A homozygous missense variant in YTHDC2 induces azoospermia in two siblings.

Male infertility is a complex multifactorial reproductive disorder with highly heterogeneous phenotypic presentations. Azoospermia is a medically non-manageable cause of male infertility affecting ∼1% of men. Precise etiology of azoospermia is not known in approximately three-fourth of the cases. To explore the genetic basis of azoospermia, we performed whole exome sequencing in two non-obstructive azoospermia affected siblings from a consanguineous Pakistani family. Bioinformatic filtering and segregation analysis of whole exome sequencing data resulted in the identification of a rare homozygous missense variant (c.962G>C, p. Arg321Thr) in YTHDC2, segregating with disease in the family. Structural analysis of the missense variant identified in our study and two previously reported functionally characterized missense changes (p. Glu332Gln and p. His327Arg) in mice showed that all these three variants may affect Mg2+ binding ability and helicase activity of YTHDC2. Collectively, our genetic analyses and experimental observations revealed that missense variant of YTHDC2 can induce azoospermia in humans. These findings indicate the important role of YTHDC2 deficiency for azoospermia and will provide important guidance for genetic counseling of male infertility.

Combining Network Pharmacology and Transcriptomics to Investigate the Mechanisms of Yujiang Paidu Decoction in the Treatment of Chronic Rhinosinusitis with Nasal Polyps.

Background: Yujiang Paidu Decoction (YJPD) has demonstrated clinical efficacy in the treatment of chronic rhinosinusitis. However, the effects and mechanisms of the YJPD on chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear. Purpose: This study aimed to elucidate the potential mechanism of action of YJPD in the treatment of CRSwNP based on network pharmacology, transcriptomics and experiments. Methods: A CRSwNP mouse model was established using ovalbumin (OVA) and staphylococcus aureus enterotoxin B (SEB) for 12 weeks and the human nasal epithelial cell (HNEpC) model was induced with IL-13 in vitro. Behavioral tests, scanning electron microscopy (SEM), micro-CT and pathological change of nasal tissues were observed to investigate the therapeutic effects of YJPD. Network pharmacology and transcriptomics were launched to explore the pharmacological mechanisms of YJPD in CRSwNP treatment. Finally, an ELISA, immunofluorescence, RT-qPCR, Western blotting and Tunel were performed for validation. Results: Different doses of YJPD intervention effectively alleviated rubbing and sneezing symptoms in CRSwNP mice. Additionally, YJPD significantly reduced abnormal serological markers, structural damage of the nasal mucosa, inflammatory cell infiltration, goblet cell increases, and inhibited OVA-specific IgE levels and the secretion of Th2 cytokines such as IL-4, IL-5, and IL-13. Moreover, transcriptomics and network pharmacology analyses indicated that YJPD may exert anti-inflammatory and anti-apoptotic effects by inhibiting the MAPK/AP-1 signaling pathway. The experimental findings supported this conclusion, which was further corroborated by similar results observed in IL13-induced HNEpCs in vitro. Conclusion: YJPD could alleviate inflammatory status and epithelial apoptosis by inhibiting aberrant activation of MAPK/AP-1 signaling pathway. This finding provides a strong basis for using YJPD as a potential treatment in CRSwNP.

Encoding and display technologies for combinatorial libraries in drug discovery: The coming of age from biology to therapy.

Drug discovery is a sophisticated process that incorporates scientific innovations and cutting-edge technologies. Compared to traditional bioactivity-based screening methods, encoding and display technologies for combinatorial libraries have recently advanced from proof-of-principle experiments to promising tools for pharmaceutical hit discovery due to their high screening efficiency, throughput, and resource minimization. This review systematically summarizes the development history, typology, and prospective applications of encoding and displayed technologies, including phage display, ribosomal display, mRNA display, yeast cell display, one-bead one-compound, DNA-encoded, peptide nucleic acid-encoded, and new peptide-encoded technologies, and examples of preclinical and clinical translation. We discuss the progress of novel targeted therapeutic agents, covering a spectrum from small-molecule inhibitors and nonpeptidic macrocycles to linear, monocyclic, and bicyclic peptides, in addition to antibodies. We also address the pending challenges and future prospects of drug discovery, including the size of screening libraries, advantages and disadvantages of the technology, clinical translational potential, and market space. This review is intended to establish a comprehensive high-throughput drug discovery strategy for scientific researchers and clinical drug developers.

