Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas.

BACKGROUND: Current cancer therapies often fall short in addressing the complexities of malignancies, underscoring the urgent need for innovative treatment strategies. RNA interference technology, which specifically suppresses gene expression, offers a promising new approach in the fight against tumors. Recent studies have identified a novel immunostimulatory small-interfering RNA (siRNA) with a unique sequence (sense strand, 5'-C; antisense strand, 3'-GGG) capable of activating the RIG-I/IRF3 signaling pathway. This activation induces the release of type I and III interferons, leading to an effective antiviral immune response. However, this class of immunostimulatory siRNA has not yet been explored in cancer therapy. METHODS: IsiBCL-2, an innovative immunostimulatory siRNA designed to suppress the levels of B-cell lymphoma 2 (BCL-2), contains a distinctive motif (sense strand, 5'-C; antisense strand, 3'-GGG). Glioblastoma cells were subjected to 100 nM isiBCL-2 treatment in vitro for 48 h. Morphological changes, cell viability (CCK-8 assay), proliferation (colony formation assay), migration/invasion (scratch test and Transwell assay), apoptosis rate, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Western blotting and immunofluorescence analyses were performed to assess RIG-I and MHC-I molecule levels, and ELISA was utilized to measure the levels of cytokines (IFN-ß and CXCL10). In vivo heterogeneous tumor models were established, and the anti-tumor effect of isiBCL-2 was confirmed through intratumoral injection. RESULTS: IsiBCL-2 exhibited significant inhibitory effects on glioblastoma cell growth and induced apoptosis. BCL-2 mRNA levels were significantly decreased by 67.52%. IsiBCL-2 treatment resulted in an apoptotic rate of approximately 51.96%, accompanied by a 71.76% reduction in MMP and a 41.87% increase in ROS accumulation. Western blotting and immunofluorescence analyses demonstrated increased levels of RIG-I, MAVS, and MHC-I following isiBCL-2 treatment. ELISA tests indicated a significant increase in IFN-ß and CXCL10 levels. In vivo studies using nude mice confirmed that isiBCL-2 effectively impeded the growth and progression of glioblastoma tumors. CONCLUSIONS: This study introduces an innovative method to induce innate signaling by incorporating an immunostimulatory sequence (sense strand, 5'-C; antisense strand, 3'-GGG) into siRNA, resulting in the formation of RNA dimers through Hoogsteen base-pairing. This activation triggers the RIG-I signaling pathway in tumor cells, causing further damage and inducing a potent immune response. This inventive design and application of immunostimulatory siRNA offer a novel perspective on tumor immunotherapy, holding significant implications for the field.

Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Unraveling EGFR-TKI resistance in lung cancer with high PD-L1 or TMB in EGFR-sensitive mutations.

BACKGROUND: Although EGFR-TKI resistance mechanisms in non-small cell lung cancer (NSCLC) have been extensively studied, certain patient subgroups remain with unclear mechanisms. This retrospective study analysed mutation data of NSCLC patients with EGFR-sensitive mutations and high programmed death-ligand 1 (PD-L1) expression or high TMB to identify primary resistance mechanisms. METHODS: Hybrid capture-based next-generation sequencing (NGS) was used to analyse mutations in 639 genes in tumor tissues and blood samples from 339 NSCLC patients. PD-L1 immunohistochemical staining was also performed on the same cell blocks. Molecular and pathway profiles were compared among patient subgroups. RESULTS: TMB was significantly higher in lung cancer patients with EGFR-sensitive mutations and high PD-L1 expression. Compared with the high-expression PD-L1 or high TMB and low-expression or TMB groups, the top 10 genes exhibited differences in both gene types and mutation rates. Pathway analysis revealed a significant mutations of the PI3K signaling pathway in the EGFR-sensitive mutation group with high PD-L1 expression (38% versus 12%, p < 0.001) and high TMB group (31% versus 13%, p < 0.05). Notably, PIK3CA and PTEN mutations emerged as the most important differentially mutated genes within the PI3K signaling pathway. CONCLUSIONS: Our findings reveal that the presence of PI3K signaling pathway mutations may be responsible for inducing primary resistance to EGFR-TKIs in NSCLC patients with EGFR-sensitive mutations along with high PD-L1 expression or high TMB. This finding is of great significance in guiding subsequent precision treatments in NSCLC.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

Epigallocatechin-3-gallate ameliorates lipopolysaccharide-induced acute thymus involution in mice via AMPK/Sirt1 pathway.

