Association of methyl donor nutrients dietary intake and sleep disorders in the elderly revealed by the intestinal microbiome.

Currently, sleep disorders (SD) in the elderly are gaining prominence globally and are becoming a significant public health concern. Methyl donor nutrients (MDNs), such as vitamin B6, vitamin B12, folate, and choline, have been reported to have the potential to improve sleep disorders. Moreover, MDNs help to maintain gut flora homeostasis, and are closely associated with the development of SD. Nevertheless, there has been a lack of comprehensive human studies examining the association between MDNs intake and SD. In our study, we comprehensively evaluated the association between MDNs intake and SD in the elderly and used 16S rRNA gene sequencing to explore the underlying mechanism. We found that the SD group (n = 91) had a lower methyl-donor nutritional quality index (MNQI) and a trend toward lower intake compared to the control group (n = 147). Based on the intestinal microbiome, the beta diversity of the intestinal flora was higher in the high methyl-donor nutritional quality (HQ) group compared to the low methyl-donor nutritional quality (LQ) group, and it was lower in the SD group compared to the control group. This suggests that MDNs may regulate sleep by modulating the abundance distribution of the microbiota. Subsequently, we performed correlation analyses between the relative abundance of the microbiota, MDNs intake, and the Pittsburgh Sleep Quality Index (PSQI), identifying five genera with potential regulatory roles. The KEGG pathway analysis indicated that energy metabolism and one-carbon metabolism might be the pathways through which MDNs modulate sleep. This study offers dietary guidance strategies for managing SD in the elderly and provides insights for targeted microbiota intervention.

Reveal more mechanisms of precondition mesenchymal stem cells inhibiting inflammation.

Hypoxia can get more ability to inhibit inflammation. But how it impact on survival time of mesenchymal stem cells (MSCs) is confusing and how preconditioned MSCs inhibiting inflammation are partially known. Those issues decided the value of preconditioned MSCs by hypoxia.

GPR55 activation improves anxiety- and depression-like behaviors of mice during methamphetamine withdrawal.

Methamphetamine is a potent and highly addictive neurotoxic psychostimulant that triggers a spectrum of adverse emotional responses during withdrawal. G-protein coupled receptor 55 (GPR55), a novel endocannabinoid receptor, is closely associated with mood regulation. Herein, we developed a murine model of methamphetamine-induced anxiety- and depressive-like behavior during abstinence which showed a decreased GPR55 expression in the hippocampus. Activation of GPR55 mitigated these behavioral symptoms, concomitantly ameliorating impairments in hippocampal neurogenesis and reducing neuroinflammation. These findings underscore the pivotal role of GPR55 in mediating the neuropsychological consequences of methamphetamine withdrawal, potentially via mechanisms involving the modulation of hippocampal neurogenesis and inflammation.

Compromised Dynamic Cerebral Autoregulation in Patients with Restless Legs Syndrome.

Background: Restless legs syndrome (RLS) is a prevalent sensorimotor nervous system disorder in patients accompanied with insomnia, blood pressure fluctuation, and sympathetic dysfunction. These symptoms may disrupt cerebral hemodynamics. Dynamic cerebral autoregulation (dCA) describes the temporary response of cerebrovascular system to abrupt fluctuations in blood pressure, which keep cerebral blood flow stable and serve as a marker of cerebrovascular system ability. Objective: This research aimed to assess dCA in RLS patients. Methods: In this study, RLS patients were recruited and subsequently classified into four groups (mild, moderate, severe, and very severe) based on the International RLS Rating Scale (IRLS). Healthy controls matched for age and sex were enrolled. All participants were evaluated dCA by assessing phase difference (PD). A portion of patients with RLS was reassessed for dCA after one month of medication therapy (pramipexole [0.125 mg/day] and gabapentin [300 mg/day]). Results: There were altogether 120 patients with RLS and 30 controls completed the polysomnography and dCA assessment. PD was lower in the moderate, severe, and very severe RLS groups than that in the controls and mild RLS groups. Periodic limb movement index (PLMI), arousal index, and IRLS all showed a linear correlation with PD in RLS patients. Additionally, PD increased in RLS patients after therapy. Conclusion: The dCA was compromised in moderate, severe, and very severe RLS patients and was negatively correlated with the IRLS, arousal index, and PLMI. After 1 month of therapy, dCA improved in RLS patients.

