CircALMS1 Alleviates Pulmonary Microvascular Endothelial Cell Dysfunction in Pulmonary Hypertension.

BACKGROUND: Circular RNAs can serve as regulators influencing the development of pulmonary hypertension (PH). However, their function in pulmonary vascular intimal injury remains undefined. Thus, we aimed to identify specifically expressed circular RNAs in pulmonary microvascular endothelial cells (PMECs) under hypoxia and PH. METHODS AND RESULTS: Deep RNA sequencing and quantitative real-time polymerase chain reaction revealed that circALMS1 (circular RNA Alstrom syndrome protein 1) was reduced in human PMECs under hypoxia (P<0.0001). Molecular biology and histopathology experiments were used to elucidate the roles of circALMS1 in regulating PMEC dysfunction among patients with PH. The circALMS1 expression was decreased in the plasma of patients with PH (P=0.0315). Patients with lower circALMS1 levels had higher risk of death (P=0.0006). Moreover, the circALMS1 overexpression of adeno-associated viruses improved right ventricular function and reduced pulmonary vascular remodeling in monocrotaline-PH and sugen/hypoxia-PH rats (P<0.05). Furthermore, circALMS1 overexpression promoted apoptosis and inhibited PMEC proliferation and migration under hypoxia by directly downregulating miR-17-3p (P<0.05). Dual luciferase assay confirmed the direct binding of circALMS1 to miR-17-3p and miR-17-3p binding to its target gene YT521-B homology domain-containing family protein 2 (YTHDF2) (P<0.05). The YTHDF2 levels were also downregulated in hypoxic PMECs (P<0.01). The small interfering RNA YTHDF2 reversed the effects of miR-17-3p inhibitors on PMEC proliferation, migration, and apoptosis. Finally, the results indicated that, although YTHDF2, as an N(6)-methyladenosine reader protein, contributes to the degradation of many circular RNAs, it could not regulate the circALMS1 levels in PMECs (P=0.9721). CONCLUSIONS: Our study sheds new light on circALMS1-regulated dysfunction of PMECs by the miR-17-3p/YTHDF2 pathway under hypoxia and provides insights into the underlying pathogenesis of PH.

A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement.

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 ± 6.9 nmol/L) and M channels (IC50 = 10.1 ± 2.4 µmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits.

Impact of different sequential triple oral combination therapies based selexipag on outcomes in pulmonary arterial hypertension.

BACKGROUND: While the GRIPHON study and others have confirmed the efficacy and safety of selexipag with single, dual, and initial triple combination therapy for patients with pulmonary arterial hypertension (PAH), multicenters studies concerning diverse triple oral combination therapies based on selexipag are limited. HYPOTHESIS: This study was conducted to evaluate the effects of various sequential triple oral combination therapies on PAH outcomes. METHODS: A retrospective study was carried out involving 192 patients from 10 centers, who were receiving sequential triple oral combination therapy consisting of an endothelin receptor antagonist (ERA), a phosphodiesterase 5 inhibitor (PDE5i)/riociguat and selexipag. Clinical parameters, event-free survival, and all-cause survival were assessed and analyzed at baseline and posttreatment. RESULTS: Among the 192 patients, 37 were treated with ERA + riociguat + selexipag, and 155 patients received ERA + PDE5i + selexipag. Both sequential triple oral combination therapies improved the World Health Organization functional class and raised the count of low-risk parameters. As a result of the larger patients' population in the ERA + PDE5i + selexipag group, these individuals exhibited significant increases in 6-minute walking distance (6MWD), pulmonary arterial systolic pressure, pulmonary arterial pressure, right ventricle, and eccentricity index, and significant decreases in N-terminal probrain natriuretic peptide after 6 months of treatment. Nevertheless, both sequential triple oral combination therapy groups demonstrated similar shifts in these clinical parameters between baseline and 6 months. Baseline 6MWD and mean pulmonary arterial pressure were independent predictors of survival in patients undergoing ERA + PDE5i + selexipag therapy. Importantly, no significant differences were found in 6-month event-free survival and all-cause survival between two groups. CONCLUSIONS: Different oral sequential triple combination therapies based on selexipag could comparably improve outcomes in patients with PAH.