The thymus, a site to culture the naïve T lymphocytes, is susceptible to atrophy or involution due to aging, inflammation, and oxidation. Epigallocatechin-3-gallate (EGCG) has been proven to possess anti-inflammatory, antioxidant, and antitumor activity. Here, we investigate the effects of EGCG on thymic involution induced by lipopolysaccharide (LPS), an endotoxin derived from Gram-negative bacteria. The methodology included an in vivo experiment on female Kunming mice exposed to LPS and EGCG. Morphological assessment of thymic involution, immunohistochemical detection, and thymocyte subsets analysis by flow cytometry were further carried out to evaluate the potential role of EGCG on the thymus. As a result, we found that EGCG alleviated LPS-induced thymic atrophy, increased mitochondrial membrane potential and superoxide dismutase levels, and decreased malondialdehyde and reactive oxygen species levels. In addition, EGCG pre-supplement restored the ratio of thymocyte subsets, the expression of autoimmune regulator, sex-determining region Y-box 2, and Nanog homebox, and reduced the number of senescent cells and collagen fiber deposition. Western blotting results indicated that EGCG treatment elevated LPS-induced decrease in pAMPK, Sirt1 protein expression. Collectively, EGCG relieved thymus architecture and function damaged by LPS via regulation of AMPK/Sirt1 signaling pathway. Our findings may provide a new strategy on protection of thymus from involution caused by LPS by using EGCG. And EGCG might be considered as a potential agent for the prevention and treatment of thymic involution.

Advanced Glycation End Products (AGEs) Inhibit Macrophage Efferocytosis of Apoptotic ß Cells through Binding to the Receptor for AGEs.

Pancreatic ß cell apoptosis is important in the pathogenesis of type 2 diabetes mellitus (T2DM). Generally, apoptotic ß cells are phagocytosed by macrophages in a process known as "efferocytosis." Efferocytosis is critical to the resolution of inflammation and is impaired in T2DM. Advanced glycation end products (AGEs), which are increased in T2DM, are known to suppress phagocytosis function in macrophages. In this study, we found that AGEs inhibited efferocytosis of apoptotic ß cells by primary peritoneal macrophages in C57BL/6J mice or mouse macrophage cell line Raw264.7. Mechanistically, AGEs inhibit efferocytosis by blocking Ras-related C3 botulinum toxin substrate 1 activity and cytoskeletal rearrangement through receptor for advanced glycation end products/ras homolog family member A/Rho kinase signaling in macrophages. Furthermore, it was observed that AGEs decreased the secretion of anti-inflammatory factors and promoted the proinflammatory ones to modulate the inflammation function of efferocytosis. Taken together, our results indicate that AGEs inhibit efferocytosis through binding to receptor for advanced glycation end products and activating ras homolog family member A/Rho kinase signaling, thereby inhibiting the anti-inflammatory function of efferocytosis.

Impact of caregiving on mental, self-rated, and physical health: evidence from the China health and retirement longitudinal study.

OBJECTIVES: Given the escalating demand for care services, understanding the impact of informal caregiving, providing unpaid care for family members, on own health is essential. This study longitudinally analyzed the association of caregiving (and different caregiver types) with mental, physical, and self-rated health. Urban-rural, gender, and employment heterogeneity were further investigated. METHOD: Based on three-wave data (2011, 2013, and 2018) from the China Health and Retirement Longitudinal Study, we used growth curve models to assess the impact of informal caregiving (providing care to family members) and caregiver types (caregivers to grandchildren, parents, spouses, or multiple family members) on three health outcomes (depressive symptoms, self-rated health, and activities of daily living limitations). RESULTS: Our study included 13,377 individuals. Results showed a negative correlation of caregiving with mental, physical, and self-rated health. Compared to noncaregivers, spousal caregivers and multiple caregivers were both associated with worsening mental, self-rated, and physical health. In contrast, adult child caregivers were only negatively associated with mental health, and grandparent caregiving did not significantly affect any health outcomes. Further heterogeneity analysis showed that gender did not moderate the relationship between caregiving and health, whereas the negative association between caregiving and health was more pronounced among the rural population and those employed in agriculture. DISCUSSION: Findings from the present study suggest that caregiving is detrimental to health, and recommend considering caregiver type when examining caregiving and health. These findings have vital implications for policymakers in addressing the challenges of structuring and implementing a sustainable informal care system.