FF-MAS prevents porcine ovarian granulosa cells from hypoxia-induced apoptosis via inhibiting STAT4 expression.

Follicular fluid meiosis-activating sterol (FF-MAS) is a small molecule compound found in follicular fluid, named for its ability to induce oocyte resumption of meiosis. Granulosa cells (GCs) within the follicle are typically located in a hypoxic environment under physiologic conditions due to limited vascular distribution. Previous research suggests that hypoxia-induced cell cycle arrest and apoptosis in GCs may be crucial triggering factors in porcine follicular atresia. However, the impact of FF-MAS on GCs within follicles has not been explored so far. In this study, we uncovered a novel role of FF-MAS in facilitating GC survival under hypoxic conditions by inhibiting STAT4 expression. We found that STAT4 expression was upregulated in porcine GCs exposed to 1% O2. Both gain and loss of function assays confirmed that STAT4 was required for cell apoptosis under hypoxia conditions, and that the GC apoptosis caused by hypoxia was markedly attenuated following FF-MAS treatment through inhibition of STAT4 expression. Correlation analysis in vivo revealed that GC apoptosis was associated with increased STAT4 expression, while the FF-MAS content in follicular fluid was negatively correlated with STAT4 mRNA levels and cell apoptosis. These findings elucidate a novel role of FF-MAS-mediated protection of GCs by inhibiting STAT4 expression under hypoxia, which might contribute to the mechanistic understanding of follicular development.

EGFR-mutant NSCLC may remodel TME from non-inflamed to inflamed through acquiring resistance to EGFR-TKI treatment.

BACKGROUND: EGFR-TKI represent the standard first-line therapy for advanced NSCLC harboring EGFR mutations. However, resistance to EGFR-TKI inevitably develops in nearly all patients. Previous clinical study have demonstrated that, some patients that failed EGFR-TKI therapy show a benefit outcome from immunotherapy. Our objective is to explore the immune microenviroment remodeling induced by EGFR-TKI treatment in EGFR mutant lung cancer patients and to investigate the immune cell types and potential molecular signatures involved. METHODS: A cohort of 37 EGFR mutant advanced-stage NSCLC patients, who are resistant to at least one type of TKI treatment, was retrospectively established. Both pre-treatment and TKI resistance tumor FFPE samples of each pairs were collected. Transcriptional profiling and bioinformatics analysis were employed to evaluate the change of immune associated hallmarks before and after EGFR-TKI therapy. RESULTS: Tumor samples after EGFR-TKI treatment displayed enrichment of proinflammatory signaling like interferon-γ, allograft rejection and inflammatory response. Of note, cytotoxic factor granzyme A as well as PD-L1 were found to be more expressed in EGFR-TKI resistance samples. Approximately 33.3 % (11/33) of EGFR-TKI treated samples were classified as "hot" tumor, especially for EGFR L858R mutated NSCLC patients (46.7 %,7/15). Effector cells were significantly overexpressed in 'hot' tumors feature following TKI resistance. In addition, we found that four effector genes (CD8A, CDB8, GZMB, GZMK) showed higher expression in 'hot' tumors post-TKI resistance, and its 4-gene effector cell signature was found to have a good correlation with survival benefit in external immunotherapy database. CONCLUSIONS: TKI treatment may initiate immune activation in EGFR mutant NSCLC, leading to changes in immune cell infiltration following TKI resistance. We mechanistically explored that this might be due to an increased immune response caused by the rise in effector cells post-TKI resistance.

A systematic review of microplastics emissions in kitchens: Understanding the links with diseases in daily life.

