Women's autonomy in fertility decision-making is essential for improved health and social outcomes. Guided by the social-ecological model, this investigation explores multilevel influences on the fertility autonomy of women with an unmet need for family planning in rural Uganda. We conducted four focus groups with men and women (n?=?26), and 15 key informant interviews with community leaders and individuals involved in the provision of family planning. The data were analyzed thematically. The results highlight how community-level norms reinforce gender inequalities in decision-making and underpin beliefs to not limit men's number of children. Religious norms and polygamy practices were shown to influence attitudes towards family size and family planning, as well as shape relationship dynamics related to fertility. Concerns about poverty were identified as a driver of shifting preferences and increasing acceptance of family planning. Results showcase how health system weaknesses limit women's access to family planning services, contribute to mistrust of health systems and drive misinformation about contraceptives, especially among men. This study underscores the need for multifaceted gender transformative interventions to increase women's fertility autonomy. This study also highlights health system strengthening, religious leader endorsement and male engagement as approaches to increase women's autonomous use of family planning.

Objective: To explore the synergistic effect of nano-pearl powder (NPP) and adipose-derived stem cell exosomes (ADSC-Exos) on the osteogenic potential of MC3T3-E1 cells.

Methods: The water-soluble matrix of NPP (NPP-WSM) was extracted via freeze-drying, and ADSC-Exos were isolated by ultracentrifugation. NPP-WSM was incorporated into ADSC-Exos through co-incubation to generate NPP-WSM-Exos. MC3T3-E1 cells were treated with NPP-WSM or NPP-WSM-Exos. Cell proliferation and migration were evaluated using CCK-8 and wound-healing assays, respectively. Osteogenic differentiation was assessed by Alizarin Red S staining and alkaline phosphatase (ALP) activity. The expression of osteogenesis-related genes (COL1A1, RUNX2, OCN, and OPN) was measured by qPCR and Western blotting. Transcriptome sequencing (RNA-seq) was conducted to identify signaling pathways activated by NPP-WSM-Exos.

Results: NPP-WSM-Exos displayed distinct exosome morphology and biomarkers, confirming their successful preparation. Significantly, NPP-WSM-Exos enhanced the viability of MC3T3-E1 cells compared to NPP-WSM alone and upregulated the expression of osteogenic genes, including COL1A1, RUNX2, OCN, and OPN, at both the transcriptional and translational levels. Additionally, NPP-WSM-Exos strongly promoted mineralization, as evidenced by the increased calcification observed through Alizarin Red S staining, and elevated alkaline phosphatase (ALP) activity, indicating excellent potential for osteogenic differentiation. Transcriptome sequencing showed that NPP-WSM-Exos significantly enhanced the PI3K/AKT pathway in MC3T3-E1 cells, while protein level detection indicated that NPP-WSM-Exos could increase AKT phosphorylation levels and inhibit GSK3β activity to improve osteogenic efficiency.

Conclusion: The use of adipose-derived stem cell exosomes to encapsulate NPP-WSM can increase the utilization of WSM, promote the proliferation of MC3T3-E1, and enhance the osteogenic differentiation ability.

Regular exercise training can significantly improve the gut environment and influence the metabolic activity of the gut microbiota. These changes promote the production of beneficial metabolites, which may modulate blood pressure regulation through multiple mechanisms. The beneficial microbial species including Faecalibacterium prausnitzii, Bifidobacterium spp., Lactobacillus spp., Roseburia spp.,and Bacteroides spp. These beneficial microbes produce various metabolites during metabolism, including short-chain fatty acids, vitamins, lactic acid, bileacids, and gamma-aminobutyric acid. These metabolites are not only essential for maintaining gut health but also positively influence hypertension by modulating the nervous system, immune system, and improving metabolic function. This review aims to elucidate the complex interactions among exercise training, gut microbiota, and hypertension.

Background: Phenylcapsaicin (PC) may enhance high-intensity exercise performance by reducing perceived exertion, increasing mechanical output, and limiting muscle damage, making it potentially beneficial for CrossFit^? (CF) athletes.

Objective: To examine the acute effects of PC supplementation on performance, recovery, and metabolic responses during a CF session.

Methods: This study had a randomized, triple-blind, placebo-controlled crossover design. Fifty CF-trained athletes (50% women) ingested either 2.5?mg of PC or a placebo (PLA) 45 minutes before a standardized CF session, including a warm-up, weightlifting block, and WOD. Delayed-onset muscle soreness (DOMS) was assessed 24- and 48-hours post-session. Countermovement jump (CMJ) was evaluated pre- and post-session, while a deep squat at 70% 1RM was performed post-session. Throughout the session, heart rate, capillary lactate, rating of perceived exertion (RPE), and perceived recovery status (PRS) were monitored.

Results: Compared to PLA, PC improved squat performance at 70% 1RM in both load and repetitions (P?≤?0.035), attenuated the decline in CMJ (P?P interaction?=?0.011), with significantly higher load in round 9 (P?=?0.030). No differences were observed during the WOD (P interaction?≥?0.826). DOMS was significantly lower in the PC group at both 24?h and 48?h (P?=?0.030), while no group differences were found for lactate, RPE, PRS, or heart rate (P interaction?≥?0.340). Analysis stratified by sex showed that PC reduced CMJ loss in men (P?=?0.043) and increased squat load in women (P?=?0.021).

Conclusion: In conclusion, acute PC supplementation enhances performance and recovery in CF athletes.

Objective: To introduce bilateral hypertensive retinopathy (HR) (grade 4) complicated with macular edema (ME) patients with binocular intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) treatment.

