Effect of moxibustion on the SIRT1/FOXO3a signaling pathway in ApoE-/- mice with atherosclerosis. / 艾灸对ApoE-/-åŠ¨è„‰ç²¥æ ·ç¡¬åŒ–å°é¼ SIRT1/FOXO3a信号通路的影响.

OBJECTIVES: To observe the effects of moxibustion on blood lipid metabolism, pathological morphology of thoracic aorta, and the expression of silent information regulator 1 (SIRT1) and forkhead box transcription factor O3a (FOXO3a) in ApoE-/- atherosclerosis (AS) mice, so as to explore the potential mechanism of moxibustion in preventing and treating AS. METHODS: Ten C57BL/6J mice were fed a normal diet as the control group, and 30 ApoE-/- mice were fed a high-fat diet to establish the AS model, which were randomly divided into the model group, simvastatin group, and moxibustion group, with 10 mice in each group. From the first day of modeling, mice in the moxibustion group received mild moxibustion treatment at "Shenque"(CV8), "Yinlingquan"(SP9), bilateral "Neiguan"(PC6) and "Xuehai"(SP10) for 30 min per time；the mice in the simvastatin group were given simvastatin orally (2.5 mg·kg-1·d-1), with both treatments given once daily, 5 times a week, with a total intervention period of 12 weeks. The body weight and general condition of the mice were observed and recorded during the intervention period. After the intervention, the contents of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured using an automated biochemistry analyzer. Hematoxylin eosin (HE) staining was used to observe the pathological morphology of the thoracic aorta. ELISA was used to measure the contents of serum oxidized low-density lipoprotein (ox-LDL) and superoxide dismutase (SOD) activity. Western blot and real-time fluorescent quantitative PCR analysis were used to detect the expression levels of SIRT1 and FOXO3a protein and mRNA in the thoracic aorta. RESULTS: Compared with the control group, body weight at the 8th and 12th week, serum TC, TG, LDL-C, and ox-LDL contents of the model group mice were significantly increased(P<0.05, P<0.01), while the HDL-C contents, SOD activity, and the expression levels of SIRT1 protein and mRNA in the thoracic aorta were significantly decreased(P<0.05, P<0.01). HE staining showed thickening of the aortic intima, endothelial cell degeneration, swelling, and shedding. Compared with the model group, body weight at the 8th and 12th week, serum TC, TG, LDL-C, and ox-LDL contents of mice in the simvastatin group and moxibustion group were significantly decreased(P<0.01), while the serum SOD activity, expression levels of SIRT1 protein and mRNA in the thoracic aorta were significantly increased(P<0.01). The HDL-C contents were significantly increased in the simvastatin group(P<0.05). The thoracic aortic structure was more intact in both groups, with a more regular lumen and orderly arrangement of the elastic membrane in the media, and a slight amount of endothelial cell degeneration and swelling in the intima. There was no significant difference in the evaluated indexes between the moxibustion group and the simvastatin group and the pathological changes in the thoracic aorta were similar between the two groups. CONCLUSIONS: Moxibustion can reduce the body weight of AS model mice, regulate lipid levels, repair vascular intima, and alleviate endothelial damage. Its mechanism of action may be related to the regulation of the SIRT1/FOXO3a signaling pathway to improve oxidative damage.

Plain Language Summary of the KarMMa-3 study of ide-cel or standard of care regimens in people with relapsed or refractory multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This plain language summary describes the results of a Phase 3 study called KarMMa-3. In this ongoing study, researchers looked at a relatively new treatment for people with multiple myeloma, a type of blood cancer, whose cancer got worse despite treatment (refractory) or had cancer that at first improved with treatment, but eventually stopped responding (relapsed). HOW WAS THIS STUDY CONDUCTED?: In the KarMMa-3 study, people with relapsed or refractory multiple myeloma received either a one-time infusion of a new treatment, named ide-cel, or one of the standard of care regimens currently available for patients with this cancer. People were treated with the standard of care regimens in weekly or monthly cycles until the cancer got worse, there were unacceptable side effects, or the person withdrew from the study. WHAT WERE THE RESULTS?: The results of this study showed that people receiving the one-time infusion of ide-cel lived longer without the cancer getting worse and had a greater reduction in cancer cells than patients receiving the standard of care regimen. A higher percentage of patients receiving ide-cel responded to treatment than patients receiving the standard of care regimen, and the response to treatment was better with idecel. These results show that ide-cel is a promising treatment for this challenging disease. Clinical Trial Registration: NCT03651128 (KarMMa-3 study).

AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. METHODS: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. RESULTS: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. CONCLUSIONS: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart disease that leads to abnormal heartbeats and a higher risk of sudden cardiac death. ARVC is often caused by changes in a gene called PKP2, that then makes less PKP2 protein. PKP2 protein is important for the normal structure and function of the heart. Human ARVC characteristics can be mimicked in a mouse model missing this gene. Given no therapeutic option, our goal was to test if adding a working copy of PKP2 gene in the heart of this mouse model, using a technique called gene therapy that can deliver genes to cells, could improve heart function. Here, we show that a single dose of PKP2 gene therapy can improve heart function and heartbeats as well as extend lifespan in mice. PKP2 gene therapy may be a promising approach to treat ARVC patients with PKP2 mutations.

Diagnostic value of plasma-derived exosomal miR-223 for epithelial ovarian cancer.

OBJECTIVES: To evaluate the diagnostic value of plasma exosomal miR-223 and its combination with CA125 for the diagnosis of early-stage epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Exosomes derived from the plasma of 78 EOC patients, 40 patients with epithelial benign ovarian tumors, and 52 healthy participants were isolated using the ultracentrifugation method and identified by transmission electron microscopy (TEM) and western blot. RESULTS: The expression of exosomal miR-223 was significantly upregulated in the plasma of EOC patients compared to that in healthy subjects and patients with benign diseases. The combination of exosomal miR-223 and CA125 from plasma had an equivalent area under the ROC curve (AUC) to CA125 alone for discriminating between EOC and non-EOC cases, including healthy subjects and benign ovarian tumors. However, the AUC value of the combination was 0.944 (95% CI: 0.899-0.990) for differentially diagnosing early-stage EOC from healthy subjects, slightly higher than that of CA125 alone (0.928, 95% CI: 0.875-0.981), with a sensitivity and specificity of 0.9784 and 0.885, respectively. CONCLUSION: Our data suggest that plasma exosomal miR-223 can be used as a complement to CA125 to increase the diagnostic power for differentiating early-stage EOC from healthy subjects.

Aging Increases Hypoxia-Induced Endothelial Permeability and Blood-Brain Barrier Dysfunction by Upregulating Arginase-II.

Increased endothelial permeability plays an important role in blood-brain barrier (BBB) dysfunction and is implicated in neuronal injury in many diseased conditions. BBB disruption is primarily determined by dysfunction of endothelial cell-cell junctions. Deprivation of oxygen supply or hypoxia, a common feature of a variety of human diseases, is a major risk factor for BBB disruption. The molecular regulatory mechanisms of hypoxia-induced BBB dysfunction remain incompletely understood. The mitochondrial enzyme, arginase type II (Arg-II), has been shown to promote endothelial dysfunction. However, its role in hypoxia-induced BBB dysfunction has not been explored. In the C57BL/6J mouse model, hypoxia (8% O2, 24 hours) augments vascular Arg-II in the hippocampus, decreases cell-cell junction protein levels of Zonula occludens-1 (ZO-1), occludin, and CD31 in endothelial cells, increases BBB leakage in the brain in old mice (20 to 24 months) but not in young animals (3 to 6 months). These effects of hypoxia in aging are suppressed in arg-ii-/- mice. Moreover, the age-associated vulnerability of endothelial integrity to hypoxia is demonstrated in senescent human brain microvascular endothelial cell (hCMEC/D3) culture model. Further results in the cell culture model show that hypoxia augments Arg-II, decreases ZO-1 and occludin levels, and increases endothelial permeability, which is prevented by arg-ii gene silencing or by inhibition of mitochondrial reactive oxygen species (mtROS) production. Our study demonstrates an essential role of Arg-II in increased endothelial permeability and BBB dysfunction by promoting mtROS generation, resulting in decreased endothelial cell-cell junction protein levels under hypoxic conditions particularly in aging.