Neural stem cell-derived exosomes regulate cell proliferation, migration, and cell death of brain microvascular endothelial cells via the miR-9/Hes1 axis under hypoxia.

BACKGROUND: Our previous study found that mouse embryonic neural stem cell (NSC)-derived exosomes (EXOs) regulated NSC differentiation via the miR-9/Hes1 axis. However, the effects of EXOs on brain microvascular endothelial cell (BMEC) dysfunction via the miR-9/Hes1 axis remain unknown. Therefore, the current study aimed to determine the effects of EXOs on BMEC proliferation, migration, and death via the miR-9/Hes1 axis. METHODS: Immunofluorescence, quantitative real-time polymerase chain reaction, cell counting kit-8 assay, wound healing assay, calcein-acetoxymethyl/propidium iodide staining, and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs. RESULTS: EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions. The overexpression of miR-9 promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions. Moreover, miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death. Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death. Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice. Meanwhile, EXO treatment improved cerebrovascular alterations. CONCLUSION: NSC-derived EXOs can promote BMEC proliferation and migration and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions. Therefore, EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.

Clinical Characteristics of Children Infected with SARS-CoV-2 Omicron (B.1.1.529) in China's Shanghai.

Introduction: The pandemic of SARS-CoV-2 brings great challenge and threats to humans worldwide. Multiple variants of SARS-CoV-2 tend to be epidemic, among which Omicron is highly infectious within China. The aim of this study was to analyze the clinical characteristics of children infected with SARS-CoV-2 variant B.1.1.529 (Omicron) in the Shanghai, China. Methods: We included 9378 pediatric patients diagnosed with Omicron and treated in the Shanghai International Convention and Exhibition Center between April 1, 2022 and May 31, 2022. We recorded and summarized the clinical characteristics, infectious conditions and biological features of the children infected with Omicron. Results: A total of 9355 paediatric patients were treated in isolation since Makeshift became available, including 5564 males (59.48%) and 3791 females (40.52%). More than half (55.56%) of the affected children were identified at premises screening. The number of symptomatic or asymptomatic patients was 4530 (48.42%) and 4825 (51.58%), respectively. Initial signs or symptoms in asymptomatic patients included fatigue (3582, 38.29%), cough (560, 5.99%), fever (242, 2.59%) and other (146, 1.56%). Age and number of vaccinations in paediatric patients were negatively associated with the number of days from positive to negative nucleic acid test results. Conclusion: Age and number of vaccinations were key factors influencing the conversion of nucleic acid test results in paediatric patients. Early childhood vaccination is encouraged to establish a complete immune barrier.

TMT-based quantitative proteomics reveals the nutritional and stress resistance functions of anaerobic fungi in yak rumen during passage at different time intervals.

OBJECTIVES: Anaerobic fungi are critical for nutrient digestion in the yak rumen. Although studies have reported the effects of passage at different time intervals on the community structure of yak rumen anaerobic fungi, it is unknown whether passage culture at different time intervals affects the microbial proteins of rumen anaerobic fungi and their functions. METHODS: Mycelium was obtained using the anaerobic continuous batch culture (CBC) of yak rumen fluid at intervals of 3 d, 5 d and 7 d. Quantitative analysis of fungal proteins and functional analysis was performed using tandem mass tagging (TMT) and bioinformatics. RESULTS: A total of 56 differential proteins (DPs) were found in 5 d vs. 3 d and 7 d vs. 3 d. Gene ontology (GO) enrichment indicated that the up-regulated proteins were mainly involved in biological regulation, cellular process, metabolic process, macromolecular complex, membrane, cell part, organelle, binding, catalytic activity and transporter activity. The downregulated proteins were mainly enriched in metabolic process, cell part, binding and catalytic activity. Furthermore, the downregulated proteins in 7 d vs. 3 d were related to membrane and organelle. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicated that DPs were enriched in 14 pathways in 5 d vs. 3 d and 7 d vs. 3 d, mainly including terpenoid backbone biosynthesis, alaine, aspartate and glutamate metabolism, arginine biosynthesis, hypotaurine, cyanoamino acid, glutathione, ß-alanine, pyrimidine, purine, galactose and propanate metabolism, steroid biosynthesis, ribosome biogenesis in eukaryotes and aminoacyl tRNA biosynthesis. The DPs were enriched in only 2 pathways in 5 d vs 3 d, lysine biosynthesis and cysteine and methionine metabolism. N-glycan biosynthesis and retinol metabolism are only found in the metabolism of DPs in 7 d vs 3 d. CONCLUSIONS: Yak rumen anaerobic fungal proteins are involved in nutrition and stress tolerance during passage at different time intervals.