Increased serum extrachromosomal circular DNA SORBS1circle level is associated with insulin resistance in patients with newly diagnosed type 2 diabetes mellitus.

BACKGROUND: Extrachromosomal circular DNAs (eccDNAs) exist in human blood and somatic cells, and are essential for oncogene plasticity and drug resistance. However, the presence and impact of eccDNAs in type 2 diabetes mellitus (T2DM) remains inadequately understood. METHODS: We purified and sequenced the serum eccDNAs obtained from newly diagnosed T2DM patients and normal control (NC) subjects using Circle-sequencing. We validated the level of a novel circulating eccDNA named sorbin and SH3-domain- containing-1circle97206791-97208025 (SORBS1circle) in 106 newly diagnosed T2DM patients. The relationship between eccDNA SORBS1circle and clinical data was analyzed. Furthermore, we explored the source and expression level of eccDNA SORBS1circle in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. RESULTS: A total of 22,543 and 19,195 eccDNAs were found in serum samples obtained from newly diagnosed T2DM patients and NC subjects, respectively. The T2DM patients had a greater distribution of eccDNA on chromosomes 1, 14, 16, 17, 18, 19, 20 and X. Additionally, 598 serum eccDNAs were found to be upregulated, while 856 eccDNAs were downregulated in T2DM patients compared with NC subjects. KEGG analysis demonstrated that the genes carried by eccDNAs were mainly associated with insulin resistance. Moreover, it was validated that the eccDNA SORBS1circle was significantly increased in serum of newly diagnosed T2DM patients (106 T2DM patients vs. 40 NC subjects). The serum eccDNA SORBS1circle content was positively correlated with the levels of glycosylated hemoglobin A1C (HbA1C) and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM patients. Intracellular eccDNA SORBS1circle expression was significantly enhanced in the high glucose and palmitate (HG/PA)-induced hepatocyte (HepG2 cell) insulin resistance model. Moreover, the upregulation of eccDNA SORBS1circle in the HG/PA-treated HepG2 cells was dependent on generation of apoptotic DNA fragmentation. CONCLUSIONS: These results provide a preliminary understanding of the circulating eccDNA patterns at the early stage of T2DM and suggest that eccDNA SORBS1circle may be involved in the development of insulin resistance.

Application Effect of 6S Management Mode in Operating Room Nursing.

Background: The nursing work in the operating room is heavy, intensive, and irregular, and the quality of nursing work can directly affect the surgical effect and patient prognosis. Therefore, nursing management in the operating room should be strengthened to protect patients' life safety effectively. Objective: To assess the effectiveness of applying the 6S management model in operating room nursing. Design: This was a retrospective study. Setting: This study was conducted at the Department of Anesthesia Surgery, Nanfang Hospital, Southern Medical University. Participants: The research included 100 operating room nurses on duty between January 2020 and December 2022. Intervention: From January 2020 to June 2021, the hospital conducted routine training programs for nurses in the operating room. From July 2021 to December 2022, the hospital adopted the 6S management model for overseeing nursing work in the operating room. Primary Outcome Measures: (1) nursing quality score (2) nursing staff safety awareness (3) nursing disputes and complaints (4) incidence of adverse reactions (5) patient satisfaction with the quality of nursing care. Results: Following the adoption of the 6S management model, there was a noticeable improvement in the nursing quality scores, the nursing staff's awareness of safety, and the satisfaction levels of patients with the quality of care provided by operation nurses (P < .05). Additionally, the incidence of nursing disputes, complaints, and adverse events among patients decreased significantly compared to before the implementation of 6S (P = .01). Conclusion: Implementing 6S management with a focus on the work of operation room nurses enhanced the competence of the nursing staff and improved management effectiveness, ultimately leading to increased patient satisfaction.

Association of urinary and seminal plasma vanadium concentrations with semen quality: A repeated-measures study of 1135 healthy men.

