant women without HG in early gestation and delivered in our hospital from January 2019-January 2020, and we collected and followed up the clinical information of the pregnant women and their offspring. RESULTS: Pregnant women with HG were more likely to have severe urinary ketones, the rate of early miscarriage and mid-term miscarriage was significantly higher in women with HG compared to pregnant women without HG. Fetal and neonatal head and abdominal circumferences were smaller in HG group than in control group. Neonatal birth weight and length were also lower in the HG group and cardiovascular anomalies were more likely to occur in the offspring of women with HG when all births were followed up for 3 years. CONCLUSIONS: HG may cause poor obstetric outcomes and was associated with the development of cardiovascular disease in the offspring of women with HG.

XGBoost-based machine learning test improves the accuracy of hemorrhage prediction among geriatric patients with long-term administration of rivaroxaban.

BACKGROUND: Hemorrhage is a potential and serious adverse drug reaction, especially for geriatric patients with long-term administration of rivaroxaban. It is essential to establish an effective model for predicting bleeding events, which could improve the safety of rivaroxaban use in clinical practice. METHODS: The hemorrhage information of 798 geriatric patients (over the age of 70 years) who needed long-term administration of rivaroxaban for anticoagulation therapy was constantly tracked and recorded through a well-established clinical follow-up system. Relying on the 27 collected clinical indicators of these patients, conventional logistic regression analysis, random forest and XGBoost-based machine learning approaches were applied to analyze the hemorrhagic risk factors and establish the corresponding prediction models. Furthermore, the performance of the models was tested and compared by the area under curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: A total of 112 patients (14.0%) had bleeding adverse events after treatment with rivaroxaban for more than 3 months. Among them, 96 patients had gastrointestinal and intracranial hemorrhage during treatment, which accounted for 83.18% of the total hemorrhagic events. The logistic regression, random forest and XGBoost models were established with AUCs of 0.679, 0.672 and 0.776, respectively. The XGBoost model showed the best predictive performance in terms of discrimination, accuracy and calibration among all the models. CONCLUSION: An XGBoost-based model with good discrimination and accuracy was built to predict the hemorrhage risk of rivaroxaban, which will facilitate individualized treatment for geriatric patients.

DNA Methylome Mapping Identifies Epigenetic Abnormalities in Intestinal Lymphocyte Regulation in Human Necrotizing Enterocolitis.

BACKGROUND: Epigenetic changes occur in response to environmental factors during the pathogenesis of necrotizing enterocolitis (NEC) in animal models, but the DNA methylation signature in human patients with NEC has not been examined. AIM: To illustrate the signature and function of DNA methylation in the intestine of human NEC. METHODS: DNA methyltransferases (DNMTs) were compared between intestinal tissue with NEC and control. Genome-wide DNA methylation was analyzed by reduced representation bisulfite sequencing (RRBS). The biological functions of the potential methylation regulated genes were analyzed by Gene Ontology. Gene methylation and expression were confirmed by bisulfite genomic sequencing (BGS) and RT-qPCR. RESULTS: By screening the expression of DNMTs, we identified a marked reduction in DNMT3A at both the mRNA and protein levels in NEC. Genome-wide variation of DNA methylation was detected in NEC lesions. The CG methylation level in almost all unique regions except CpG islands (CGIs) was lower in NEC compared with control. A total of 287 differentially methylated regions (DMRs) were identified across the whole genome in NEC, 123 of them are located on the CGI in the promoter. The DMR-associated genes were linked to intestinal epithelial permeability, platelet aggregation, and lymphocyte proliferation. Four genes (ZNF335, MPL, RASAL3, and KDM6A) with roles in the regulation of lymphocytes that may predispose the intestine to imbalanced immune processes were further confirmed to be hypermethylated and transcriptionally downregulated. CONCLUSIONS: These findings underscore the novel relationship between epigenetic changes and lymphocyte regulation in human NEC, which may have potential diagnostic and therapeutic relevance for NEC.

Interleukin-36γ aggravates macrophage foam cell formation and atherosclerosis progression in ApoE knockout mice.

