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In recent years, mesenchymal stem cells (MSCs)–derived extracellular vesicles (EVs) are emerging as a potential therapeutic agent for pulmonary hypertension (PH). However, the full realization of MSCs-derived EVs therapy has been hampered by the absence of standardization in MSCs culture and the challenges of industrial scale-up. The study was to exploit an alternative replacement for MSCs using currently commercialized stem cell lines for effective targeted PH therapy. ReNcell VM—a human neural stem cell line—has been utilized here as a reliable and easily adoptable source of EVs. We first demonstrated that ReNcell-derived EVs (ReNcell-EVs) pretreatment effectively prevented Su/Hx (SU5416/hypoxia)-induced PH in mice. Then for targeted therapy, we conjugated ReNcell-EVs with CAR (CARSKNKDC) peptide (CAR-EVs)—a peptide identified to specifically target hypertensive pulmonary arteries, by bio-orthogonal chemistry. Intravenous administration of CAR-EVs selectively targeted hypertensive pulmonary artery lesions especially pulmonary artery smooth muscle cells. Moreover, compared with unmodified ReNcell-EVs, CAR-EVs treatment significantly improved therapeutic effect in reversing Su/Hx-induced PH in mice. Mechanistically, ReNcell-EVs inhibited hypoxia-induced proliferation, migration, and phenotype switch of pulmonary artery smooth muscle cells, at least in part, via the delivery of its endogenous highly expressed miRNAs, let-7b-5p, miR-92b-3p, and miR-100-5p. In addition, we also found that ReNcell-EVs inhibited hypoxia-induced cell apoptosis and endothelial-mesenchymal transition in human microvascular endothelial cells. Taken together, our results provide an alternative to MSCs-derived EVs–based PH therapy via using ReNcell as a reliable source of EVs. Particularly, our CAR-conjugated EVs may serve as a novel drug carrier that enhances the specificity and efficiency of drug delivery for effective PH-targeted therapy.

The incidence of breast cancer (BC) is the highest among women. Identification of miRNAs as biomarkers may help to improve the diagnosis of BC. The purpose of this study was to assess the expression levels of miR-1976 in plasma samples and the biological functions in the progression of BC. The expression levels of miR-1976 in plasma samples and tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The associations between the expression levels and clinicopathological features were studied. Cell supernatants were used to simulate circulation. The biological functions of miR-1976 were assessed in vitro and in vivo. The expression levels of miR-1976 in plasma samples were found significantly lower in patients with BC than those in healthy controls, and were associated with Ki-67. The expression levels in BC tissues were lower than those in adjacent normal tissues, and were correlated with the number of lymph nodes and Ki-67. The expression levels in BC cell supernatants and cell lines were lower than that in normal human breast epithelial cell line HBL-100. miR-1976 knockdown promoted proliferation in vitro and in vivo. miR-1976 may serve as a promising non-invasive biomarker for the diagnosis of BC in the future.

Multi-organ fibrosis among end stage renal disease (ESRD) patients cannot be explained by uremia alone. Despite mitigation of thrombosis during hemodialysis (HD), subsequent platelet dysfunction and tissue dysregulation are less understood. We comprehensively profiled plasma and platelets from ESRD patients before and after HD to examine HD-modulation of platelets beyond thrombotic activation. Basal plasma levels of proteolytic regulators and fibrotic factors were elevated in ESRD patients compared to healthy controls, with isoform-specific changes during HD. Platelet lysate (PL) RNA transcripts for growth and coagulative factors were elevated post-HD, with upregulation correlated to HD vintage. Platelet secretome correlations to plasma factors reveal acutely induced pro-fibrotic platelet phenotypes in ESRD patients during HD characterized by preferentially enhanced proteolytic enzyme translation and secretion, platelet contribution to inflammatory response, and increasing platelet dysfunction with blood flow rate (BFR) and Vintage. Compensatory mechanisms of increased platelet growth factor synthesis with acute plasma matrix metalloproteinase (MMP) and tissue inhibitor of MMPs (TIMP) increases show short-term mode-switching between dialysis sessions leading to long-term pro-fibrotic bias. Chronic pro-fibrotic adaptation of platelet synthesis were observed through changes in differential secretory kinetics of heterogenous granule subtypes. We conclude that chronic and acute platelet responses to HD contribute to a pro-fibrotic milieu in ESRD.