The intensification of microplastics (MPs) pollution has emerged as a formidable environmental challenge, with profound global implications. The pervasive presence of MPs across a multitude of environmental mediums, such as the atmosphere, soil, and oceans, extends to commonplace items, culminating in widespread human ingestion and accumulation via channels like food, water, and air. In the domestic realm, kitchens have become significant epicenters for MPs pollution. A plethora of kitchen utensils, encompassing coated non-stick pans, plastic cutting boards, and disposable utensils, are known to release substantial quantities of MPs particles in everyday use, which can then be ingested alongside food. This paper conducts a thorough examination of contemporary research addressing the release of MPs from kitchen utensils during usage and focuses on the health risks associated with MPs ingestion, as well as the myriad factors influencing the release of MPs in kitchen utensils. Leveraging the insights derived from this analysis, this paper proposes a series of strategic recommendations and measures targeted at mitigating the production of MPs in kitchen settings. These initiatives are designed not solely to diminish the release of MPs but also to enhance public awareness regarding this pressing environmental concern. By adopting more informed practices in kitchens, we can significantly contribute to the reduction of the environmental burden of MPs pollution, thus safeguarding both human health and the ecological system.

Understanding the links between micro/nanoplastics-induced gut microbes dysbiosis and potential diseases in fish: A review.

At present, the quantity of micro/nano plastics in the environment is steadily rising, and their pollution has emerged as a global environmental issue. The tendency of their bioaccumulation in aquatic organisms (especially fish) has intensified people's attention to their persistent ecotoxicology. This review critically studies the accumulation of fish in the intestines of fish through active or passive intake of micro/nano plastics, resulting in their accumulation in intestinal organs and subsequent disturbance of intestinal microflora. The key lies in the complex toxic effect on the host after the disturbance of fish intestinal microflora. In addition, this review pointed out the characteristics of micro/nano plastics and the effects of their combined toxicity with adsorbed pollutants on fish intestinal microorganisms, in order to fully understand the characteristics of micro/nano plastics and emphasize the complex interaction between MNPs and other pollutants. We have an in-depth understanding of MNPs-induced intestinal flora disorders and intestinal dysfunction, affecting the host's systemic system, including immune system, nervous system, and reproductive system. The review also underscores the imperative for future research to investigate the toxic effects of prolonged exposure to MNPs, which are crucial for evaluating the ecological risks posed by MNPs and devising strategies to safeguard aquatic organisms.

Benefit from luteal phase progestin-primed ovarian stimulation with clomiphene citrate supplementation in young women with diminished ovarian reserve: a retrospective study. / åµæ³¡æœŸå’Œé»„ä½“æœŸé«˜å­•æ¿€ç´ çŠ¶æ€ä¿ƒæŽ’åµæ–¹æ¡ˆåœ¨å¹´è½»åµå·¢å‚¨å¤‡åŠŸèƒ½å‡é€€å¥³æ€§ä¸­çš„åº”ç”¨.

OBJECTIVES: To compare the pregnant outcomes of luteal phase progestin-primed ovarian stimulation (PPOS) protocol with clomiphene citrate supplementation (LPPOS+CC) and follicular phase PPOS+CC protocol (FPPOS+CC) in young women with diminished ovarian reserve (DOR). METHODS: A total of 483 women aged ≤35 years with DOR, who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)/embryo transfer (ET) with controlled ovarian stimulation using LPPOS+CC (n=257) or FPPOS+CC (n=226) protocols during June 2018 and December 2021 at the First Affiliated Hospital of Wenzhou Medical University, were included in this retrospective study. The baseline characteristics, ovarian stimulation, endocrinological indicators, clinical outcomes between the two groups, and pregnancy outcomes of women achieved at least one high-quality cleavage-stage embryo or good-morphology blastocyst between the two groups were compared. RESULTS: No statistically significant differences were identified between the groups with respect to number of oocytes retrieved, oocyte maturation rate, high-quality cleavage-stage embryo cycle rate, the percentage of women with profound pituitary suppression, preterm birth rate, and live birth rate (P>0.05). Compared to FPPOS+CC group, the duration of stimulation [11.0 (9.0,12.0) vs. 9.0 (8.0,11.0) d, P<0.01] was significantly longer in the LPPOS+CC group. The LH levels on the day of trigger [4.0 (2.7,5.3) vs. 5.1 (3.2,7.2) IU/L, P<0.01], the percentage of women with LH levels of >10 IU/L on the trigger day (3.13% vs. 10.67%, P<0.01), and the two pronucleate (2PN) rate of ICSI oocytes (72.16% vs. 79.56%, P<0.05) were significantly lower in the LPPOS+CC group than those in the FPPOS+CC group. The consumption of total gonadotropin [2213 (1650,2700) vs. 2000 (1575,2325) IU, P<0.01], the progesterone levels on the day of trigger [1.3 (0.8,2.9) vs. 0.9 (0.6,1.2) ng/mL, P<0.01], the clinical pregnancy rate [61.88% vs. 46.84%, P<0.01], and implantation rate [42.20% vs. 31.07%, P<0.01] in the LPPOS+CC group were significantly higher than those in the FPPOS+CC group. CONCLUSIONS: Compared to FPPOS+CC, the LPPOS+CC protocol appears to have better pregnancy outcomes for young women with DOR undergoing IVF-ICSI-ET.