Atherosclerosis-related cardiovascular diseases are the leading cause of mortality worldwide. Macrophage-derived foam cell formation is a critical early event in atherogenesis. However, the molecular pathways involved in this disease have not been fully elucidated. Interleukin (IL)-36 plays a crucial role in inflammation, and this study was conducted to investigate the possible role of IL-36γ in the pathogenesis and regulation of atherosclerosis. In this study, we show that IL-36γ regulates inflammatory responses and lipoprotein metabolic processes in macrophages and exerts its atherosclerosis-promoting effects by increasing macrophage foam cell formation and uptake of oxidized low-density lipoproteins. Mechanistically, IL-36γ specifically upregulates expression of the scavenger receptor CD36 through the phosphoinositide 3-kinase pathway in macrophages. These results contribute to our understanding of IL-36γ as a novel regulator of foam cell formation and atherogenesis progression.

Distal-less homeobox 5 promotes the osteo-/dentinogenic differentiation potential of stem cells from apical papilla by activating histone demethylase KDM4B through a positive feedback mechanism.

Understanding the mechanism of osteo-/dentinogenic differentiation is beneficial for jaw bone and dental tissue regeneration. DLX5 is highly expressed in dental tissue-derived mesenchymal stem cells (MSCs) and is upregulated by lysine-specific demethylase 4B (KDM4B), enabling it to regulate osteo-/dentinogenic differentiation, while the function of DLX5 in osteo-/dentinogenesis has not been thoroughly elucidated to date. Therefore, we investigated DLX5 function using stem cells from apical papilla (SCAPs). SCAPs were obtained from the human wisdom tooth. Alkaline phosphatase (ALP) assay, Alizarin red staining (ARS), quantitative analysis of calcium, osteo-/dentinogenesis-related gene expression and in vivo transplantation were used to determine the osteo-/dentinogenic differentiation potential. Luciferase and ChIP assays were used to investigate the physical relationship between DLX5 and KDM4B. DLX5 and KDM4B were upregulated during osteogenic induction and were induced by BMP4 in SCAPs. Next, we found that DLX5 enhanced ALP activity, mineralization in vitro, and the expression of dentin sialophosphoprotein (DSPP), dentin matrix acidic phosphoprotein 1 (DMP1), osteopontin (OPN), and the key transcription factor osterix (OSX). Moreover, transplant experiments showed that DLX5 promoted osteo-/dentinogenesis in vivo. Interestingly, DLX5 enhanced KDM4B transcription by directly binding with its promoter. In addition, KDM4B upregulated DLX5 in SCAPs. These results indicate that DLX5 and KDM4B are positive effectors of BMP signaling and regulate each other via a positive feedback mechanism. DLX5 enhanced osteo-/dentinogenic differentiation via upregulated KDM4B in SCAPs, suggesting that activation of the DLX5/KDM4B signaling pathway might serve as an intrinsic mechanism that promotes tissue regeneration mediated by dental-derived MSCs.

Nuclear retention of the lncRNA SNHG1 by doxorubicin attenuates hnRNPC-p53 protein interactions.

The protein p53 plays a crucial role in the regulation of cellular responses to diverse stresses. Thus, a major priority in cell biology is to define the mechanisms that regulate p53 activity in response to stresses or maintain it at basal levels under normal conditions. Moreover, further investigation is required to establish whether RNA participates in regulating p53's interaction with other proteins. Here, by conducting systematic experiments, we discovered a p53 interactor-hnRNPC-that directly binds to p53, destabilizes it, and prevents its activation under normal conditions. Upon doxorubicin treatment, the lncRNA SNHG1 is retained in the nucleus through its binding with nucleolin and it competes with p53 for hnRNPC binding, which upregulates p53 levels and promotes p53-dependent apoptosis by impairing hnRNPC regulation of p53 activity. Our results indicate that a balance between lncRNA SNHG1 and hnRNPC regulates p53 activity and p53-dependent apoptosis upon doxorubicin treatment, and further indicate that a change in lncRNA subcellular localization under specific circumstances is biologically significant.

[Effects of different drying conditions on protein in Cordyceps].