The sigma-1 receptor-TAMM41 axis modulates neuroinflammation and attenuates memory impairment during the latent period of epileptogenesis.

BACKGROUND: Therapy in the latent period is favorable for retarding the process of epileptogenesis. Recently, we have discovered that the activated sigma-1 receptor (Sig-1R) attenuates the hippocampus pathological injury and memory impairment in the latent period of epileptogenesis. But the molecular mechanism needs further investigation. METHODS: PRE-084 was utilized as a research tool to highly selectively activate Sig-1R in epileptic mice. After the treatment of PRE-084, the pro-inflammatory cytokines, neuropathological traits, and the level of mitochondrial translocator assembly and maintenance 41 homolog (TAMM41) in the hippocampus were examined. The mode in which the Sig-1R interacts with TAMM41 was explored. The role of TAMM41 in the protecting effect of PRE-084 was established. RESULTS: PRE-084 inhibited the growth of pro-inflammatory cytokines, reduced the formation of gliosis, alleviated neuronal damage in the hippocampus, and attenuated memory impairment in the latent period of epileptogenesis. The protein level of TAMM41 decreased in the hippocampi of epileptic mice and increased in the PRE-084-treated mice. The Sig-1R bound with TAMM41 directly, maintaining the stability of TAMM41. Knockdown of TAMM41 reversed the protective effect of PRE-084, and overexpression of TAMM41 exhibited a similar protective action to that of PRE-084. CONCLUSION: We presented the concept of the "sigma-1 receptor-TAMM41 axis" and proposed that augmenting this axis can attenuate neuroinflammation and memory impairment in the process of epileptogenesis.

Comparison of Structural Features of CRISPR-Cas Systems in Thermophilic Bacteria.

The clustered regularly interspaced short palindromic repeat (CRISPR) is an adaptive immune system that defends most archaea and many bacteria from foreign DNA, such as phages, viruses, and plasmids. The link between the CRISPR-Cas system and the optimum growth temperature of thermophilic bacteria remains unclear. To investigate the relationship between the structural characteristics, diversity, and distribution properties of the CRISPR-Cas system and the optimum growth temperature in thermophilic bacteria, genomes of 61 species of thermophilic bacteria with complete genome sequences were downloaded from GenBank in this study. We used CRISPRFinder to extensively study CRISPR structures and CRISPR-associated genes (cas) from thermophilic bacteria. We statistically analyzed the association between the CRISPR-Cas system and the optimum growth temperature of thermophilic bacteria. The results revealed that 59 strains of 61 thermophilic bacteria had at least one CRISPR locus, accounting for 96.72% of the total. Additionally, a total of 362 CRISPR loci, 209 entirely distinct repetitive sequences, 131 cas genes, and 7744 spacer sequences were discovered. The average number of CRISPR loci and the average minimum free energy (MFE) of the RNA secondary structure of repeat sequences were positively correlated with temperature whereas the average length of CRISPR loci and the average number of spacers were negatively correlated. The temperature did not affect the average number of CRISPR loci, the average length of repeats, or the guanine-cytosine (GC) content of repeats. The average number of CRISPR loci, the average length of the repeats, and the GC content of the repeats did not reflect temperature dependence. This study may provide a new basis for the study of the thermophilic bacterial adaptation mechanisms of thermophilic bacteria.

The Impact of Abnormal Lipid Metabolism on the Occurrence Risk of Idiopathic Pulmonary Arterial Hypertension.

