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Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.

Molecular biology: in the midst of things Most miRNA target sequences that have been studied reside in the 3′ UTR, the part of the messenger RNA that is downstream of the coding region. In this work Rigoutsos and colleagues demonstrate that the coding regions of several genes encoding transcription factors involved in the maintenance of stem cell identity, such as Nanog , Oct4 , and Sox2 , have miRNA target sites. Three miRNAs that are upregulated when embryonic stem cells are induced to differentiate bind these sites in various combinations, and thereby confer specific phenotypes. The coding regions of several genes that encode transcription factors involved in maintenance of stem cell identity, such as Nanog , Oct4 , and Sox2 , have miRNA target sites. Three miRNAs that are upregulated when embryonic stem cells are induced to differentiate bind these sites in various combinations, and thereby confer specific phenotypes. MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner 1 , 2 , 3 , 4 , 5 , 6 , 7 . For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3′ untranslated regions of mRNAs 1 , fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog , Oct4 (also known as Pou5f1 ) and Sox2 genes 8 , 9 , 10 , 11 and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon–exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3′ untranslated region.

Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6 −/− ) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6 −/− -BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6 −/− -BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6 −/− -BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.

Hypothyroidism, a prevalent endocrine disorder, carries significant implications for maternal and infant health, especially in the context of maternal hypothyroidism. Despite a gradual surge in recent research, achieving a comprehensive understanding of the current state, focal points, and developmental trends in this field remains challenging. Clarifying these aspects and advancing research could notably enhance maternal-infant health outcomes. Therefore, this study employs bibliometric methods to systematically scrutinize maternal hypothyroidism research, serving as a reference for further investigations. Through bibliometric analysis, this study seeks to unveil key research focus areas, developmental trends, and primary contributors in Maternal Hypothyroidism. The findings offer insights and recommendations to inform future research endeavors in this domain. Literature metrics analysis was performed on data retrieved and extracted from the Web of Science Core Collection database. The analysis examined the evolution and thematic trends of literature related to Maternal Hypothyroidism. Data were collected on October 28, 2023, and bibliometric analysis was performed using VOSviewer, CiteSpace, and the Bibliometrix software package, considering specific characteristics such as publication year, country/region, institution, authorship, journals, references, and keywords. Retrieved from 1,078 journals, 4,184 articles were authored by 18,037 contributors in 4,580 institutions across 113 countries/regions on six continents. Maternal Hypothyroidism research publications surged from 44 to 310 annually, a 604.54% growth from 1991 to 2022. The USA (940 articles, 45,233 citations), China Medical University (82 articles, 2,176 citations), and Teng, Weiping (52 articles, 1,347 citations) emerged as the most productive country, institution, and author, respectively. \"Thyroid\" topped with 233 publications, followed by \"Journal of Clinical Endocrinology & Metabolism\" (202) with the most citations (18,513). \"Pregnancy\" was the most cited keyword, with recent high-frequency keywords such as \"outcome,\" \"gestational diabetes,\" \"iodine intake,\" \"preterm birth,\" \"guideline,\" and \"diagnosis\" signaling emerging themes in Maternal Hypothyroidism. This study unveils developmental trends, global collaboration patterns, foundational knowledge, and emerging frontiers in Maternal Hypothyroidism. Over 30 years, research has predominantly focused on aspects like diagnosis, treatment guidelines, thyroid function during pregnancy, and postpartum outcomes, with a central emphasis on the correlation between maternal and fetal health.

This study uses fly ash and slag as the main raw materials to replace 80% of the cement, and prepares a sponge-structured cement paste with storage and absorption functions. This paste is then used to bind the coarse aggregate of permeable concrete to improve the water absorption and storage performance of the permeable concrete. This research examined the influence of mineral admixture ratios on mechanical strength, capillary absorption and storage capacity, and analyzed the formation mechanisms of microporous structure. Sponge structure cement stone was prepared with a cementitious material ratio of 70% grade II fly ash, 10% slag and 20% cement. The findings indicate an optimal mix proportion that provides enhanced compressive strength, capillary water absorption, and volumetric water storage capacity. Compared with standard curing, water-bath curing was found to be unfavorable for enhancing the water absorption performance of sponge-structured cement paste; therefore, standard curing is recommended for its preparation. The pore structure of sponge-structured cement paste was analyzed using the Bruker-Emmett-Taylor (BET) method, scanning electron microscopy (SEM), Image-Pro Plus (IPP) image processing technology, and mercury intrusion porosimetry (MIP). Results indicated that the volume fraction of capillary pores in the 100-1000 nm range was positively correlated with water absorption and storage performance. The exponential relationship model between the content of grade II fly ash and the capillary pore content of sponge-structured cement stone was determined.

HighlightsA promising solar-powered environmentally friendly process for the synthesis and application of catalysts for hydrogen evolution reaction has been proposed.A delicate NiCo(OH)x-CoyW catalyst with a bush-like heterostructure was realized via gas-template-assisted electrodeposition, followed by electrochemical etching process.The excellent catalytic effect of NiCo(OH)x-CoyW for the hydrogen evolution reaction was systematically investigated through various physical and electrochemical analyses.To achieve high efficiency of water electrolysis to produce hydrogen (H2), developing non-noble metal-based catalysts with considerable performance have been considered as a crucial strategy, which is correlated with both the interphase properties and multi-metal synergistic effects. Herein, as a proof of concept, a delicate NiCo(OH)x-CoyW catalyst with a bush-like heterostructure was realized via gas-template-assisted electrodeposition, followed by an electrochemical etching-growth process, which ensured a high active area and fast gas release kinetics for a superior hydrogen evolution reaction, with an overpotential of 21 and 139 mV at 10 and 500 mA cm−2, respectively. Physical and electrochemical analyses demonstrated that the synergistic effect of the NiCo(OH)x/CoyW heterogeneous interface resulted in favorable electron redistribution and faster electron transfer efficiency. The amorphous NiCo(OH)x strengthened the water dissociation step, and metal phase of CoW provided sufficient sites for moderate H immediate adsorption/H2 desorption. In addition, NiCo(OH)x-CoyW exhibited desirable urea oxidation reaction activity for matching H2 generation with a low voltage of 1.51 V at 50 mA cm−2. More importantly, the synthesis and testing of the NiCo(OH)x-CoyW catalyst in this study were all solar-powered, suggesting a promising environmentally friendly process for practical applications.