Methods: Three cases of hypertensive retinopathy were observed. The fundus examination was consistent with HR (grade 4). The patients received anti-VEGF intraocular injection.

Results: The patient's ME and optic nerve edema were significantly reduced, visual acuity was significantly improved, and a case of secondary choroidal neovascularization (CNV) in the fundus of HR (grade 4) was also noted.

Conclusions: The use of intravitreal anti-VEGF agents in stage IV hypertensive retinopathy appears satisfactory but not perfect. In severe cases with vitreous hemorrhage, early injection avoids vitrectomy.

Endogenous or adoptively transferred tumor-infiltrating lymphocytes (TILs) often lose their functional capacity due to the activation of intrinsic inhibitory pathways, which then limits their ability to control tumor growth. In this study, we examined the effects of blocking a key intracellular inhibitory enzyme, diacylglycerol kinase (DGK) in human T cells, using a novel inhibitor (DGKi) called INCB165451 that blocks both DGKα and DGKζ, the two primary DGK isoenzymes that negatively regulate T cells through the diacylglycerol (DAG) signaling pathway. We first evaluated the effects of the DGKi in enhancing the efficacy of adoptive human T cell transfer in a non-small cell lung cancer (NSCLC) mouse model and found that the DGKi significantly potentiated anti-tumor efficacy through multiple mechanisms, including increased intratumoral T cell infiltration, upregulation of genes associated with inflammatory responses, and reduction of TIL hypofunction, as evidenced by enhanced cytokine production following ex vivo anti-CD3 antibody stimulation. We next studied the effects of the DGKi on human TILs derived from tumor digests or studied in situ in precision-cut tumor slices of both head and neck cancer and NSCLC patient samples. After stimulation of the TILs with anti-CD3 antibodies, we found that the DGKi enhanced gene and protein expression of proinflammatory cytokines and chemokines. Finally, we demonstrated that the DGKi could augment T cell activation in human tumor slices that were stimulated by an anti-EGFR/anti-CD3 bispecific T cell engager (BiTE). These data demonstrate strong activity of the DGKi in human TILs and highlight promising potential avenues for clinical translation.

Objective: Mitochondria are central to energy production and cellular homeostasis. Beyond importing diverse RNAs, they also encode hundreds of their own non-coding RNAs, contributing to a complex and dynamic RNA landscape. Early-life nutritional insults, such as fetal and postnatal protein deficiency, can impair mitochondrial function and increase the long-term diabetes risk. However, the mitochondrial non-coding transcriptome of pancreatic islets, particularly its responsiveness to nutritional cues, remains largely unexplored.

Methods: We performed RNA sequencing to profile small non-coding RNAs in mitochondrial fractions of islet cells from offspring of rats exposed to low-protein (LP) or control diets during gestation and lactation and employed mRNA-miRNA network analysis to explore the potential regulatory roles of differentially expressed mitomiRs in LP-exposed pups.

Results: Protein deficiency during gestation and lactation led to a profound remodeling of the small non-coding RNA landscape in whole islets, with microRNAs and piRNAs showing the most pronounced changes. In mitochondrial fractions, LP exposure resulted in a striking shift in microRNA composition, with 33 mitomiRs detected in control islets versus 23 in LP-exposed rats, and only 5 shared between groups. Notably, ten mitomiRs were selectively depleted from the cytosol and enriched in mitochondria of LP-exposed islets. Amongst these, miR-10a-5p and miR-126a-5p, are predicted to target genes involved in mitochondrial metabolism and structural organization.

Conclusion: Early-life protein restriction triggers a highly selective reorganization of the mitomiR landscape in pancreatic islets. The identified mitomiRs may serve as regulators of mitochondrial function and intracellular signaling, potentially influencing β-cell metabolic coupling and contributing to diabetes susceptibility.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally with high mortality rates, highlighting the urgent need for novel therapeutic strategies. We investigated the efficacy of combining phosphoinositide 3-kinase gamma (PI3Kγ) inhibition with programmed death-ligand 1 (PD-L1) blockade in a poorly immunogenic HNSCC model.

Materials and methods: Mouse bone marrow-derived macrophages (BMDMs) were differentiated and polarized in the presence or absence of the PI3Kγ inhibitor IPI-549 or culture supernatants from MOC2 cells treated with or without IPI-549. MOC2 cells were orthotopically injected into C57BL/6 mice, and treated with anti-PD-L1, IPI-549, combined anti-PD-L1 and IPI-549 or vehicle control. Tumor burden, survival, and immunological responses were evaluated.

Results and conclusion: Dual inhibition of PI3Kγ (using IPI-549) and PD-L1 demonstrated nearly significant reduction in primary tumor burden and significantly increased survival compared to single or control treatments. PI3Kγ inhibition promoted macrophage differentiation toward an antitumoral M1 phenotype. In the bone marrow, dual therapy significantly increased MHC-II expression across various myeloid cell subsets and effectively normalized myelopoiesis. Notably, combination therapy increased CD8+?T-cell infiltration into tumors while decreasing T-cell exhaustion marker (LAG-3, CTLA-4, and TIM-3) and protumoral cytokine (IL-4). Combined PI3Kγ and PD-L1 inhibition offers a promising strategy for treating poorly immunogenic HNSCC by simultaneously targeting multiple immunosuppressive mechanisms. These findings provide a strong rationale for combining PI3Kγ and PD-L1 inhibitors as a therapeutic strategy for poorly immunogenic HNSCC, potentially improving clinical outcomes for patients.