The aim was to determine whether lipid molecules can be used as potential biomarkers for idiopathic pulmonary arterial hypertension (IPAH), providing important reference value for early diagnosis and treatment. Liquid chromatography-mass spectrometry-based lipidomic assays allow for the simultaneous detection of a large number of lipids. In this study, lipid profiling was performed on plasma samples from 69 IPAH patients and 30 healthy controls to compare the levels of lipid molecules in the 2 groups of patients, and Cox regression analysis was used to identify meaningful metrics, along with receiver operator characteristic curves to assess the ability of the lipid molecules to predict the risk of disease in patients. Among the 14 lipid subclasses tested, 12 lipid levels were significantly higher in IPAH patients than in healthy controls. Free fatty acids (FFA) and monoacylglycerol (MAG) were significantly different between IPAH patients and healthy controls. Logistic regression analysis showed that FFA (OR: 1.239, 95%CI: 1.101, 1.394, p < 0.0001) and MAG (OR: 3.711, 95%CI: 2.214, 6.221, p < 0.001) were independent predictors of IPAH development. Among the lipid subclasses, FFA and MAG have potential as biomarkers for predicting the pathogenesis of IPAH, which may improve the early diagnosis of IPAH.

A clinicopathological and prognostic study of 18 children with C1q nephropathy and focal segmental glomerulosclerosis: an 18-year experience from a single center.

BACKGROUND: C1q nephropathy is a relatively rare glomerulonephritis characterized by dominant mesangial deposition of C1q. Even though C1q nephropathy has been described for more than three decades, the clinicopathological features and renal outcomes remain unclear. C1q nephropathy may present diverse morphological patterns, including focal segmental glomerulosclerosis and, the notion of C1q nephropathy as a separate disease entity is still debated. This study aimed to describe the clinical and prognostic relevance of C1q nephropathy in children with primary focal segmental glomerulosclerosis. METHODS: Three hundred eighty-nine children were diagnosed with primary focal segmental glomerulosclerosis in Jinling Hospital from 2003 to 2020. Among them, 18 cases fulfilled the criteria for C1q nephropathy. We then selected as a control group 18 children with primary focal segmental glomerulosclerosis without C1q nephropathy matched to those with C1q nephropathy for age, sex, and period of renal biopsy. Clinical and prognostic parameters were compared in children with and without C1q nephropathy. Renal end-point was defined as a ≥ 40% reduction in estimated glomerular filtration rate or end-stage renal disease. RESULTS: Four point sixty-three percent (18/389) of primary focal segmental glomerulosclerosis cases were diagnosed with C1q nephropathy. The male-to-female ratio of patients diagnosed with C1q nephropathy was 1:1. The median age at biopsy and age at onset was 15.63 (13.00-16.50) years and 14.50 (9.00-16.00) years, respectively. The prevalence of nephrotic syndrome, hematuria, and hypertension was 38.90% (7/18), 72.20% (13/18), and 33.30% (5/18), respectively. Four (22.2%) patients were steroid-dependent, 13 (72.2%) patients were steroid-resistant, and 1 (5.6%) patient developed secondary steroid-resistance. During a follow-up of 52.24 (25.00-72.47) months, 10 (55.6%) patients achieved remission, and 5 (27.8%) progressed to the end-point [including 2 (11.11%) patients who developed end-stage kidney disease]. There was no significant difference in the estimated end-stage renal disease-free survival rates, the estimated end-point-free survival rates, and the long-term remission rate between patients with and without C1q nephropathy (Kaplan-Meier, Log-rank, all P > 0.05). CONCLUSIONS: C1q nephropathy was rare in pediatric patients with focal segmental glomerulosclerosis. These patients usually had poor response to steroids. The long-term renal outcomes and remission of children with primary focal segmental glomerulosclerosis with C1q nephropathy were comparable to those without C1q nephropathy.

CircPMS1 promotes proliferation of pulmonary artery smooth muscle cells, pulmonary microvascular endothelial cells, and pericytes under hypoxia.