Targeting Aging and Longevity with Exogenous Nucleotides (TALENTs): Rationale, Design, and Baseline Characteristics from a Randomized Controlled Trial in Older Adults.

Nucleotides (NTs), important biomolecules involved in numerous cellular processes, have been proposed as potential candidates for anti-aging interventions. However, whether nucleotides can act as an anti-aging supplement in older adults remains unclear. TALENTs is a randomized, double-blinded, placebo-controlled trial that evaluates the efficacy and safety of NTs as an anti-aging supplement in older adults by exploring the effects of NTs on multiple dimensions of aging in a rigorous scientific setting. Eligible community-dwelling adults aged 60-70 years were randomly assigned equally to two groups: nucleotides intervention group and placebo control group. Comprehensive geriatric health assessments were performed at baseline, 2-months, and 4-months of the intervention. Biological specimens were collected and stored for age-related biomarker testing and multi-omics sequencing. The primary outcome was the change from baseline to 4 months on leukocyte telomere length and DNA methylation age. The secondary aims were the changes in possible mechanisms underlying aging processes (immunity, inflammatory profile, oxidative stress, gene stability, endocrine, metabolism, and cardiovascular function). Other outcomes were changes in physical function, body composition and geriatric health assessment (including sleep quality, cognitive function, fatigue, frailty, and psychology). In the RCT, 301 participants were assessed for eligibility and 122 were enrolled. Participants averaged 65.65 years of age, and were predominately female (67.21%). All baseline characteristics were well-balanced between groups, as expected due to randomization. The majority of participants were pre-frailty and had at least one chronic condition. The mean scores for physical activity, psychological, fatigue and quality of life were within the normal range. However, nearly half of the participants still had room for improvement in cognitive level and sleep quality. This TALENTs trial will represent one of the most comprehensive experimental clinical trials in which supplements are administered to elderly participants. The findings of this study will contribute to our understanding of the anti-aging effects of NTs and provide insights into their potential applications in geriatric healthcare.

Clock-dependent chromatin accessibility rhythms regulate circadian transcription.

Chromatin organization plays a crucial role in gene regulation by controlling the accessibility of DNA to transcription machinery. While significant progress has been made in understanding the regulatory role of clock proteins in circadian rhythms, how chromatin organization affects circadian rhythms remains poorly understood. Here, we employed ATAC-seq (Assay for Transposase-Accessible Chromatin with Sequencing) on FAC-sorted Drosophila clock neurons to assess genome-wide chromatin accessibility at dawn and dusk over the circadian cycle. We observed significant oscillations in chromatin accessibility at promoter and enhancer regions of hundreds of genes, with enhanced accessibility either at dusk or dawn, which correlated with their peak transcriptional activity. Notably, genes with enhanced accessibility at dusk were enriched with E-box motifs, while those more accessible at dawn were enriched with VRI/PDP1-box motifs, indicating that they are regulated by the core circadian feedback loops, PER/CLK and VRI/PDP1, respectively. Further, we observed a complete loss of chromatin accessibility rhythms in per01 null mutants, with chromatin consistently accessible at both dawn and dusk, underscoring the critical role of Period protein in driving chromatin compaction during the repression phase at dawn. Together, this study demonstrates the significant role of chromatin organization in circadian regulation, revealing how the interplay between clock proteins and chromatin structure orchestrates the precise timing of biological processes throughout the day. This work further implies that variations in chromatin accessibility might play a central role in the generation of diverse circadian gene expression patterns in clock neurons.