Human gestational diabetes mellitus-derived exosomes impair glucose homeostasis in pregnant mice and stimulate functional maturation of offspring-islets.

AIMS: Pancreatic islets undergo critical development and functional maturation during the perinatal period when they are highly sensitive to microenvironment. We aim to determine the effects and mechanisms of gestational diabetes mellitus (GDM) hypermetabolic stress on glucose homeostasis in pregnant mice and functional maturation of the islets of their offspring. MAIN METHODS: Exosomes were extracted from the umbilical vein blood of individuals with or without GDM for administration to pregnant mice. The blood glucose, serum insulin, glycosylated hemoglobin, and lipopolysaccharide levels were measured in pregnant mice. The expression and localization of insulin, glucagon, PC1/3, PDX1, and p-S6 in the islets of neonatal rats were continuously monitored using immunofluorescence to evaluate their functional status. Primary islet cells were cultured and treated with GDM exosomes and exendin to determine the expression of GLP-1R, AKT, p-AKT, and p-S6 via western blotting. KEY FINDINGS: GDM exosomes induced remarkable oral glucose intolerance, hyperinsulinemia, and metabolic inflammation in pregnant mice. The islets of GDM offspring exhibited high insulin, glucagon, PC1/3, PDX1, and p-S6 expression at and after birth, and activation of the local GLP-1/GLP-1R axis. The functional maturation of normal-offspring islets did not commence until after birth, while it was activated prior to birth in GDM offspring, seriously disrupting the whole process. GDM exosomes activated the GLP-1/GLP-1R axis between α and ß cells, and stimulated functional maturation of ß cells via the Akt-mTORC1-pS6 pathway. SIGNIFICANCE: These findings provide preliminary insights into the mechanisms underlying the high incidence of diabetes in the offspring of mothers with GDM.

Selective transcriptomic dysregulation of metabolic pathways in liver and retina by short- and long-term dietary hyperglycemia.

A high glycemic index (HGI) diet induces hyperglycemia, a risk factor for diseases affecting multiple organ systems. Here, we evaluated tissue-specific adaptations in the liver and retina after feeding HGI diet to mice for 1 or 12 month. In the liver, genes associated with inflammation and fatty acid metabolism were altered within 1 month of HGI diet, whereas 12-month HGI diet-fed group showed dysregulated expression of cytochrome P450 genes and overexpression of lipogenic factors including Srebf1 and Elovl5. In contrast, retinal transcriptome exhibited HGI-related notable alterations in energy metabolism genes only after 12 months. Liver fatty acid profiles in HGI group revealed higher levels of monounsaturated and lower levels of saturated and polyunsaturated fatty acids. Additionally, HGI diet increased blood low-density lipoprotein, and diet-aging interactions affected expression of mitochondrial oxidative phosphorylation genes in the liver and disease-associated genes in retina. Thus, our findings provide new insights into retinal and hepatic adaptive mechanisms to dietary hyperglycemia.

Red mud accommodated mesoporous black TiO2 framework with enhanced organic pollutant photodegradation.