BACKGROUND: Circular RNAs (circRNAs) have been recognized as significant regulators of pulmonary hypertension (PH); however, the differential expression and function of circRNAs in different vascular cells under hypoxia remain unknown. Here, we identified co-differentially expressed circRNAs and determined their putative roles in the proliferation of pulmonary artery smooth muscle cells (PASMCs), pulmonary microvascular endothelial cells (PMECs), and pericytes (PCs) under hypoxia. METHODS: Whole transcriptome sequencing was performed to analyze the differential expression of circRNAs in three different vascular cell types. Bioinformatic analysis was used to predict their putative biological function. Quantitative real-time polymerase chain reaction, Cell Counting Kit-8, and EdU Cell Proliferation assays were carried out to determine the role of circular postmeiotic segregation 1 (circPMS1) as well as its potential sponge mechanism in PASMCs, PMECs, and PCs. RESULTS: PASMCs, PMECs, and PCs exhibited 16, 99, and 31 differentially expressed circRNAs under hypoxia, respectively. CircPMS1 was upregulated in PASMCs, PMECs, and PCs under hypoxia and enhanced the proliferation of vascular cells. CircPMS1 may upregulate DEP domain containing 1 (DEPDC1) and RNA polymerase II subunit D expression by targeting microRNA-432-5p (miR-432-5p) in PASMCs, upregulate MAX interactor 1 (MXI1) expression by targeting miR-433-3p in PMECs, and upregulate zinc finger AN1-type containing 5 (ZFAND5) expression by targeting miR-3613-5p in PCs. CONCLUSIONS: Our results suggest that circPMS1 promotes cell proliferation through the miR-432-5p/DEPDC1 or miR-432-5p/POL2D axis in PASMCs, through the miR-433-3p/MXI1 axis in PMECs, and through the miR-3613-5p/ZFAND5 axis in PCs, which provides putative targets for the early diagnosis and treatment of PH.

Expression of ß-Glucosidases from the Yak Rumen in Lactic Acid Bacteria: A Genetic Engineering Approach.

ß-glucosidase derived from microorganisms has wide industrial applications. In order to generate genetically engineered bacteria with high-efficiency ß-glucosidase, in this study two subunits (bglA and bglB) of ß-glucosidase obtained from the yak rumen were expressed as independent proteins and fused proteins in lactic acid bacteria (Lactobacillus lactis NZ9000). The engineered strains L. lactis NZ9000/pMG36e-usp45-bglA, L. lactis NZ9000/pMG36e-usp45-bglB, and L. lactis NZ9000/pMG36e-usp45-bglA-usp45-bglB were successfully constructed. These bacteria showed the secretory expression of BglA, BglB, and Bgl, respectively. The molecular weights of BglA, BglB, and Bgl were about 55 kDa, 55 kDa, and 75 kDa, respectively. The enzyme activity of Bgl was significantly higher (p < 0.05) than that of BglA and BglB for substrates such as regenerated amorphous cellulose (RAC), sodium carboxymethyl cellulose (CMC-Na), desiccated cotton, microcrystalline cellulose, filter paper, and 1% salicin. Moreover, 1% salicin appeared to be the most suitable substrate for these three recombinant proteins. The optimum reaction temperatures and pH values for these three recombinant enzymes were 50 °C and 7.0, respectively. In subsequent studies using 1% salicin as the substrate, the enzymatic activities of BglA, BglB, and Bgl were found to be 2.09 U/mL, 2.36 U/mL, and 9.4 U/mL, respectively. The enzyme kinetic parameters (Vmax, Km, Kcat, and Kcat/Km) of the three recombinant strains were analyzed using 1% salicin as the substrate at 50 °C and pH 7.0, respectively. Under conditions of increased K+ and Fe2+ concentrations, the Bgl enzyme activity was significantly higher (p < 0.05) than the BglA and BglB enzyme activity. However, under conditions of increased Zn2+, Hg2+, and Tween20 concentrations, the Bgl enzyme activity was significantly lower (p < 0.05) than the BglA and BglB enzyme activity. Overall, the engineered lactic acid bacteria strains generated in this study could efficiently hydrolyze cellulose, laying the foundation for the industrial application of ß-glucosidase.

Extracellular Vesicles Derived circSH3PXD2A Inhibits Chemoresistance of Small Cell Lung Cancer by miR-375-3p/YAP1.