Plasmonic Radiation from Spin-Momentum Locking.

Chiral light emission plays a key role in sensing, tomography, quantum communication, among others. Whereas, achieving highly pure, tunable chirality emission across a broad spectrum currently presents significant challenges. Free-electron radiation emerges as a promising solution to surpass these barriers, especially in hard-to-reach regimes. Here, chiral free-electron radiation is presented by exploiting the spin-momentum locking (SML) property of spoof surface plasmons (SSPs). When the phase velocity of free electrons matches that of the SSPs, the SSPs can be excited. By implementing wavenumber compensation through perturbations, the confined SSPs are transformed into free-space free-electron radiation. Owing to the law of angular momentum conservation, this process converts the transverse spin angular momentum of SSPs into the longitudinal spin angular momentum of free-electron radiation during the process, producing pure, tunable, and chiral free-electron radiation across a broad spectrum. This method achieves an optimal degree of circular polarization approaching -1. The innovative methodology can be adapted to SML-enabled guided states or silicon photonics platforms, offering new avenues for achieving chiral emission.

Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.

BACKGROUND: The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. METHODS: To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids. RESULTS: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models. CONCLUSIONS: The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.

Machine learning-assisted optimization of food-grade spirulina cultivation in seawater-based media: From laboratory to large-scale production.

The shortage of food and freshwater sources threatens human health and environmental sustainability. Spirulina grown in seawater-based media as a healthy food is promising and environmentally friendly. This study used three machine learning techniques to identify important cultivation parameters and their hidden interrelationships and optimize the biomass yield of Spirulina grown in seawater-based media. Through optimization of hyperparameters and features, eXtreme Gradient Boosting, along with the recursive feature elimination (RFE) model demonstrated optimal performance and identified 28 important features. Among them, illumination intensity and initial pH value were critical determinants of biomass, which impacted other features. Specifically, high initial pH values (>9.0) mainly increased biomass but also increased nutrient sedimentation and ammonia (NH3) losses. Both batch and continuous additions could decrease nutrient losses by increasing their availability in the seawater-based media. When illumination intensity exceeded 200 µmol photons/m2/s, it amplified the growth of Spirulina by mitigating the light attenuation caused by a high initial inoculum level and counteracted the negative effect of low temperature (<25 °C). In large-scale cultivation, production efficiency would be reduced if illumination was not maintained at a high level. High salinity and sodium bicarbonate (NaHCO3) addition promoted carbohydrate accumulation, but suitable dilution could keep the required protein content in Spirulina with relatively low media and production costs. These findings reveal the interactive influence of cultivation parameters on biomass yield and help us determine the optimal cultivation conditions for large-scale cultivation of Spirulina-based seawater system based on a developed graphical user interface website.

Altimella gen. nov., a new genus of Cicurinidae (Arachnida, Araneae) from Xizang, China, with description of two new species.

Altimella Wang & Zhang, gen. nov., a new genus belonging to Cicurinidae, is established, and two new species are described, Altimellanedong Wang & Zhang, sp. nov. (♂♀, type species) and A.ngamring Wang & Zhang, sp. nov. (♂♀), from Xizang, China. Detailed descriptions of somatic features and genital characteristics, photos of the habitus, photos and drawings of the copulatory organs, and a distribution map are provided.

CB1 Promotes Osteogenic Differentiation Potential of Periodontal Ligament Stem Cells by Enhancing Mitochondrial Transfer of Bone Marrow Mesenchymal Stem Cells.