In this study,the protein in different Cordyceps samples,which include fresh sample( S1),22 ℃ drying sample( S2),37 ℃ drying sample( S3) and 60 ℃ drying sample( S4),were analyzed by sodium dodecylsupinate-polyacrylamide gel electrophoresis( SDS-PAGE) and two-dimensional electrophoresis( 2-DE). The total protein contents in Cordyceps samples were from 1. 655-4. 493 mg·g~(-1) and the protein contents in fresh sample was the highest. The results of SDS-PAGE showed that the mainly ranges of protein molecular weight of Cordyces samples were 10-100 kDa and the numbers of protein bands were 28 to 41,the fresh sample had the maximum number of protein bands. The 2-DE profiles were analyzed by PDQuest software. The resulted indicated that 488-876 protein spots were detected in different Cordyceps samples and the isoelectric point( pI) was distributed between 4. 5 and 6. 5,the protein molecular weight was distributed in 10-20 kDa and 25-100 kDa,the fresh sample had the maximum number of protein spots. Therefore,the drying process could decrease contents and species of protein in Cordyceps,and the different drying conditions had different effects on protein. These results provide a reference for improving the drying process of Cordyceps.

The effects of dentoalveolar distraction extraction on alveolar ridge preservation: Cone-beam computed tomography and X-ray analysis in canine model.

OBJECTIVE: This study aims to evaluate the effect of dentoalveolar distraction extraction (DDE) on site preservation, and to evaluate how the technique keeps the height and width of alveolar bones to a greater extent. METHODS: 12 beagle dogs, randomly divided into three groups (DDE group, NH group, BOG group), were used. In the dogs of three groups, the root of the left or right third mandibular premolars were respectively extracted by three methods namely, DDE, traditional extraction with natural healing, and traditional extraction with Bio-Oss bone dust implanted and guided bone regeneration (GBR). Cone-beam computed tomography (CBCT) scans and X-rays were taken immediately and three months after the tooth extraction. The height and width of the alveolar ridges were compared among different groups. RESULTS: Three months after tooth extraction, at the 1 mm level below the alveolar ridge crest, the amount and degree of buccal alveolar ridge width resorption in DDE group were significantly lower than that of NH and BOG group (P < 0.05). At the 2 mm and 3 mm level below the alveolar ridge crest, the amount and degree of buccal alveolar ridge width resorption in DDE group and BOG had no significant difference, and both were significant lower than that of NH group (P < 0.05). The height resorption of alveolar ridge in DDE group was significantly lower than NH and BOG groups (P < 0.05), while NH and BOG group had no statistically significant. CONCLUSIONS: To a greater extent, the alveolar ridge preservation through DDE could preserve the height and width of alveolar ridge crest.

Plasmonic Metasurfaces Based on Nanopin-Cavity Resonator for Quantitative Colorimetric Ricin Sensing.

In view of the toxic potential of a bioweapon threat, rapid visual recognition and sensing of ricin has been of considerable interest while remaining a challenging task up to date. In this study, a gold nanopin-based colorimetric sensor is developed realizing a multicolor variation for ricin qualitative recognition and analysis. It is revealed that such plasmonic metasurfaces based on nanopin-cavity resonator exhibit reflective color appearance, due to the excitation of standing-wave resonances of narrow bandwidth in visible region. This clear color variation is a consequence of the reflective color mixing defined by different resonant wavelengths. In addition, the colored metasurfaces appear sharp color difference in a narrow refractive index range, which makes them especially well-suited for sensing applications. Therefore, this antibody-functionalized nanopin-cavity biosensor features high sensitivity and fast response, allowing for visual quantitative ricin detection within the range of 10-120 ng mL-1 (0.15 × 10-9 -1.8 × 10-9 m), a limit of detection of 10 ng mL-1 , and the typical measurement time of less than 10 min. The on-chip integration of such nanopin metasurfaces to portable colorimetric microfluidic device may be envisaged for the quantitative studies of a variety of biochemical molecules.

Genetic Investigation of Complement Pathway Genes in Type 2 Diabetic Retinopathy: An Inflammatory Perspective.

Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs of SERPING1 and C5 were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the six C5 SNPs, a marginal association was first detected between rs17611 and total DR patients (P = 0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (Pcorr = 0.032, OR = 0.65 and Pcorr = 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (Pcorr = 0.023). Regarding other variants in C5 and SERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (all P > 0.05). Our study revealed an association between DR and C5 polymorphisms with clinical significance, whereas SERPING1 is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis.

Oxidative Stress Is Involved in the Renal Dysfunction Induced by Sinoaortic Denervation in Rats.