Introduction: Small cell lung cancer (SCLC) is a subtype of lung cancer with high malignancy and poor prognosis. Rapid acquisition of chemoresistance is one of the main reasons leading to clinical treatment failure of SCLC. Studies have indicated that circRNAs participate in multiple processes of tumor progression, including chemoresistance. However, the molecular mechanisms of circRNAs driving the chemoresistance of SCLC are not well specified. Methods: The differentially expressed circRNAs were screened by transcriptome sequencing of chemoresistant and chemosensitive SCLC cells. The EVs of SCLC cells were isolated and identified by ultracentrifugation, Western blotting, transmission electron microscopy, nanoparticle tracking analysis and EVs uptake assays. The expression levels of circSH3PXD2A in serum and EVs of SCLC patients and healthy individuals were detected by qRT‒PCR. The characteristics of circSH3PXD2A were detected by Sanger sequencing, RNase R assay, nuclear-cytoplasmic fraction assay, and fluorescence in situ hybridization assay. The mechanisms of circSH3PXD2A inhibiting SCLC progression were studied by bioinformatics analysis, chemoresistance assay, proliferation assay, apoptosis assay, transwell assay, pull-down assay, luciferase reporting assay, and mouse xenograft assay. Results: It was identified that the circSH3PXD2A was a prominently downregulated circRNA in chemoresistant SCLC cells. The expression level of circSH3PXD2A in EVs of SCLC patients was negatively associated with chemoresistance, and the combination of EVs-derived circSH3PXD2A and serum ProGRP (Progastrin-releasing peptide) levels had better indications for DDP-resistant SCLC patients. CircSH3PXD2A inhibited the chemoresistance, proliferation, migration, and invasion of SCLC cells through miR-375-3p/YAP1 axis in vivo and in vitro. SCLC cells cocultured with EVs secreted by circSH3PXD2A-overexpressing cells exhibited decreased chemoresistance and cell proliferation. Conclusion: Our results manifest that EVs-derived circSH3PXD2A inhibits the chemoresistance of SCLC through miR-375-3p/YAP1 axis. Moreover, EVs-derived circSH3PXD2A may serve as a predictive biomarker for DDP-resistant SCLC patients.

2,6-diazaspiro[3.4]octan-7-one derivatives as potent sigma-1 receptor antagonists that enhanced the antinociceptive effect of morphine and rescued morphine tolerance.

Opioids are efficacious analgesics for pain treatments. However, their repeated use in large doses often leads to analgesic tolerance, which limits the clinical application. Sigma-1 receptor (σ1R) antagonists were reported to synergistically enhance the analgesic effect of mu opioid receptor (MOR) agonists without amplifying the adverse effects. Therefore, the σ1R is considered a promising drug target for pain management. Based on the recently elucidated co-crystal structure of σ1R with 4-IBP, we designed and developed a series of σ1R antagonists harboring the 2,6-diazaspiro[3.4]octan-7-one scaffold. Through a detailed structure-activity relationship study, we identified compound 32 as a potent σ1R antagonist, which significantly enhanced the antinociceptive effect of morphine and rescued morphine-induced analgesic tolerance. Our results support σ1R antagonism as a promising strategy to develop novel analgesics and highlight the therapeutic potential of compound 32 to prevent morphine tolerance.

IgM deposition is a risk factor for delayed remission and early relapse of the pediatric minimal change disease.

Background: Minimal change disease (MCD) is the most common pathological subtype of pediatric idiopathic nephrotic syndrome (INS). It has been suggested that IgM deposition might predict kidney function deterioration in the course of MCD. However, the specific role of IgM deposition in the prognosis of MCD is still controversial. This study aims to investigate the clinical significance of IgM deposition on delayed remission and early relapse in a pediatric population. Methods: This study enrolled 283 children diagnosed with MCD by renal biopsy in a single center from 2010 to 2022. These cases were divided into two groups according to the histopathological deposition of IgM. Patients' demographics, clinical parameters, and follow-up data were collected and analyzed. The primary and secondary outcomes were defined as the time to the first remission and the first relapse. Results: The IgM-positive group had a weaker response to steroids (steroid-sensitive: 23.5% vs. 40.8%; steroid-dependent: 74.0% vs. 51.0%; steroid-resistant: 18.4% vs. 8.2%, P = 0.001), and showed more recurrent cases (47.2% vs. 34.4%, P = 0.047) compared with the IgM-negative group. The Kaplan-Meier analysis showed that the IgM-positive group had a lower cumulative rate of the first remission (Log-rank, P < 0.001) and a higher rate of the first relapse (Log-rank, P = 0.034) than the IgM-negative group. Multivariate Cox analysis showed that IgM deposition was independently associated with the delayed first remission (hazard ratio [HR] = 0.604, 95% confidence interval [CI] = 0.465-0.785, P < 0.001) and the early first relapse (HR = 1.593, 95% CI = 1.033-2.456, P = 0.035). Conclusion: IgM deposition was associated with a weaker steroid response. MCD children with IgM deposition were prone to delayed first remission and early first relapse.