Although animal studies have shown the reproductive toxicity of vanadium, less is known about its effects on semen quality in humans. Among 1135 healthy men who were screened as potential semen donors, we investigated the relationships of semen quality with urinary and seminal plasma vanadium levels via inductively coupled plasma-mass spectrometry (ICP-MS). Spearman rank correlation tests and linear regression models were used to assess the correlations between average urinary and within-individual pooled seminal plasma vanadium concentrations (n = 1135). We utilized linear mixed-effects models to evaluate the associations of urinary and seminal plasma vanadium levels (n = 1135) with repeated sperm quality parameters (n = 5576). Seminal plasma vanadium concentrations were not significantly correlated with urinary vanadium concentrations (r = 0.03). After adjusting for possible confounders, we observed inverse relationships of within-individual pooled seminal plasma vanadium levels with total count, semen volume, and sperm concentration (all P values for trend < 0.05). Specifically, subjects in the highest (vs. lowest) tertile of seminal plasma vanadium concentrations had - 11.3% (-16.4%, -5.9%), - 11.1% (-19.1%, -2.4%), and - 20.9% (-29.0%, -11.8%) lower sperm volume, concentration, and total count, respectively; moreover, urinary vanadium levels appeared to be negatively associated with sperm motility. These relationships showed monotonically decreasing dose-response patterns in the restricted cubic spline analyses. Our results demonstrated a poor correlation between urinary and seminal plasma levels of vanadium, and elevated vanadium concentrations in urine and seminal plasma may be adversely related to male semen quality.

Genetic Variants of the COL4A3 , COL4A4 , and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients.

BACKGROUND: Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen-built of α 3, α 4, and α 5 chains, encoded by COL4A3 / COL4A4 / COL4A5 genes-is the major component of glomerular basement membrane (GBM). In recent years, mutations in type IV collagen-encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3 / COL4A4 / COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear. METHODS: We compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3 / COL4A4 / COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA. RESULTS: The patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3 / COL4A4 / COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes. CONCLUSIONS: COL4A3 / COL4A4 / COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions.

Targeted chemical profiling for p-HAP glycosides by using molecular networking and comparative analysis of their contents between Artemisia japonica and Artemisia capillaris.

A total of 65 phenolic acid compounds were annotated or identified by UHPLC-MS/MS method, among them, 17 p-HAP (p-hydroxyacetophenone) glycosides were firstly targeted profiled based on molecular networking. Their characteristic product ions of MS/MS spectra were found and examined on the guideline of targeted isolation. As a result, a new p-HAP glycoside was thus obtained and determined as 2'-O-caffeoyl-p-HAP-4-O-ß-D-glucopyranoside (33) based on 1D and 2D NMR data. Besides, multicomponents quantitative analysis indicated the distinct regional variability in chemicals distribution of A. japonica, and meanwhile, the contents of p-HAP glycosides from A. japonica were higher than those in A. capillaris as a whole, which further suggested the potential medicinal value of A. japonica.

Longitudinal examination of cognitive function in older adults after the death of a child.

This study examined the relationship between the death of a child and cognitive function, considering how this association varies with the timing and number of losses. Utilizing four waves of the China Health and Retirement Longitudinal Study, linear mixed models assessed the impact of child loss on cognition, while mediation analysis was conducted using the Karlson-Holm-Breen method. Findings indicate a detrimental effect of child loss on cognitive function, particularly for losses occurring before age 30 and after age 60. A dose-response relationship was noted, suggesting greater cognitive decline with increasing instances of child loss. Mediation analysis revealed that psychological distress, physical functioning limitations, and social engagement partly explain this link. Moreover, the negative effect was more significant in mothers. These insights underscore the need for targeted support and cognitive monitoring for bereaved parents.

Multi-imaging platform for rhizosphere studies: Phosphorus and oxygen fluxes.

Rhizosphere is a soil volume of high spatio-temporal heterogeneity and intensive plant-soil-microbial interactions, for which visualization and process quantification is of highest scientific and applied relevance, but still very challenging. A novel methodology for quick assessment of two-dimensional distribution of available phosphorus (P) in rhizosphere was suggested, tested, and development up to the application platform. Available P was firstly trapped by an in-situ diffusive gradients in thin-films (DGT) sampler with precipitated zirconia as the binding gel, and subsequently, the loaded gel was analyzed with an optimized colorimetric imaging densitometry (CID). The imaging platform was established linking: i) DGT, ii) planar optode, and iii) soil zymography techniques to simultaneously determine available P, oxygen, and acid phosphatase in rhizosphere at sub-millimeter spatial scales. The DGT identified available P level in rice rhizosphere were spatially overlapping to the localized redox hotspots and phosphatase activity. The spatial relationship between available P and acid phosphatase activity was dependent on root development. The root radial oxygen loss (ROL) remained active during the experimental observations (2-3 days), while a flux of available P of 10 pg cm-2 s-1 was visualized within 2-3 mm of roots, confirming the correlative response of rice roots to oxygen secretion and P uptake. Summarizing, the established imaging platform is suitable to capture spatial heterogeneity and temporal dynamics of root activities, nutrient bioavailability, ROL and enzyme activities in rhizosphere.