MechanoBase: a comprehensive database for the mechanics of tissues and cells.

Mechanical aspects of tissues and cells critically influence a myriad of biological processes and can substantially alter the course of diverse diseases. The emergence of diverse methodologies adapted from physical science now permits the precise quantification of the cellular forces and the mechanical properties of tissues and cells. Despite the rising interest in tissue and cellular mechanics across fields like biology, bioengineering and medicine, there remains a noticeable absence of a comprehensive and readily accessible repository of this pertinent information. To fill this gap, we present MechanoBase, a comprehensive tissue and cellular mechanics database, curating 57 480 records from 5634 PubMed articles. The records archived in MechanoBase encompass a range of mechanical properties and forces, such as modulus and tractions, which have been measured utilizing various technical approaches. These measurements span hundreds of biosamples across more than 400 species studied under diverse conditions. Aiming for broad applicability, we design MechanoBase with user-friendly search, browsing and data download features, making it a versatile tool for exploring biomechanical attributes in various biological contexts. Moreover, we add complementary resources, including the principles of popular techniques, the concepts of mechanobiology terms and the cellular and tissue-level expression of related genes, offering scientists unprecedented access to a wealth of knowledge in this field of research. Database URL: https://zhanglab-web.tongji.edu.cn/mechanobase/ and https://compbio-zhanglab.org/mechanobase/.

Single-cell RNA sequencing reveals the process of CA19-9 production and dynamics of the immune microenvironment between CA19-9 (+) and CA19-9 (-) PDAC.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the main types of malignant tumor of the digestive system, and patient prognosis is affected by difficulties in early diagnosis, poor treatment response, and a high postoperative recurrence rate. Carbohydrate antigen 19-9 (CA19-9) has been widely used as a biomarker for the diagnosis and postoperative follow-up of PDAC patients. Nevertheless, the production mechanism and potential role of CA19-9 in PDAC progression have not yet been elucidated. METHODS: We performed single-cell RNA sequencing on six samples pathologically diagnosed as PDAC (three CA19-9-positive and three CA19-9-negative PDAC samples) and two paracarcinoma samples. We also downloaded and integrated PDAC samples (three each from CA19-9-positive and CA19-9-negative patients) from an online database. The dynamics of the proportion and potential function of each cell type were verified through immunofluorescence. Moreover, we built an in vitro coculture cellular model to confirm the potential function of CA19-9. RESULTS: Three subtypes of cancer cells with a high ability to produce CA19-9 were identified by the markers TOP2A, AQP5, and MUC5AC. CA19-9 production bypass was discovered on antigen-presenting cancer-associated fibroblasts (apCAFs). Importantly, the proportion of immature ficolin-1 positive (FCN1+) macrophages was high in the CA19-9-negative group, and the proportion of mature M2-like macrophages was high in the CA19-9-positive group. High proportions of these two macrophage subtypes were associated with an unfavourable clinical prognosis. Further experiments indicated that CA19-9 could facilitate the transformation of M0 macrophages into M2 macrophages in the tumor microenvironment. CONCLUSIONS: Our study described CA19-9 production at single-cell resolution and the dynamics of the immune atlas in CA19-9-positive and CA19-9-negative PDAC. CA19-9 could promote M2 polarization of macrophage in the pancreatic tumor microenvironment.