Balanced basal-levels of ROS (redox-biology), and very-low-levels of pro-inflammatory cytokines (cold-inflammaging), as signaling molecules can prevent or slow-down overt-inflammaging, and the aging-associated decline of adaptive-homeostasis.

Both reactive oxygen species (ROS) from redox-biology and pro-inflammatory cytokines from innate immunity/and other sources, in addition to their role in redox-biology, and in defense and repair, have long been regarded as potentially harmful factors associated with oxidative stress and inflammatory states. However, their important physiological functions as signaling molecules have been demonstrated to be of importance, also in Geroscience, particularly when ROS are at balanced basal levels (redox-biology) and pro-inflammatory cytokines are at very low levels (cold-inflammaging). Under these conditions, both of these components (alone or in combination) may act as signaling/response molecules involved in regulating/maintaining or restoring adaptive homeostasis during aging, particularly in the early phases of even very-mild non-damaging internal or external environmental stimuli that could nevertheless elicit low-grade warnings-signals for homeostatic stability. If signals potentially perturbing homeostasis persist, the levels of ROS and pro-inflammatory mediators increase resulting in a switch from adaptive to maladaptive responses which may lead to oxidative stress and overt-inflammaging (or even to an overt inflammatory state), thus paving the way to the risks of aging-related diseases (ARDs). Conversely, upon adaptive-responses, low-levels of ROS and very-low-levels of pro-inflammatory-cytokines, alone or in combination, can result in an amplified capacity to prevent or slow-down overt-inflammaging (2-fold to 4-fold increase of pro-inflammatory cytokines) thus maintaining or restoring homeostasis. Therefore, these signaling molecules may also have the sequential incremental potential to prevent or slow the subsequent decline of adaptive homeostasis that will occur later in the lifespan. These scenarios may lead us to conceive of, and conceptualize, both these molecules and their basal-low levels, as well as their dynamics and the time-course of responses, as 'potential important pillars of adaptive-homeostasis in aging' since the earliest phases of the occurrence of any even very- mild environmental potential imbalance.

SKF83959 Attenuates Memory Impairment and Depressive-like Behavior during the Latent Period of Epilepsy via Allosteric Activation of the Sigma-1 Receptor.

Memory impairment and emotional disorder are two common clinical comorbidities in patients with epilepsy. It is imperative to develop a novel therapeutic agent or a strategy. 6-Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a dopamine-1 receptor agonist and sigma-1 receptor allosteric modulator, which displays the neuron-protective and anti-neuroinflammation activity. We examined the effect of SKF83959 on the memory impairment and emotional disorder in the latent period of epilepsy using the mice post-status epilepticus model. We found that SKF83959 ameliorated memory impairment and depressive-like mood, alleviated the neuron damage and the formation of gliosis in hippocampus, suppressed the rise of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1ß, and induced nitric oxide synthase in the latent period of epilepsy. Additionally, SKF83959 significantly inhibited the activity of calcineurin and glycogen synthase kinase-3ß. All of these protective actions were reversed by BD1047 (a sigma-1 receptor antagonist). In addition, the intra-hippocampus injection of ketoconazole (a dehydroepiandrosterone synthesis inhibitor) also reversed the protective activity of SKF83959. Thus, we concluded that SKF83959 ameliorated the memory impairment and depressive-like mood in epilepsy via allosterically activating the sigma-1 receptor and subsequently inhibiting the calcineurin/glycogen synthase kinase-3ß pathway.