The Impact of Informal Care on Healthcare Utilization of Older Adults with Functional Limitations in China.

Our study examines the impact of informal care on healthcare utilization, focusing on caregiver types, urban-rural, and gender differences. Analyzing data from the China Health and Retirement Longitudinal Study and using fixed effects models, we discovered complementary effects between informal care and healthcare. Specifically, spousal care increased inpatient care use, adult child care boosted both inpatient and outpatient use, and dual care from children and spouses showed the most significant impact on healthcare use. The association between informal care and healthcare use varied across gender or urban-rural residence. Our findings highlight the importance of caregivers in accessing healthcare services.

IL-33-ST2 pathway regulates AECII transdifferentiation by targeting alveolar macrophage in a bronchopulmonary dysplasia mouse model.

Evidence points to the indispensable function of alveolar macrophages (AMs) in normal lung development and tissue homeostasis. However, the importance of AMs in bronchopulmonary dysplasia (BPD) has not been elucidated. Here, we identified a significant role of abnormal AM proliferation and polarization in alveolar dysplasia during BPD, which is closely related to the activation of the IL-33-ST2 pathway. Compared with the control BPD group, AMs depletion partially abolished the epithelialmesenchymal transition process of AECII and alleviated pulmonary differentiation arrest. In addition, IL-33 or ST2 knockdown has protective effects against lung injury after hyperoxia, which is associated with reduced AM polarization and proliferation. The protective effect disappeared following reconstitution of AMs in injured IL-33 knockdown mice, and the differentiation of lung epithelium was blocked again. In conclusion, the IL-33-ST2 pathway regulates AECII transdifferentiation by targeting AMs proliferation and polarization in BPD, which shows a novel strategy for manipulating the IL-33-ST2-AMs axis for the diagnosis and intervention of BPD.

Lineage-specific amplification and epigenetic regulation of LTR-retrotransposons contribute to the structure, evolution, and function of Fabaceae species.

BACKGROUND: Long terminal repeat (LTR)-retrotransposons (LTR-RTs) are ubiquitous and make up the majority of nearly all sequenced plant genomes, whereas their pivotal roles in genome evolution, gene expression regulation as well as their epigenetic regulation are still not well understood, especially in a large number of closely related species. RESULTS: Here, we analyzed the abundance and dynamic evolution of LTR-RTs in 54 species from an economically and agronomically important family, Fabaceae, and also selected two representative species for further analysis in expression of associated genes, transcriptional activity and DNA methylation patterns of LTR-RTs. Annotation results revealed highly varied proportions of LTR-RTs in these genomes (5.1%~68.4%) and their correlation with genome size was highly positive, and they were significantly contributed to the variance in genome size through species-specific unique amplifications. Almost all of the intact LTR-RTs were inserted into the genomes 4 Mya (million years ago), and more than 50% of them were inserted in the last 0.5 million years, suggesting that recent amplifications of LTR-RTs were an important force driving genome evolution. In addition, expression levels of genes with intronic, promoter, and downstream LTR-RT insertions of Glycine max and Vigna radiata, two agronomically important crops in Fabaceae, showed that the LTR-RTs located in promoter or downstream regions suppressed associated gene expression. However, the LTR-RTs within introns promoted gene expression or had no contribution to gene expression. Additionally, shorter and younger LTR-RTs maintained higher mobility and transpositional potential. Compared with the transcriptionally silent LTR-RTs, the active elements showed significantly lower DNA methylation levels in all three contexts. The distributions of transcriptionally active and silent LTR-RT methylation varied across different lineages due to the position of LTR-RTs located or potentially epigenetic regulation. CONCLUSION: Lineage-specific amplification patterns were observed and higher methylation level may repress the activity of LTR-RTs, further influence evolution in Fabaceae species. This study offers valuable clues into the evolution, function, transcriptional activity and epigenetic regulation of LTR-RTs in Fabaceae genomes.

Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2.