In this work, black TiO2 (BTiO2) loaded on black red mud (BRM) was successfully prepared with the conversion of Fe2O3 into magnetic Fe3O4 in red mud and the reduction of partial Ti4+ to Ti3+ in TiO2 via the facile sol-gel method and H2 reduction treatment. The obtained low-cost BRM/BTiO2 composites exhibit remarkable photocatalytic degradation toward rhodamine B (91.2%) and tetracycline (83.6%) under visible light irradiation, much better than pristine TiO2. This enhancement is attributed to the narrow bandgap with the desired solar-light excitation, the black color with good solar-light absorption, and the heterojunctions with the efficient separation of photogenerated electron-hole pairs. Moreover, the desired magnetic separation of BRM/BTiO2 composites realizes the recycle and recovery of photocatalysts, favoring practical applications in environment. This work provides a cost-efficiency way to prepare RM-supported TiO2 composites for treating organic pollutants in the wastewater, which is of great significance to the comprehensive utilization of RM waste, the cost saving of the photocatalyst, and the visible-light active enhancement of TiO2.

FK-binding protein 5: Possible relevance to the pathogenesis of metabolic dysfunction and alcohol-associated liver disease.

The FK506-binding protein (FKBP5) plays significant roles in mediating stress responses by interacting with glucocorticoids, participating in adipogenesis, and influencing various cellular pathways throughout the body. In this review, we described the potential role of FKBP5 in the pathogenesis of two common chronic liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-associated liver disease (ALD). We provided an overview of the FK-binding protein family and elucidated their roles in cellular stress responses, metabolic diseases, and adipogenesis. We explored how FKBP5 may mechanistically influence the pathogenesis of MASLD and ALD and provided insights for further investigation into the role of FKBP5 in these two diseases.

Dietary fish oil enriched in very-long-chain polyunsaturated fatty acid reduces cardiometabolic risk factors and improves retinal function.

Very-long-chain polyunsaturated fatty acids (VLCPUFAs; C24-38) constitute a unique class of PUFA that have important biological roles, but the lack of a suitable dietary source has limited research in this field. We produced an n-3 C24-28-rich VLCPUFA-oil concentrated from fish oil to study its bioavailability and physiological functions in C57BL/6J mice. The serum and retinal C24:5 levels increased significantly compared to control after a single-dose gavage, and VLCPUFAs were incorporated into the liver, brain, and eyes after 8-week supplementation. Dietary VLCPUFAs resulted in favorable cardiometabolic changes, and improved electroretinography responses and visual performance. VLCPUFA supplementation changed the expression of genes involved in PPAR signaling pathways. Further in vitro studies demonstrated that the VLCPUFA-oil and chemically synthesized C24:5 are potent agonists for PPARs. The multiple potential beneficial effects of fish oil-derived VLCPUFAs on cardiometabolic risk and eye health in mice support future efforts to develop VLCPUFA-oil into a supplemental therapy.

Effects of Cascade Reservoirs on Spatiotemporal Dynamics of the Sedimentary Bacterial Community: Co-occurrence Patterns, Assembly Mechanisms, and Potential Functions.

Dam construction as an important anthropogenic activity significantly influences ecological processes in altered freshwater bodies. However, the effects of multiple cascade dams on microbial communities have been largely overlooked. In this study, the spatiotemporal distribution, co-occurrence relationships, assembly mechanisms, and functional profiles of sedimentary bacterial communities were systematically investigated in 12 cascade reservoirs across two typical karst basins in southwest China over four seasons. A significant spatiotemporal heterogeneity was observed in bacterial abundance and diversity. Co-occurrence patterns in the Wujiang Basin exhibited greater edge counts, graph density, average degree, robustness, and reduced modularity, suggesting more intimate and stronger ecological interactions among species than in the Pearl River Basin. Furthermore, Armatimonadota and Desulfobacterota, identified as keystone species, occupied a more prominent niche than the dominant species. A notable distance-decay relationship between geographical distance and community dissimilarities was identified in the Pearl River Basin. Importantly, in the Wujiang Basin, water temperature emerged as the primary seasonal variable steering the deterministic process of bacterial communities, whereas 58.5% of the explained community variance in the neutral community model (NCM) indicated that stochastic processes governed community assembly in the Pearl River Basin. Additionally, principal component analysis (PCA) revealed more pronounced seasonal dynamics in nitrogen functional compositions than spatial variation in the Wujiang Basin. Redundancy analysis (RDA) results indicated that in the Wujiang Basin, environmental factors and in Pearl River Basin, geographical distance, reservoir age, and hydraulic retention time (HRT), respectively, influenced the abundance of nitrogen-related genes. Notably, these findings offer novel insights: building multiple cascade reservoirs could lead to a cascading decrease in biodiversity and resilience in the river-reservoir ecosystem.