Roughage biodegradation by natural co-cultures of rumen fungi and methanogens from Qinghai yaks.

Anaerobic fungus-methanogen co-cultures from rumen liquids and faeces can degrade lignocellulose efficiently. In this study, 31 fungus-methanogen co-cultures were first obtained from the rumen of yaks grazing in Qinghai Province, China, using the Hungate roll-tube technique. The fungi were identified according to morphological characteristics and internal transcribed spacer (ITS) sequences. The methanogens associated with each fungus were identified by polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and 16S rRNA gene sequencing. They were five co-culture types: Neocallimastix frontalis + Methanobrevibacter ruminantium, Neocallimastix frontalis + Methanobrevibacter gottschalkii, Orpinomyces joyonii + Methanobrevibacter ruminantium, Caecomyces communis + Methanobrevibacter ruminantium, and Caecomyces communis + Methanobrevibacter millerae. Among the 31 co-cultures, during the 5-day incubation, the N. frontalis + M. gottschalkii co-culture YakQH5 degraded 59.0%-68.1% of the dry matter (DM) and 49.5%-59.7% of the neutral detergent fiber (NDF) of wheat straw, corn stalk, rice straw, oat straw and sorghum straw to produce CH4 (3.0-4.6 mmol/g DM) and acetate (7.3-8.6 mmol/g DM) as end-products. Ferulic acid (FA) released at 4.8 mg/g DM on corn stalk and p-coumaric acid (PCA) released at 11.7 mg/g DM on sorghum straw showed the highest values, with the following peak values of enzyme activities: xylanase at 12,910 mU/mL on wheat straw, ferulic acid esterase (FAE) at 10.5 mU/mL on corn stalk, and p-coumaric acid esterase (CAE) at 20.5 mU/mL on sorghum straw. The N. frontalis + M. gottschalkii co-culture YakQH5 from Qinghai yaks represents a new efficient combination for lignocellulose biodegradation, performing better than previously reported fungus-methanogen co-cultures from the digestive tract of ruminants.

Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies.

As the global aging process continues to lengthen, aging-related diseases (e.g., chronic obstructive pulmonary disease (COPD), heart failure) continue to plague the elderly population. Aging is a complex biological process involving multiple tissues and organs and is involved in the development and progression of multiple aging-related diseases. At the same time, some of these aging-related diseases are often accompanied by hypoxia, chronic inflammation, oxidative stress, and the increased secretion of the senescence-associated secretory phenotype (SASP). Hypoxia seems to play an important role in the process of inflammation and aging, but is often neglected in advanced clinical research studies. Therefore, we have attempted to elucidate the role played by different degrees and types of hypoxia in aging and aging-related diseases and their possible pathways, and propose rational treatment options based on such mechanisms for reference.

Two Children With Steroid-Resistant Significant Proteinuria Due to Nonsense Mutations of the TRIM8 Gene: A Case Report and Literature Review.

Background: TRIM8 gene mutations have been reported as the genetic basis of autosomal dominant (AD) neuro-renal syndrome in children, which presents with epileptic encephalopathy, focal segmental glomerulosclerosis (FSGS), developmental delay, and mental retardation. In this study, we report the cases of two children with significant proteinuria due to de novo nonsense mutations of the TRIM8 gene. Case Presentation: Case 1 was a 7-year-old girl who presented with proteinuria and developmental delay, and her renal biopsy showed FSGS. She developed end-stage renal disease (ESRD) 3 years after onset. Case 2 was another 7-year-old girl who developed proteinuria only at age 3, and renal biopsy showed glomerular segmental mesangial proliferative lesions. The two girls underwent genetic testing but we did not find a positive result in the whole exon. However, cluster analysis revealed two new nonsense mutations of the TRIM8 gene (c.1461C>A, p.Tyr 487* and c.1453C>T, p.Gln485*). Conclusions: We reported the clinical manifestation of this neuro-renal syndrome for the first time in China. It is necessary to perform genetic testing in children with steroid-resistant significant proteinuria to identify its etiology and avoid the side effects of immunosuppressants.