Clinical risk factors and outcomes of carbapenem-resistant Escherichia coli nosocomial infections in a Chinese teaching hospital: a retrospective study from 2013 to 2020.

The emergence of carbapenem-resistant Escherichia coli strains poses a considerable challenge to global public health, and little is known about carbapenemase-producing E. coli strains in Tianjin, China. This study aimed to investigate the risk factors for infections with carbapenem-resistant E. coli (CREC) strains. This retrospective case-control study was conducted at a tertiary teaching hospital. A total of 134 CREC clinical isolates were collected from the General Hospital of Tianjin Medical University between 2013 and 2020. The control group was selected at a ratio of 1:1 from patients with nosocomial carbapenem-susceptible E. coli infection. Risk factors for nosocomial CREC infection and clinical outcomes were analyzed using univariate and multivariate analyses. Multivariate analysis revealed that cephalosporin exposure (odd ratio OR = 2.01), carbapenem exposure (OR = 1.96), glucocorticoid exposure (OR = 32.45), and surgical history (OR = 3.26) were independent risk factors for CREC infection. The in-hospital mortality rate in the CREC group was 29.1%, and age >65 years (OR = 3.19), carbapenem exposure (OR = 3.54), and central venous catheter insertion (OR = 4.19) were independent risk factors for in-hospital mortality in patients with CREC infections. Several factors were identified in the development of nosocomial CREC infections. The CREC isolates were resistant to most antibiotics. Reducing CREC mortality requires a comprehensive consideration of appropriate antibiotic use, underlying diseases, and invasive procedures.IMPORTANCEEscherichia coli is an opportunistic pathogen that causes severe hospital-acquired infections. The spread of carbapenem-resistant E. coli is a global threat to public health, and only a few antibiotics are effective against these infections. Consequently, these infections are usually associated with poor prognosis and high mortality. Therefore, understanding the risk factors associated with the causes and outcomes of these infections is crucial to reduce their incidence and initiate appropriate therapies. In our study, several factors were found to be involved in nosocomial carbapenem-resistant E. coli (CREC) infections, and CREC isolates were resistant to most antibiotics. Reducing CREC mortality needs a comprehensive consideration of whether antibiotics are used appropriately, underlying diseases, and invasive interventions. These findings provide valuable evidence for the development of anti-infective therapy, infection prevention, and control of CREC-positive infections.

Interfering with reconsolidation by rimonabant results in blockade of heroin-associated memory.

Drug-associated pathological memory remains a critical factor contributing to the persistence of substance use disorder. Pharmacological amnestic manipulation to interfere with drug memory reconsolidation has shown promise for the prevention of relapse. In a rat heroin self-administration model, we examined the impact of rimonabant, a selective cannabinoid receptor indirect agonist, on the reconsolidation process of heroin-associated memory. The study showed that immediately administering rimonabant after conditioned stimuli (CS) exposure reduced the cue- and herion + cue-induced heroin-seeking behavior. The inhibitory effects lasted for a minimum of 28 days. The effect of Rimonabant on reduced drug-seeking was not shown when treated without CS exposure or 6 hours after CS exposure. These results demonstrate a disruptive role of rimonabant on the reconsolidation of heroin-associated memory and the therapeutic potential in relapse control concerning substance use disorder.

Analysis of Caregiver Burden and Influencing Factors in Autologous Hematopoietic Stem Cell Transplantation Patients with Bendamustine Preconditioning.

This paper comprehensively analyzes the caregiver burden and its influencing factors on primary caregivers in autologous hematopoietic stem cell transplantation (Auto-HSCT) with bendamustine preconditioning. Auto-HSCT refers to the transplantation of cells back to the patient, aiming to eliminate tumor cells and prolong the patient's life. Bendamustine, while enhancing the success rate of transplantation, has drawn considerable attention to the primary caregivers of patients. Due to the complex nature of the transplantation process, patients have diverse caregiving needs, which caregivers must address to support the entire treatment journey. The caregiver burden of primary caregivers is influenced by various factors, including the patient's disease condition, various aspects of the caregiver as an individual, and psychological factors. The article emphasizes the need for personalized care plans and psychological support to minimize caregiver burden and improve overall quality of life. This study has positive implications for optimizing the implementation of Auto-HSCT therapy.