The hypothesis that oxidative stress contributes to renal dysfunction in sinoaortically denervated (SAD) rats was investigated. Rats were sinoaortically denervated and received treatment with tempol (0.5 mmol/L in drinking water) for 8 weeks. Although the tempol treatment of the SAD rats had no significant effect on blood pressure or blood pressure viability, it significantly ameliorated the renal dysfunction as indicated by increases in renal blood flow (RBF) and the glomerular filtration rate (GFR) and reductions in plasma creatinine, blood urea nitrogen (BUN), the urine albumin excretion rate (UAE), and the glomerular sclerosis score (GSS). The SAD rats treated with tempol exhibited decreased plasma and renal malondialdehyde (MDA) levels and reduced renal formation of reactive oxygen species (ROS), superoxide (O2-), peroxynitrite (OONO-) and 3-nitrotyrosine. Treatment with tempol suppressed the nuclear concentration of nuclear factor-kappaB (NF-κB) and reduced the renal levels of macrophage chemoattractant protein 1 (MCP-1) and interleukin-6 (IL-6). The tempol-treated SAD rats exhibited decreased renal advanced glycation end product (AGE) levels and decreased receptor for advanced glycation end products (RAGE) protein expression. The tempol treatment of the SAD rats restored mitochondrial adenosine triphosphate (ATP) formation, DNA content, membrane integrity and the renal oxygen consumption rate. Additionally, the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S epoxide transferase (GST), and catalase were decreased, and the activities of xanthin oxidase (XO) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were enhanced in the kidneys of the SAD rats. In conclusion, our work firstly provided direct evidence that oxidative stress played an important role in the renal dysfunction of SAD rats.

MicroRNA-15b enhances hypoxia/reoxygenation-induced apoptosis of cardiomyocytes via a mitochondrial apoptotic pathway.

Myocardial ischemia reperfusion (I/R) can induce altered expression of microRNAs (miRNAs). The miRNAs-miR-15a, miR-15b and miR-16 have been shown to play a role in apoptosis, although not in cardiac-related models. We investigated the roles of miR-15b in hypoxia/reoxygenation (H/R)-induced apoptosis of cardiomyocytes. Quantitative real time polymerase chain reaction results showed that the expression of miR-15a and miR-15b were up-regulated in Sprague-Dawley rat hearts subjected to I/R. Expression levels of miR-15b increased more than four fold above basal levels. Similar results were obtained for cardiomyocytes exposed to H/R. Recombinant adenoviral vectors were generated to explore the functional role of miR-15b in cultured cardiomyocytes exposed to H/R. Overexpression of miR-15b enhanced cell apoptosis and the loss of mitochondrial membrane potential, as determined by flow cytometric analysis. Conversely, down-regulated expression was cytoprotective. The effects of miR-15b can by mimicked by Bcl-2 short-interfering RNAs. The inhibition of miR-15b increased expression levels of the Bcl-2 protein without affecting Bcl-2 mRNA levels, suppressed the release of mitochondrial cytochrome c to the cytosol and decreased the activities of caspase-3 and 9. It is possible that miR-15b is the upstream regulator of a mitochondrial signaling pathway for H/R induced apoptosis.

[Effects of carbon components of fine particulate matter (PM2.5) on atherogenic index of plasma].

OBJECTIVE: To evaluate associations between carbon constituents of fine particulate matter (PM2.5) and atherogenic index of plasma (AIP). METHODS: We collected subjects from two communities by a system sampling, and 112 people aged over 60 years old without cardiovascular disease were recruited. The levels of cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) of objects, and personal exposure to PM2.5 were measured on December, 2011. Total carbon (TC), organic carbon (OC) and elemental carbon (EC) of PM2.5 were detected and AIP was calculated according to its definition. RESULTS: The value of AIP among the 112 subjects was 0.05 ± 0.26. Personal exposure concentration of PM2.5 and its carbon components (TC,OC and EC) were (164.75 ± 110.67), (53.86 ± 29.65), (44.93 ± 26.37) and (9.49 ± 5.75) µg/m(3), respectively. The Pearson analysis showed the linear relationship between TC,OC,EC and AIP, all significant positive correlations. The correlation coefficients were TC (r = 0.307, P < 0.05),OC (r = 0.287, P < 0.05) and EC (r = 0.252, P < 0.05), respectively. The multiple logistic regression analysis showed that when the AIP risk categories were selected as dependent variable and low risk group as reference group, the regression coefficient of TC,OC and EC was separately 1.03 (95%CI:1.01-1.05), 1.03 (95%CI:1.01-1.05), 1.12 (95%CI:1.02-1.22) in the high risk group; while there was no statistical significance of the regression coefficient and OR in the middle risk group. CONCLUSION: There was stable associations between the carbon constituents (TC,OC and EC) of fine Particulate Matter (PM2.5) and AIP. The findings suggested that carbon components of PM2.5 should be considered as risk factors of atherogenic.