OBJECTIVE: To reveal the role and mechanism of cannabinoid receptor 1 (CB1) and mitochondria in promoting osteogenic differentiation of periodontal ligament stem cells (PDLSCs) in the inflammatory microenvironment. METHODS: Bidirectional mitochondrial transfer was performed in bone mesenchymal stem cells (BMSCs) and PDLSCs. Laser confocal microscopy and quantitative flow cytometry were used to observe the mitochondrial transfer and quantitative mitochondrial transfer efficiency. Realtime reverse transcription polymerase chain reaction (RT-PCR) was employed to detect gene expression. Alkaline phosphatase (ALP) activity, alizarin red staining (ARS) and quantitative calcium ion analysis were used to evaluate the degree of osteogenic differentiation of PDLSCs. RESULTS: Bidirectional mitochondrial transfer was observed between BMSCs and PDLSCs. The indirect co-culture system could simulate intercellular mitochondrial transfer. Compared with the conditioned medium (CM) for BMSCs, that for HA-CB1 BMSCs could significantly enhance the mineralisation ability of PDLSCs. The mineralisation ability of PDLSCs could not be enhanced after removing the mitochondria in CM for HA-CB1 BMSCs. The expression level of HO-1, PGC-1α, NRF-1, ND1 and HK2 was significantly increased in HA-CB1 BMSCs. CONCLUSION: CM for HA-CB1 BMSCs could significantly enhance the damaged osteogenic differentiation ability of PDLSCs in the inflammatory microenvironment, and the mitochondria of CM played an important role. CB1 was related to the activation of the HO-1/PGC-1α/NRF-1 mitochondrial biogenesis pathway, and significantly increased the mitochondrial content in BMSCs.

Association between patient and system delays and in-hospital mortality in primary PCI for STEMI: Findings from a large, nationwide inpatients sample.

PURPOSE: System delay is associated with mortality in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). However, the influence of patient delay has been relatively overlooked. We aimed to evaluate the influence of patient and system delays on STEMI patients undergoing primary PCI in China. METHODS: STEMI patients registered at the Nationwide Chinese Cardiovascular Association Database-Chest Pain Center from January 2017 to September 2021 were screened. The exposures were total ischemic time (TIT), system delay and patient delay. The primary outcome was in-hospital mortality. RESULTS: Among 458,260 patients from 2,529 centers, median TIT, system delay and patient delay were 4.1, 1.5 and 2.1 hours, respectively. The adjusted odds ratio of in-hospital mortality increased by 2.2% (odds ratio [OR], 1.022, 95% confidence interval [CI], 1.017-1.027), 2.3% (1.023, 1.006-1.040) and 2.2% (1.022, 1.017-1.027) for every one-hour increase in TIT, system delay and patient delay, respectively. CONCLUSIONS: Patient delay demonstrated a comparable impact to system delay on in-hospital mortality among STEMI patients undergoing primary PCI. Widespread primary PCI-capable center, improved awareness about myocardial infarction and regional transfer system are essential to shorten patient delay.

Blocking the PD-1 signal transduction by occupying the phosphorylated ITSM recognition site of SHP-2.

Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy. Here, we identify a natural pentacyclic triterpenoid, Pygenic Acid A (PA), as a PD-1 signaling inhibitor. PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction. Furthermore, we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction. Subsequently, mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2, inhibiting the recruitment of SHP-2 by PD-1. Taken together, our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors. In addition, our success in target recognition provides a paradigm of target identification and confirmation for natural products.

SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer.

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

The relationship between air pollution and the occurrence of hypertensive disorders of pregnancy: Evidence from a study in Wuhan, China.