Increased miR-3074-5p expression promotes M1 polarization and pyroptosis of macrophages via ERα/NLRP3 pathway and induces adverse pregnancy outcomes in mice.

Decidual macrophages (dMϕs) play critical roles in regulation of immune-microhomeostasis at maternal-fetal interface during pregnancy, but the underlying molecular mechanisms are still unclear. In this study, it was found that litter size and fetal weight were significantly reduced, whereas the rate of embryo resorption was increased in miR-3074-5p knock-in (3074-KI) pregnant mice, compared to that of wild-type (WT) pregnant mice. Plasma levels of pro-inflammatory cytokines in 3074-KI pregnant mice were also significantly elevated compared to WT pregnant mice at GD7.5. The quantity of M1-Mϕs in uterine tissues of 3074-KI pregnant mice was significantly increased compared to WT pregnant mice at GD13.5. Estrogen receptor-α (ERα) was validated to be a target of miR-3074-5p. Either miR-3074-5p overexpression or ERα knockdown promoted transcriptional activity of NF-κB/p65, induced M1-polarization and pyroptosis of THP1-derived Mϕs, accompanied with increased intracellular levels of cleaved Caspase-1, cleaved IL-1ß, NLRP3, cleaved GSDMD and ASC aggregation. Furthermore, ERα could not only bind to NLRP3 or ASC directly, but also inhibit the interaction between NLRP3 and ASC. The endometrial miR-3074-5p expression level at the middle secretory stage of repeated implantation failure (RIF) patients was significantly decreased compared to that of control fertile women. These data indicated that miR-3074-5p could promote M1 polarization and pyroptosis of Mϕs via activation of NLRP3 inflammasome by targeting ERα, and the dysregulation of miR-3074-5p expression in dMϕs might damage the embryo implantation and placentation by interfering with inflammatory microenvironment at the maternal-fetal interface during early pregnancy.

Mitochondrial DNA-Activated cGAS-STING Signaling in Environmental Dry Eye.

Purpose: The cGAS-STING pathway has been shown to be an important mediator of inflammation. There is emerging evidence of the importance of this signaling cascade in a variety of inflammatory diseases settings. Here, we present evidence that the mitochondrial DNA (mtDNA) damage-mediated cGAS-STING pathway plays an important role in the induction of inflammation in environmental dry eye (DE). Methods: RT-qPCR and Western blot were used to assess the induction of the cGAS-STING pathway and inflammatory cytokines in environmental DE mouse model, primary human corneal epithelial cells (pHCECs), and patients with DE. RNA sequencing was used to determine mRNA expression patterns of high osmotic pressure (HOP)-stimulated pHCECs. mtDNA was detected with electron microscopy, flow cytometry, and immunofluorescent staining. mtDNA was isolated and transfected into pHCECs for evaluating the activation of the cGAS-STING pathway. Results: The expression levels of cGAS, STING, TBK1, IRF3, and IFNß were significantly increased in an environmental DE model and HOP-stimulated pHCECs. The STING inhibitor decreased the expression of inflammatory factors in DE. An upregulation of STING-mediated immune responses and IRF3 expression mediated by TBK1 were observed in the HOP group. HOP stimulation induced mitochondrial oxidative damage and the leakage of mtDNA into the cytoplasm. Then, mtDNA activated the cGAS-STING pathway and induced intracytoplasmic STING translocated to the Golgi apparatus. Finally, we also found activated cGAS-STING signaling in the human conjunctival blot cell of patients with DE. Conclusions: Our findings suggest that the cGAS-STING pathway is activated by recognizing cytoplasmic mtDNA leading to STING translocation, further exacerbating the development of inflammation in environmental DE.

Multi-Layer Polyurethane-Fiber-Prepared Entangled Strain Sensor with Tunable Sensitivity and Working Range for Human Motion Detection.