With the atypical rise of infection (MPI) in 2023, prompt studies are needed to determine the current epidemic features and risk factors with emerging trends of MPI to furnish a framework for subsequent investigations. This multicentre, retrospective study was designed to analyse the epidemic patterns of MPI before and after the COVID-19 pandemic, as well as genotypes and the macrolide-resistance-associated mutations in sampled from paediatric patients in Southern China. Clinical data was collected from 1,33,674 patients admitted into investigational hospitals from 1 June 2017 to 30 November 2023. Metagenomic next-generation sequencing (mNGS) data were retrieved based on sequence positive samples from 299 paediatric patients for macrolide-resistance-associated mutations analysis. was used to compare categorical variables between different time frames. The monthly average cases of paediatric common respiratory infection diseases increased without enhanced public health measures after the pandemic, especially for influenza, respiratory syncytial virus infection, and MPI. The contribution of MPI to pneumoniae was similar to that in the outbreak in 2019. Compared to mNGS data between 2019-2022 and 2023, the severity of did not grow stronger despite higher rates of macrolide-resistance hypervariable sites, including loci 2063 and 2064, were detected in childhood samples of 2023. Our findings indicated that ongoing surveillance is necessary to understand the impact of post pandemic on transmission disruption during epidemic season and the severity of clinical outcomes in different scenarios.

Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters. Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. Here, the authors present cryo-EM structures of hMRP5 in different states, showing that hMRP5 can be autoinhibited by a short peptide from its N-terminal tail, which prevents the entry of substrates into hMRP5’s transport pathway.

Neutrophil extracellular traps (NETs) are produced by neutrophil activation and usually have both anti-infective and pro-damage effects. Streptococcus uberis ( S. uberis ), one of the common causative organisms of mastitis, can lead to the production of NETs. Taurine, a free amino acid abundant in the organism, has been shown to have immunomodulatory effects. In this study, we investigated the molecular mechanisms of S. uberis -induced NETs formation and the regulatory role of taurine. The results showed that NETs had a disruptive effect on mammary epithelial cells and barriers, but do not significantly inhibit the proliferation of S. uberis . S. uberis induced NADPH oxidase-dependent NETs. TLR2-mediated activation of the MAPK signaling pathway was involved in this process. Taurine could inhibit the activation of MAPK signaling pathway and NADPH oxidase by modulating the activity of TAK1, thereby inhibiting the production of ROS and NETs. The effects of taurine on NADPH oxidase and NETs in S. uberis infection were also demonstrated in vivo . These results suggest that taurine can protect mammary epithelial cells and barriers from damage by reducing S. uberis -induced NETs. These data provide new insights and strategies for the prevention and control of mastitis.

Tbx3 boosts iPS quality While much attention has been given to the study of different genetic and chemical methods for the generation of iPS (induced pluripotent stem) cell lines, relatively little is known about the variability in overall quality of iPS cells. This paper identifies a transcription factor, Tbx3, that significantly improves the quality of iPS cells. Tbx3 also accelerates the reprogramming process of mouse embryonic fibroblasts into iPS cells and significantly improves the germ-line transmission of iPS-derived germ cells in chimaeric animals. The transcription factor Tbx3 is shown to significantly improve the quality of induced pluripotent stem (iPS) cells. Tbx3 binding sites in embryonic stem cells are present in genes involved in pluripotency and reprogramming factors. Furthermore, there are intrinsic qualitative differences in iPS cells generated by different methods in terms of their pluripotency, thus highlighting the need to rigorously characterize iPS cells beyond in vitro studies. Induced pluripotent stem (iPS) cells can be obtained by the introduction of defined factors into somatic cells 1 . The combination of Oct4 (also known as Pou5f1), Sox2 and Klf4 (which we term OSK) constitutes the minimal requirement for generating iPS cells from mouse embryonic fibroblasts. These cells are thought to resemble embryonic stem cells (ESCs) on the basis of global gene expression analyses; however, few studies have tested the ability and efficiency of iPS cells to contribute to chimaerism, colonization of germ tissues, and most importantly, germ-line transmission and live birth from iPS cells produced by tetraploid complementation. Using genomic analyses of ESC genes that have roles in pluripotency and fusion-mediated somatic cell reprogramming, here we show that the transcription factor Tbx3 significantly improves the quality of iPS cells. iPS cells generated with OSK and Tbx3 (OSKT) are superior in both germ-cell contribution to the gonads and germ-line transmission frequency. However, global gene expression profiling could not distinguish between OSK and OSKT iPS cells. Genome-wide chromatin immunoprecipitation sequencing analysis of Tbx3-binding sites in ESCs suggests that Tbx3 regulates pluripotency-associated and reprogramming factors, in addition to sharing many common downstream regulatory targets with Oct4, Sox2, Nanog and Smad1. This study underscores the intrinsic qualitative differences between iPS cells generated by different methods, and highlights the need to rigorously characterize iPS cells beyond in vitro studies.