BACKGROUND & AIMS: The molecular mechanisms underlying the progression of simple steatosis to non-alcoholic steatohepatitis (NASH) remain incompletely understood, though the potential role of epigenetic regulation by microRNA (miRNAs) is an area of increasing interest. In the present study, we aimed to investigate the role of miRNAs during steatosis-to-NASH progression, as well as underlying mechanisms. METHODS: miR-145a-5p was identified as an important checkpoint in steatosis-to-NASH progression. In vivo loss-of-function and gain-of-function studies were performed to explore the role of miR-145a-5p and Nr4a2 in NASH progression. RNA-sequencing and bioinformatic analysis were used to investigate the targets of miR-145a-5p. RESULTS: Suppression of miR-145a-5p in the liver aggravated lipid accumulation and activated hepatic inflammation, liver injury and fibrosis in steatotic mice, whereas its restoration markedly attenuated diet-induced NASH pathogenesis. Mechanistically, miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 and thus inhibit the expression of NASH-associated genes. Similarly, Nr4a2 overexpression promoted steatosis-to-NASH progression while liver-specific Nr4a2 knockout mice were protected from diet-induced NASH. This role of the miR-145a-5p/Nr4a2 regulatory axis was also confirmed in primary human hepatocytes. Furthermore, the expression of miR-145a-5p was reduced and the expression of Nr4a2 was increased in the livers of patients with NASH, while their expression levels significantly negatively and positively correlated with features of liver pathology, respectively. CONCLUSIONS: Our findings highlight the role of the miR-145a-5p/Nr4a2 regulatory axis in steatosis-to-NASH progression, suggesting that either supplementation of miR-145a-5p or pharmacological inhibition of Nr4a2 in hepatocytes may provide a promising therapeutic approach for the treatment of NASH. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs for NASH. Our current study identified miR-145a-5p as a novel regulator that inhibits steatosis-to-NASH progression. We found that miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 to suppress the expression of NASH-associated genes. The differential expression of miR-145a-5p and Nr4a2 was further confirmed in patients with NASH, raising the possibility that supplementation of miR-145a-5p or suppression of Nr4a2 in hepatocytes might provide novel strategies for treating NASH.

High-Performance Biodegradable Energy Storage Devices Enabled by Heterostructured MoO3 -MoS2 Composites.

Biodegradable implantable devices are of growing interest in biosensors and bioelectronics. One of the key unresolved challenges is the availability of power supply. To enable biodegradable energy-storage devices, herein, 2D heterostructured MoO3 -MoS2 nanosheet arrays are synthesized on water-soluble Mo foil, showing a high areal capacitance of 164.38 mF cm-2 (at 0.5 mA cm-2 ). Employing the MoO3 -MoS2 composite as electrodes of a symmetric supercapacitor, an asymmetric Zn-ion hybrid supercapacitor, and an Mg primary battery are demonstrated. Benefiting from the advantages of MoO3 -MoS2 heterostructure, the Zn-ion hybrid supercapacitors deliver a high areal capacitance (181.86 mF cm-2 at 0.5 mA cm-2 ) and energy density (30.56 µWh cm-2 ), and the Mg primary batteries provide a stable high output voltage (≈1.6 V) and a long working life in air/liquid environment. All of the used materials exhibit desirable biocompatibility, and these fabricated devices are also fully biodegradable. Demonstration experiments display their potential applications as biodegradable power sources for various electronic devices.

Esculetin improves murine mastitis induced by streptococcus isolated from bovine mammary glands by inhibiting NF-κB and MAPK signaling pathways.

Cow mastitis, caused by Streptococcus infection of the mammary glands, is a common clinical disease that can lead to decreased milk quality and threaten animal welfare and performance. Esculetin (ESC) is a coumarin with anti-inflammatory and anti-asthmatic effects. However, whether ESC has therapeutic effects on mastitis remains unexplored. This study was conducted to investigate the protective effect of ESC against murine mastitis caused by Streptococcus isolated from bovine mammary glands and elucidate the underlying mechanisms. Streptococcus uberis was used to construct a mouse model of mastitis. The results showed that the mice exhibited edema and thickening of the acinar wall with inflammatory infiltration after S. uberis treatment. Intraperitoneal injection of ESC significantly reduced inflammatory cell infiltration, restored normal physiological function, and inhibited the production of the inflammatory cytokines interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot analysis revealed that ESC reduced P38 phosphorylation, further inhibited the influence of mammary Streptococcus on cytoplasmic translocation of nuclear factor-κB (P65), and inhibited the transcriptional activation of P65, thus inhibiting the generation of inflammatory cells. Collectively, ESC may inhibit mitogen-activated protein kinase and nuclear factor-κB, thereby highlighting its potential for the treatment and prevention of mastitis.