Ambient air pollution has been reported to be a risk factor for hypertensive disorders of pregnancy (HDP). Past studies have reported supportive evidence, but evidence from China is scarce and does not integrate the different periods of the pregnancy course. In this study, 1945 pregnant women with HDP and healthy pregnancies between 2016 and 2022 from the Renmin Hospital of Wuhan University registry network database were analysed. The geographic information, biological information and demographic information of the case were fused in the analysis. Machine learning methods were used to obtain the weight of the variable. Then, we used the generalized linear mixed model to evaluate the relationship between increased exposure to each pollutant at different periods of HDP and examined it in different groups. The results showed that SO2 had the predominate impact (12.65 %) on HDP compared with other air pollutants. SO2 exposure was associated with an increased risk of HDP. Increased unit SO2 concentrations were accompanied by an increased risk of HDP (OR = 1.33, 95 % CI: 1.13, 1.566), and the susceptible window for this effect was mainly in the first trimester (OR = 1.242, 95 % CI: 1.092, 1.412). In addition, SO2 exposure was associated with an increased risk of HDP in urban maternity (OR = 1.356, 95 % CI: 1.112, 1.653), obese maternity (OR = 3.58, 95 % CI: 1.608, 7.971), no higher education maternity (OR = 1.348, 95 % CI: 1.065, 1.706), nonzero delivery maternity (OR = 1.981, 95 % CI: 1.439, 2.725), maternal with first time maternity (OR = 1.247, 95 % CI: 1.007, 1.544) and other groups. In summary, SO2 exposure in early pregnancy is one of the risk factors for HDP, and the increased risk of HDP due to increased SO2 exposure may be more pronounced in obese, urban, low-education, and nonzero delivery populations.

Integrative microbiome and metabolome profiles reveal the impacts of periodontitis via oral-gut axis in first-trimester pregnant women.

BACKGROUND: Periodontitis results from host-microbe dysbiosis and the resultant dysregulated immunoinflammatory response. Importantly, it closely links to numerous systemic comorbidities, and perplexingly contributes to adverse pregnancy outcomes (APOs). Currently, there are limited studies on the distal consequences of periodontitis via oral-gut axis in pregnant women. This study investigated the integrative microbiome-metabolome profiles through multi-omics approaches in first-trimester pregnant women and explored the translational potentials. METHODS: We collected samples of subgingival plaques, saliva, sera and stool from 54 Chinese pregnant women at the first trimester, including 31 maternal periodontitis (Perio) subjects and 23 Non-Perio controls. By integrating 16S rRNA sequencing, untargeted metabolomics and clinical traits, we explored the oral-gut microbial and metabolic connection resulting from periodontitis among early pregnant women. RESULTS: We demonstrated a novel bacterial distinguisher Coprococcus from feces of periodontitis subjects in association with subgingival periodontopathogens, being different from other fecal genera in Lachnospiraceae family. The ratio of fecal Coprococcus to Lachnoclostridium could discriminate between Perio and Non-Perio groups as the ratio of subgingival Porphyromonas to Rothia did. Furthermore, there were differentially abundant fecal metabolic features pivotally enriched in periodontitis subjects like L-urobilin and kynurenic acid. We revealed a periodontitis-oriented integrative network cluster, which was centered with fecal Coprococcus and L-urobilin as well as serum triglyceride. CONCLUSIONS: The current findings about the notable influence of periodontitis on fecal microbiota and metabolites in first-trimester pregnant women via oral-gut axis signify the importance and translational implications of preconceptional oral/periodontal healthcare for enhancing maternal wellbeing.

The value of phenylalanine in predicting atrial fibrillation risk in chronic heart failure.

Backgrounds: Atrial fibrillation (AF) is a common complication of chronic heart failure (HF). Serum phenylalanine (Phe) levels are related to inflammation disorder. It is meaningful to study the circulating Phe with AF occurrence in HF. Methods: The cross-sectional study recruited 300 patients (78.0% male; mean age, 65 ± 13 years) with HF (left ventricular ejection fraction of ≤50%, containing 70 AF patients) and 100 normal controls. Serum Phe value was measured by liquid chromatography-tandem mass spectrometry. Logistic regression analysis was conducted to measure the association between Phe and AF risk in HF. The association between Phe and high-sensitivity C-reactive protein (hsCRP) was assessed by simple correlation analysis. In the prospective study, the 274 HF subjects (76.6% male; mean age, 65 ± 13 years) were followed up for a mean year (10.99 ± 3.00 months). Results: Serum Phe levels increased across the control, the HF without AF, and the HF with AF groups (77.60 ± 8.67 umol/L vs. 95.24 ± 28.58 umol/L vs. 102.90 ± 30.43 umol/L, ANOVA P < 0.001). Serum Phe value was the independent risk factor for predicting AF in HF [odds ratio (OR), 1.640; 95% CI: 1.150-2.339; P = 0.006]. Phe levels were correlated positively with hsCRP value in HF patients with AF (r = 0.577, P < 0.001). The elevated Phe levels were associated with a higher risk of HF endpoint events in HF patients with AF (log-rank P = 0.005). Conclusions: In HF with AF subjects, elevated Phe value confers an increased risk for prediction AF and was more related to poor HF endpoint events. Phe can be a valuable index of AF in HF.