HMGB2 is a potential diagnostic marker and therapeutic target for liver fibrosis and cirrhosis.

BACKGROUND: High mobility group proteins 1 and 2 (HMGB1 and HMGB2) are 80% conserved in amino acid sequence. The function of HMGB1 in inflammation and fibrosis has been extensively characterized. However, an unaddressed central question is the role of HMGB2 on liver fibrosis. In this study, we provided convincing evidence that the HMGB2 expression was significantly upregulated in human liver fibrosis and cirrhosis, as well as in several mouse liver fibrosis models. METHODS: The carbon tetrachloride (CCl4) induced liver fibrosis mouse model was used. AAV8-Hmgb2 was utilized to overexpress Hmgb2 in the liver, while Hmgb2-/- mice were used for loss of function experiments. The HMGB2 inhibitor inflachromene and liposome-shHMGB2 (lipo-shHMGB2) were employed for therapeutic intervention. RESULTS: The serum HMGB2 levels were also markedly elevated in patients with liver fibrosis and cirrhosis. Deletion of Hmgb2 in Hmgb2-/- mice or inhibition of HMGB2 in mice using a small molecule ICM slowed the progression of CCl4-induced liver fibrosis despite constant HMGB1 expression. In contrast, AAV8-mediated overexpression of Hmgb2 enchanced CCl4-incuded liver fibrosis. Primary hepatic stellate cells (HSCs) isolated from Hmgb2-/- mice showed significantly impaired transdifferentiation and diminished activation of α-SMA, despite a modest induction of HMGB1 protein. RNA-seq analysis revealed the induction of top 45 CCl4-activated genes in multiple signaling pathways including integrin signaling and inflammation. The activation of these genes by CCl4 were abolished in Hmgb2-/- mice or in ICM-treated mice. These included C-X3-C motif chemokine receptor 1 (Cx3cr1) associated with inflammation, cyclin B (Ccnb) associated with cell cycle, DNA topoisomerase 2-alpha (Top2a) associated with intracellular component, and fibrillin (Fbn) and fibromodulin (Fmod) associated with extracellular matrix. CONCLUSION: We conclude that HMGB2 is indispensable for stellate cell activation. Therefore, HMGB2 may serve as a potential therapeutic target to prevent HSC activation during chronic liver injury. The blood HMGB2 level may also serve as a potential diagnostic marker to detect early stage of liver fibrosis and cirrhosis in humans.

Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial.

Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.5% achieved VGPR or better and 38.7% achieved CR or stringent CR. Among exploratory endpoints, median duration of response, progression-free survival (PFS) and overall survival were 10.3, 8.8 and 34.2 months, respectively, and ide-cel expansion in blood and bone marrow correlated with clinical efficacy and postinfusion reduction of soluble BCMA. Patients with PFS ≥ 18 months had more naive and less exhausted T cells in apheresis material and improved functional T cell phenotype in the drug product compared with those with less durable responses. These results confirm ide-cel safety, tolerability and efficacy and describe T cell qualities that correlate with durable response. Clinicaltrials.gov identifier : NCT02658929 .

Pterostilbene alleviated cerebral ischemia/reperfusion-induced blood-brain barrier dysfunction via inhibiting early endothelial cytoskeleton reorganization and late basement membrane degradation.