Chronic obstructive pulmonary disease (COPD) is a common and heterogeneous respiratory disease, the molecular complexity of which remains poorly understood, as well as the mechanisms by which aging and smoking facilitate COPD development. Here, using single-cell RNA sequencing of more than 65,000 cells from COPD and age-stratified control lung tissues of donors with different smoking histories, we identified monocytes, club cells, and macrophages as the most disease-, aging-, and smoking-relevant cell types, respectively. Notably, we found these highly cell-type specific changes under different conditions converged on cellular dysfunction of the alveolar epithelium. Deeper investigations revealed that the alveolar epithelium damage could be attributed to the abnormally activated monocytes in COPD lungs, which could be amplified via exhaustion of club cell stemness as ages. Moreover, the enhanced intercellular communications in COPD lungs as well as the pro-inflammatory interaction between macrophages and endothelial cells indued by smoking could facilitate signaling between monocyte and the alveolar epithelium. Our findings complement the existing model of COPD pathogenesis by emphasizing the contributions of the previously less appreciated cell types, highlighting their candidacy as potential therapeutic targets for COPD.

Introduction Several Mendelian randomization studies have been conducted that identified multiple risk factors for Alzheimer's disease (AD). However, they typically focus on a few pre‐selected risk factors. Methods A two‐sample Mendelian randomization (MR) study was used to systematically examine the potential causal associations of 1037 risk factors/medical conditions and 31 drugs with the risk of late‐onset AD. To correct for multiple comparisons, the false discovery rate was set at

IntroductionSeveral Mendelian randomization studies have been conducted, which identified multiple risk factors for Alzheimer’s disease (AD). However, they typically focus on a few pre-selected risk factors.MethodsTwo-sample Mendelian randomization (MR) study was used to systematically examine the potential causal associations of 1,054 risk factors/medical conditions and 28 drugs with the risk of late- onset AD. To correct for multiple comparisons, the false discovery rate was set at <0.05.ResultsThere were strong evidence of a causal association between glioma risk, reduced trunk fat-free mass, lower education levels, lower intelligence and a higher risk of AD. For 28 investigated treatments (such as antihypertensive drugs), we found limited evidence for their associations.ConclusionMR found robust evidence of causal associations between glioma, trunk fat-free and AD. Our study also confirms that higher educational attainment and higher intelligence are associated with a reduced risk of AD.

The manufacture of metal electrode window on the ridge structure of laser diodes (LDs) is a confused issue in the LDs fabrication process. We show that the processing of the self-aligned step and negative photosensitive polyimide (NPP) thermal imidization which can achieve both accurate alignment of p-electrode window on the ridge structure and integrated dielectric layer at once time. This back word exposure technic can effectively simplify the process of accuracy of alignment and avoid etching of isolating layer. The optical and electrical performance of the LD chip measured at room temperature under a pulse current condition (the current duty ratio was 25%) were shown. The output optical power was greater than 20 mW, at 7.7 V operating voltage, and the reversed current is 3.9 × 10−5 mA when the bias voltage is −5 V. A lasing peak wavelength at around 442 nm became dominant at 320 mA. Our results provide an alternative effective approach to fabricate the well behavior LDs.

The experiment was conducted to evaluate the safety of selenium protein powder, a novel organic selenium nutritional supplement, and reported corresponding data and results based on a series of toxicological tests. It was examined to evaluate oral acute toxicity by median lethal dose test and mutagenic potential by bone marrow cell micronucleus test and sperm abnormality test using Kun-Ming mice. The results showed that the oral LD 50 of selenium protein powder exceeded 31.25 g/kg body weight in mice. No mutagenicity was found by mouse bone marrow cell micronucleus test and mouse sperm abnormality test. The results suggested greater safety of selenium protein powder as a nutritional selenium supplement, and selenium protein powder has the potential for development and application in food systems or functional foods.