Metal-Free Perovskite Ferroelectrics with the Most Equivalent Polarization Axes.

Ferroelectricity in metal-free perovskites (MFPs) has emerged as an academic hotspot for their lightweight, eco-friendly processability, flexibility, and degradability, with considerable progress including large spontaneous polarization, high Curie temperature, large piezoelectric response, and tailoring coercive field. However, their equivalent polarization axes as a key indicator are far from enough, although multiaxial ferroelectrics are highly preferred for performance output and application flexibility that profit from as many equivalent polarization directions as possible with easier reorientation. Here, by implementing the synergistic overlap of regulating anionic geometries (from spherical I- to octahedral [PF6]- and to tetrahedral [ClO4]- or [BF4]-) and cationic asymmetric modification, we successfully designed multiaxial MFP ferroelectrics CMDABCO-NH4-X3 (CMDABCO = N-chloromethyl-N'-diazabicyclo[2.2.2]octonium; X = [ClO4]- or [BF4]-) with the lowest P1 symmetry. More impressively, systemic characterizations indicate that they possess 24 equivalent polarization axes (Aizu notations of 432F1 and m3̅mF1, respectively)─the maximum number achievable for ferroelectrics. Benefiting from the multiaxial feature, CMDABCO-NH4-[ClO4]3 has been demonstrated to have excellent piezoelectric sensing performance in its polycrystalline sample and prepared composite device. Our study provides a feasible strategy for designing multiaxial MFP ferroelectrics and highlights their great promise for use in microelectromechanical, sensing, and body-compatible devices.

Biomechanical behavior of temporomandibular joint movements driven by mastication muscles.

Surgery of jawbones has a high potential risk of causing complications associated with temporomandibular joint disorder (TMD). The objective of this study was to investigate the effects of two drive modeling methods on the biomechanical behavior of the temporomandibular joint (TMJ) including articular disc during mandibular movements. A finite element (FE) model from a healthy human computed tomography was used to evaluate TMJ dynamic using two methods, namely, a conventional spatial-oriented method (displacement-driven) and a compliant muscle-initiated method (masticatory muscle-driven). The same virtual FE model was 3D printed and a custom designed experimental platform was established to validate the accuracy of experimental and theoretical results of the TMJ biomechanics during mandibular movements. The results show that stress distributed to TMJ and articular disc from mandibular movements provided better representation from the muscle-driving approach than those of the displacement-driven modeling. The simulation and experimental data exhibited significant strong correlations during opening, protrusion, and laterotrusion (with canonical correlation coefficients of 0.994, 0.993, and 0.932, respectively). The use of muscle-driven modeling holds promise for more accurate forecasting of stress analysis of TMJ and articular disc during mandibular movements. The compliant approach to analyze TMJ dynamics would potentially contribute to clinic diagnosis and prediction of TMD resulting from occlusal disease and jawbone surgery such as orthognathic surgery or tumor resection.

Mesenchymal stem cell-derived exosomal microRNA-367-3p mitigates lower limb ischemia/reperfusion injury in mouse skeletal muscle via EZH2 targeting.

OBJECTIVE: This study aimed to investigate the protective effect of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-exo) against lower limb ischemia/reperfusion (I/R) injury-induced pyroptosis in skeletal muscle. METHODS: A mouse model of lower limb I/R injury was utilized to assess the impact of BMSCs-exo, particularly when loaded with microRNA-367-3p (miR-367-3p), on pyroptosis. Histological examination, wet weight/dry weight ratio measurements, and luciferase assays were employed to elucidate the mechanisms involved. KEY FINDINGS: BMSCs-exo effectively suppressed pyroptosis in injured skeletal muscle tissue. Loading BMSCs-exo with miR-367-3p enhanced this protective effect by downregulating key pyroptosis-related proteins. Luciferase assays identified enhancer of zeste homolog 2 (EZH2) as a direct target of miR-367-3p in BMSCs-exo. CONCLUSIONS: BMSCs-exo loaded with miR-367-3p safeguarded mouse skeletal muscle against pyroptosis-induced I/R injury by targeting EZH2. These findings offer valuable insights into potential therapeutic strategies for lower limb I/R injuries, emphasizing the therapeutic potential of BMSCs-exo in mitigating tissue damage caused by pyroptosis.