Pterostilbene, an important analogue of the star molecule resveratrol and a novel compound naturally occurring in blueberries and grapes, exerts a significant neuroprotective effect on cerebral ischemia/reperfusion (I/R), but its mechanism is still unclear. This study aimed to follow the molecular mechanisms behind the potential protective effect of pterostilbene against I/R induced injury. For fulfilment of our aim, we investigated the protective effects of pterostilbene on I/R injury caused by middle cerebral artery occlusion (MCAO) in vivo and oxygen-glucose deprivation (OGD) in vitro. Machine learning models and molecular docking were used for target exploration and validated by western blotting. Pterostilbene significantly reduced the cerebral infarction volume, improved neurological deficits, increased cerebral microcirculation and improved blood-brain barrier (BBB) leakage. Machine learning models confirmed that the stroke target MMP-9 bound to pterostilbene, and molecular docking demonstrated the strong binding activity. We further found that pterostilbene could depolymerize stress fibers and maintain the cytoskeleton by effectively increasing the expression of the non-phosphorylated actin depolymerizing factor (ADF) in the early stage of I/R. In the late stage of I/R, pterostilbene could activate the Wnt pathway and inhibit the expression of MMP-9 to decrease the degradation of the extracellular basement membrane (BM) and increase the expression of junction proteins. In this study, we explored the protective mechanisms of pterostilbene in terms of both endothelial cytoskeleton and extracellular matrix. The early and late protective effects jointly maintain BBB stability and attenuate I/R injury, showing its potential to be a promising drug candidate for the treatment of ischemic stroke.

Gastrodin ameliorates cognitive dysfunction in diabetes by inhibiting PAK2 phosphorylation.

Diabetes is associated with higher prevalence of cognitive dysfunction, while the underlying mechanism is still elusive. In this study, we aim to explore the potential mechanism of diabetes-induced cognitive dysfunction and assess the therapeutic effects of Gastrodin on cognitive dysfunction. Diabetes was induced by a single injection of streptozotocin. The Morris Water Maze Test was employed to assess the functions of spatial learning and memory. Transcriptome was used to identify the potential factors involved. Western blot and immunofluorescence were applied to detect the protein expression. Our results have shown that spatial learning was impaired in diabetic rats, coupled with damaged hippocampal pyramidal neurons. Gastrodin intervention ameliorated the spatial learning impairments and neuronal damages. Transcriptomics analysis identified differential expression genes critical for diabetes-induced hippocampal damage and Gastrodin treatment, which were further confirmed by qPCR and western blot. Moreover, p21 activated kinase 2 (PAK2) was found to be important for diabetes-induced hippocampal injury and its inhibitor could promote the survival of primary hippocampal neurons. It suggested that PAK2 pathway may be involved in cognitive dysfunction in diabetes and could be a therapeutic target for Gastrodin intervention.

Elevation of Arginase-II in Podocytes Contributes to Age-Associated Albuminuria in Male Mice.

One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of an age-associated increase in arginase-II (Arg-II) in proximal tubules of both male and female mice. However, it is unclear whether Arg-II is also involved in aging glomeruli. The current study investigates the role of the sex-specific elevation of Arg-II in podocytes in age-associated increased albuminuria. Young (3-4 months) and old (20-22 months) male and female mice of wt and arginase-II knockout (arg-ii-/-) were used. Albuminuria was employed as a readout of glomerular function. Cellular localization and expression of Arg-II in glomeruli were analyzed using an immunofluorescence confocal microscope. A more pronounced age-associated increase in albuminuria was found in male than in female mice. An age-associated induction of Arg-II in glomeruli and podocytes (as demonstrated by co-localization of Arg-II with the podocyte marker synaptopodin) was also observed in males but not in females. Ablation of the arg-ii gene in mice significantly reduces age-associated albuminuria in males. Also, age-associated decreases in podocyte density and glomerulus hypertrophy are significantly prevented in male arg-ii-/- but not in female mice. However, age-associated glomerulosclerosis is not affected by arg-ii ablation in both sexes. These results demonstrate a role of Arg-II in sex-specific podocyte injury in aging. They may explain the sex-specific differences in the development of renal disease in humans during aging.