Hypermethylation of Klotho and Peroxisome Proliferator-Activated Receptor γ Concomitant with Overexpression of DNA Methyltransferase 1 in Adenomyosis.

Cellular senescence is known to be involved in tissue repair, but its role in adenomyosis remains unclear. This study was tasked to evaluate the expression of Klotho, a well-known aging-suppressing protein, as well as PPARγ and DNMT1 in adenomyotic lesions (AD) in comparison with that of control endometrium (CT). We performed immunohistochemistry analysis of markers of cellular senescence p16 and p21, along with Klotho, PPARγ and DNMT1 in CT and AD samples, followed by the quantification of gene expression of Klotho, PPARγ and DNMT1 in epithelial organoids derived from AD and CT samples and methylation-specific PCR to evaluate promoter methylation status. The effect of forced expression and knockdown of DNMT1 on Klotho and PPARγ expression in ectopic endometrial epithelial cells was evaluated. We found that both p16 and p21 immunoreactivity in AD was significantly higher while that of Klotho and PPARγ was significantly lower than CT samples, which was concomitant with elevated immunoexpression of DNMT1. The results were confirmed by transcriptional analysis using epithelial organoids derived from AD and CT samples. In addition, the promoter regions of both Klotho and PPARγ genes were hypermethylated in AD as compared with CT, and treatment with HDAC and DNMT inhibitors reactivated the expression of both Klotho and PPARγ. Forced expression of DNMT1 resulted in downregulation of both Klotho and PPARγ but its knockdown increased their expression. Thus, overexpression of DNMT1 seems to facilitate the promoter hypermethylation of both Klotho and PPARγ in AD, resulting in their reduced expression that is suggestive of the role of senescence in adenomyosis.

Investigation of the shared gene signatures and molecular mechanisms between obstructive sleep apnea syndrome and asthma.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is highly related with asthma from the epidemiology to pathogenesis, while the underlying mechanism is still unclear. Herein, we aimed to reveal the shared gene signatures and molecular mechanisms underlying the coexistence of OSAS and asthma and verified relating pathway in mouse models. We downloaded GSE75097 of OSAS and GSE165934 of asthma from GEO database and performed differential expression analysis and functional enrichment analysis to screen differentially expressed genes (DEGs) and potential pathogenic pathway. PPI network was constructed with the STRING database. Hub genes were identified with cytoHubba and immune infiltration analysis was performed with cibersort for further verification. Potential drugs were screened with Comparative Toxicogenomics Database and miRNA-gene network was constructed. Besides, to test the pulmonary function and inflammatory cytokine, mouse models with OSAS and asthma were constructed, followed by validating the involvement of NOD1/NOD2-RIPK2-NF-κB-MCPIP-1 pathway in associated diseases. RESULTS: In total, 104 DEGs were identified, in which PLAUR, RIPK2, PELI1, ZC3H12A, and TNFAIP8 are the hub genes, while NOD-like receptor signaling pathway and apoptosis signaling pathway were the potential influential pathways. Increased γδT cells and neutrophils were detected in asthma patients through immune infiltration analysis. Significant difference was detected among genders in OSAS, and acetaminophen is a potential drug in the comorbidity by screening the drugs in the Comparative Toxicogenomics Database. Mice with OSAS and asthma presented with worse pulmonary function and higher levels of inflammatory cytokines. The relative proteins, including NOD1, NOD2, RIPK2, NF-κB, and MCPIP-1, were up-regulated in mice with the OSAS and asthma. CONCLUSIONS: This research firstly elucidates NOD1/NOD2-RIPK2-NF-κB-MCPIP-1 pathway as the shared pathway in the development of OSAS and asthma through bioinformatics and experimental methods. There is an interactive deterioration model between OSAS and asthma. This study may provide some potential biomarkers in the future research of the underlying pathogenesis and treatment of comorbidity of OSAS and asthma.

Response of upper tropospheric water vapor to global warming and ENSO.