Relationship between maternal postpartum depression, fatigue, sleep quality and infant growth: A cross-sectional study.

BACKGROUND: Current research separately analyzed the connection between postpartum depression, fatigue, sleep and infant development. However, depression, fatigue and sleep quality often coexisted as adverse symptoms in postpartum women and influenced infant development together. This study explored the maternal postpartum symptoms on infant growth. METHODS: Our study included 224 pairs of singleton full-term mothers and their infants who underwent routine pediatric outpatient clinics. Latent profile analysis was applied to identify the latent classes based on mothers' postpartum depression, fatigue and sleep profile characteristics. We evaluated the maternal adverse symptoms and infant development using multivariable logistic regressions. RESULTS: Totally, 224 pairs of eligible mothers (28.85 ± 4.43 years) and infants (30.93 ± 3.26 days) participated in this study. Latent profile analysis identified 3 latent groups: mild (58.04%), moderate (34.37%), and severe (7.59%) postpartum adverse symptoms. Postpartum adverse symptoms were associated with delayed development in the baby's motor level (χ2 = 6.572, p = .037) and weight-for-length (χ2 = 9.652, p = .008). After controlling for mother and infant related factors, postpartum adverse symptoms remained a risk factor for infant motor level (odds ratio [OR]: 4.35; 95% confidence interval [CI]: 1.25-15.08) and weight-for-length (OR: 5.53; 95% CI: 1.55-19.74). CONCLUSIONS: Maternal postpartum depression, fatigue and sleep quality are associated with infant development. Clinically, mothers with these symptoms should be intervened timely to avoid the aggravation of maternal symptoms, which affect baby's development.

Leech Poecilobdella manillensis protein extract ameliorated hyperuricemia by restoring gut microbiota dysregulation and affecting serum metabolites.

BACKGROUND: Hyperuricemia (HUA) is a public health concern that needs to be solved urgently. The lyophilized powder of Poecilobdella manillensis has been shown to significantly alleviate HUA; however, its underlying metabolic regulation remains unclear. AIM: To explore the underlying mechanisms of Poecilobdella manillensis in HUA based on modulation of the gut microbiota and host metabolism. METHODS: A mouse model of rapid HUA was established using a high-purine diet and potassium oxonate injections. The mice received oral drugs or saline. Additionally, 16S rRNA sequencing and ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry-based untargeted metabolomics were performed to identify changes in the microbiome and host metabolome, respectively. The levels of uric acid transporters and epithelial tight junction proteins in the renal and intestinal tissues were analyzed using an enzyme-linked immunosorbent assay. RESULTS: The protein extract of Poecilobdella manillensis lyophilized powder (49 mg/kg) showed an enhanced anti-trioxypurine ability than that of allopurinol (5 mg/kg) (P < 0.05). A total of nine bacterial genera were identified to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which included the genera of Prevotella, Delftia, Dialister, Akkermansia, Lactococcus, Escherichia_Shigella, Enterococcus, and Bacteroides. Furthermore, 22 metabolites in the serum were found to be closely related to the anti-trioxypurine activity of Poecilobdella manillensis powder, which correlated to the Kyoto Encyclopedia of Genes and Genomes pathways of cysteine and methionine metabolism, sphingolipid metabolism, galactose metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. Correlation analysis found that changes in the gut microbiota were significantly related to these metabolites. CONCLUSION: The proteins in Poecilobdella manillensis powder were effective for HUA. Mechanistically, they are associated with improvements in gut microbiota dysbiosis and the regulation of sphingolipid and galactose metabolism.