Embryo development, pregnancy and live birth outcomes following IVF treatment were not compromised during the COVID-19 pandemic.

PURPOSE: To evaluate whether outcomes of in vitro fertilization (IVF) are affected during the coronavirus disease-19 (COVID-19) pandemic. METHODS: This was a single-center, retrospective study. Embryo development, pregnancy, and live birth outcomes were compared between COVID-19 and pre-COVID-19 groups. Blood samples from patients during the COVID-19 pandemic were tested for COVID-19. RESULTS: After 1:1 random matching, 403 cycles for each group were included in the study. The rates of fertilization, normal fertilization, and blastocyst formation were higher in the COVID-19 group than in the pre-COVID-19 group. No difference was observed in the rates of day 3 good-quality embryos and good-quality blastocysts between the groups. A multivariate analysis showed that the live birth rate in the COVID-19 group was higher than that in the pre-COVID-19 group (51.4% vs. 41.4%, P = 0.010). In fresh cleavage-stage embryo and blastocyst transfer cycles, there were no differences between the groups in terms of pregnancy, obstetric, and perinatal outcomes. In the freeze-all cycles, the live birth rate was higher during the COVID-19 pandemic (58.0% vs. 34.5%, P = 0.006) than during the pre-COVID-19 period following frozen cleavage stage embryo transfer. The rate of gestational diabetes during the COVID-19 pandemic was higher than that during the pre-COVID-19 period (20.3% vs. 2.4%, P = 0.008) following frozen blastocyst transfer. All the serological results of the patients during the COVID-19 pandemic were negative. CONCLUSION: Our results indicate that embryo development, pregnancy, and live birth outcomes in uninfected patients were not compromised during the COVID-19 pandemic at our center.

Physalin A Induces Apoptosis and Autophagy in Hepatocellular Carcinoma via Inhibition of PI3K/Akt Signaling Pathway.

Physalin A (PA) is a bioactive withanolide with multiple pharmacological properties and has been indicated to be cytotoxic to hepatocellular carcinoma (HCC) cell line HepG2. This study aims to explore the mechanisms underlying PA antitumor activity in HCC. HepG2 cells were exposed to various concentrations of PA. Cell counting kit-8 assay and flow cytometry were implemented for evaluating cell viability and apoptosis, respectively. Immunofluorescence staining was utilized for detecting autophagic protein LC3. Western blotting was employed for measuring levels of autophagy-, apoptosis- and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling-related proteins. A xenograft mouse model was established to verify the antitumor activity of PA in vivo. PA impaired HepG2 cell viability, and triggered apoptosis as well as autophagy. Inhibiting autophagy augmented PA-evoked HepG2 cell apoptosis. PA repressed PI3K/Akt signaling in HCC cells and activating PI3K/Akt reversed PA-triggered apoptosis and autophagy. PA treatment inhibited tumor growth in tumor-bearing mice. PA triggers HCC cell apoptosis and autophagy by inactivating PI3K/Akt signaling.

PSNSleep: a self-supervised learning method for sleep staging based on Siamese networks with only positive sample pairs.

Traditional supervised learning methods require large quantities of labeled data. However, labeling sleep data according to polysomnography by well-trained sleep experts is a very tedious job. In the present day, the development of self-supervised learning methods is making significant progress in many fields. It is also possible to apply some of these methods to sleep staging. This is to remove the dependency on labeled data at the stage of representation extraction. Nevertheless, they often rely too much on negative samples for sample selection and construction. Therefore, we propose PSNSleep, a novel self-supervised learning method for sleep staging based on Siamese networks. The crucial step to the success of our method is to select appropriate data augmentations (the time shift block) to construct the positive sample pair. PSNSleep achieves satisfactory results without relying on any negative samples. We evaluate PSNSleep on Sleep-EDF and ISRUC-Sleep and achieve accuracy of 80.0% and 74.4%. The source code is publicly available at https://github.com/arthurxl/PSNSleep.