The upper tropospheric water vapor is a key component of Earth's climate. Understanding variations in upper tropospheric water vapor and identifying its influencing factors is crucial for enhancing our comprehension of global climate change. While many studies have shown the impact of El Niño-Southern Oscillation (ENSO) and global warming on water vapor, how they affect the upper tropospheric water vapor remains unclear. Long-term, high-precision ERA5 specific humidity data from the European Centre for Medium-Range Weather Forecasts (ECMWF) provided the data foundation for this study. On this basis, we successfully obtained the patterns of global warming (Independent Component 1, IC1) and ENSO (Independent Component 2, IC2) by employing the strategy of independent component analysis (ICA) combined with non-parametric optimal dimension selection to investigate the upper tropospheric water vapor variations and responses to ENSO and global warming. The results indicate that global warming and ENSO are the primary factors contributing to water vapor variations in the upper troposphere, achieving the significant correlations of 0.87 and 0.61 with water vapor anomalies respectively. Together, they account for 86% of the global interannual variations in water vapor. Consistent with previous studies, our findings also find positive anomalies in upper tropospheric water vapor during El Niño years and negative anomalies during La Niña years. Moreover, the influence extent of ENSO on upper tropospheric water vapor varies with the changing seasons.

Telomerase Reverse Transcriptase Regulates Intracellular Ca2+ Homeostasis and Mitochondrial Function via the p53/PGC-1α Pathway in HL-1 Cells.

BACKGROUND: Telomere shortening is strongly associated with cardiovascular aging and disease, and patients with shorter telomeres in peripheral blood leukocytes are at higher risk of cardiovascular diseases such as heart failure and atrial fibrillation (AF). Telomerase reverse transcriptase (TERT) maintains telomere length, and overexpression of TERT has been shown to reduce cardiomyocyte apoptosis and myocardial infarct size, and extend the lifespan of aged mice. However, the specific impact of TERT on the electrophysiology of cardiomyocytes remains to be elucidated. The aims of this study were to evaluate the role of TERT in Ca2+ homeostasis and mitochondrial function in atrial myocytes as well as the underlying mechanisms. METHODS: TERT overexpressed and silenced HL-1 cells were constructed with lentiviruses, and the respective empty lentiviral vectors were used as negative controls. Then the patch clamp technique was used to record the electrophysiological characteristics such as cell action potential duration (APD) and L-type Ca2+ currents (ICa,L), flow cytometry was used to detect intracellular Ca2+ concentration and mitochondrial membrane potential (MMP), and the Seahorse assay was used to measure the oxygen consumption rate (OCR). RESULTS: TERT silencing led to intracellular Ca2+ overload, shortened APD, decreased ICa,L current density, altered Ca2+ gating mechanism, decreased MMP and OCR, and increased reactive oxygen species (ROS), whereas TERT overexpression led to the reverse effects. Additionally, TERT silencing resulted in intracellular Ca2+ overload with decreased expression of the SERCA2a, CaV1.2, and NCX1.1, whereas TERT overexpression had opposing effects. Furthermore, we discovered that TERT could regulate the expression of p53 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The expression of PGC-1α was downregulated by the p53 agonist Tenovin-6 but upregulated by the p53 inhibitor PFTα. The effects of the PGC-1α inhibitor SR-18292 on intracellular Ca2+ and cell electrophysiology were similar to those of silencing TERT, whereas the PGC-1α agonist ZLN005 produced comparable outcomes to TERT overexpression. CONCLUSIONS: TERT silencing-induced Ca2+ overload and mitochondrial dysfunction may be one mechanism of age-related AF. Overexpression of TERT reduced the basis for arrhythmia formation such as AF, suggesting a favorable safety profile for TERT therapy. TERT regulated intracellular Ca2+ homeostasis and mitochondrial function through the p53/PGC-1α pathway. In addition, PGC-1α might be a novel target for AF, suggesting that intervention for AF should be not limited to abnormal cation handling.

Microorganism-regulated autophagy in gastrointestinal cancer.

Gastrointestinal cancer has always been one of the most urgent problems to be solved, and it has become a major global health issue. Microorganisms in the gastrointestinal tract regulate normal physiological and pathological processes. Accumulating evidence reveals the role of the imbalance in the microbial community during tumorigenesis. Autophagy is an important intracellular homeostatic process, where defective proteins and organelles are degraded and recycled under stress. Autophagy plays a dual role in tumors as both tumor suppressor and tumor promoter. Many studies have shown that autophagy plays an important role in response to microbial infection. Here, we provide an overview on the regulation of the autophagy signaling pathway by microorganisms in gastrointestinal cancer.