The entanglement of fibers can form physical and topological structures, with the resulting bending and stretching strains causing localized changes in pressure. In this study, a multi-layer polyurethane-fiber-prepared (MPF) sensor was developed by coating the CNT/PU sensing layer on the outside of an elastic electrode through a wet-film method. The entangled topology of two MPFs was utilized to convert the stretching strain into localized pressure at the contact area, enabling the perception of stretching strain. The influence of coating mechanical properties and surface structure on strain sensing performance was investigated. A force regulator was introduced to regulate the mechanical properties of the entangled topology of MPF. By modifying the thickness and length proportion of the force regulator, the sensitivity factor and sensitivity range of the sensor could be controlled, achieving a high sensitivity factor of up to 127.74 and a sensitivity range of up to 58%. Eight sensors were integrated into a sensor array and integrated into a dance costume, successfully monitoring the multi-axis motion of the dancer's lumbar spine. This provides a new approach for wearable biomechanical sensors.

circular RNA circ-231 promotes protein biogenesis of TPI1 and PRDX6 through mediating the interaction of eIF4A3 with STAU1 to facilitate unwinding of secondary structure in 5' UTR, enhancing progression of human esophageal squamous cell carcinoma (ESCC).

Background: The nuclear cap-binding complex (CBC)-dependent translation (CT) is an important initial translation pathway for 5'-cap-dependent translation in normal mammal cells. Eukaryotic translation initiation factor 4A-III (eIF4A3), as an RNA helicase, is recruited to CT complex and enhances CT efficiency through participating in unwinding of secondary structure in the 5' UTR. However, the detailed mechanism for eIF4A3 implicated in unwinding of secondary structure in the 5' UTR in normal mammal cells is still unclear. Specially, we need to investigate whether the kind of mechanism in normal mammal cells extrapolates to cancer cells, e.g. ESCC, and further interrogate whether and how the mechanism triggers malignant phenotype of ESCC, which are important for identifying a potential therapeutic target for patients with ESCC. Methods: Bioinformatics analysis, RNA immunoprecipitation and RNA pulldown assays were performed to detect the interaction of circular RNA circ-231 with eIF4A3. In vitro and in vivo assays were performed to detect biological roles of circ-231 in ESCC. RNA immunoprecipitation, RNA pulldown, mass spectrometry analysis and co-immunoprecipitation assays were used to measure the interaction of circ-231, eIF4A3 and STAU1 in HEK293T and ESCC. In vitro EGFP reporter and 5' UTR of mRNA pulldown assays were performed to probe for the binding of circ-231, eIF4A3 and STAU1 to secondary structure of 5' UTR. Results: RNA immunoprecipitation assays showed that circ-231 interacted with eIF4A3 in HEK293T and ESCC. Further study confirmed that circ-231 orchestrated with eIF4A3 to control protein expression of TPI1 and PRDX6, but not for mRNA transcripts. The in-depth mechanism study uncovered that both circ-231 and eIF4A3 were involved in unwinding of secondary structure in 5' UTR of TPI1 and PRDX6. More importantly, circ-231 promoted the interaction between eIF4A3 and STAU1. Intriguingly, both circ-231 and eIF4A3 were dependent on STAU1 binding to secondary structure in 5' UTR. Biological function assays revealed that circ-231 promoted the migration and proliferation of ESCC via TPI1 and PRDX6. In ESCC, the up-regulated expression of circ-231 was observed and patients with ESCC characterized by higher expression of circ-231 have concurrent lymph node metastasis, compared with control. Conclusions: Our data unravels the detailed mechanism by which STAU1 binds to secondary structure in 5' UTR of mRNAs and recruits eIF4A3 through interacting with circ-231 and thereby eIF4A3 is implicated in unwinding of secondary structure, which is common to HEK293T and ESCC. However, importantly, our data reveals that circ-231 promotes migration and proliferation of ESCC and the up-regulated circ-231 greatly correlates with tumor lymph node metastasis, insinuating that circ-231 could be a therapeutic target and an indicator of risk of lymph node metastasis for patients with ESCC.