Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular ...calcification often occurs with osteoporosis, a contradictory association called "calcification paradox". Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.
In elderly people particularly in postmenopausal women, inadequate bone formation by osteoblasts originating from bone marrow mesenchymal stem cells (BMSCs) for compensation of bone resorption by ...osteoclasts is a major reason for osteoporosis. Enhancing osteoblastic differentiation of BMSCs is a feasible therapeutic strategy for osteoporosis. Here, bone marrow stromal cell (ST)-derived exosomes (STExos) are found to remarkably enhance osteoblastic differentiation of BMSCs
in vitro
. However, intravenous injection of STExos is inefficient in ameliorating osteoporotic phenotypes in an ovariectomy (OVX)-induced postmenopausal osteoporosis mouse model, which may be because STExos are predominantly accumulated in the liver and lungs, but not in bone. Hereby, the STExo surface is conjugated with a BMSC-specific aptamer, which delivers STExos into BMSCs within bone marrow. Intravenous injection of the STExo-Aptamer complex enhances bone mass in OVX mice and accelerates bone healing in a femur fracture mouse model. These results demonstrate the efficiency of BMSC-specific aptamer-functionalized STExos in targeting bone to promote bone regeneration, providing a novel promising approach for the treatment of osteoporosis and fracture.
A novel strategy to deliver therapeutic exosomes to bone is developed for the first time by conjugating a specific BMSC-targeting aptamer to the exosomal surface.
Dendrite growth of alkali metal anodes limited their lifetime for charge/discharge cycling. Here, we report near-perfect anodes of lithium, sodium, and potassium metals achieved by electrochemical ...polishing, which removes microscopic defects and creates ultra-smooth ultra-thin solid-electrolyte interphase layers at metal surfaces for providing a homogeneous environment. Precise characterizations by AFM force probing with corroborative in-depth XPS profile analysis reveal that the ultra-smooth ultra-thin solid-electrolyte interphase can be designed to have alternating inorganic-rich and organic-rich/mixed multi-layered structure, which offers mechanical property of coupled rigidity and elasticity. The polished metal anodes exhibit significantly enhanced cycling stability, specifically the lithium anodes can cycle for over 200 times at a real current density of 2 mA cm
with 100% depth of discharge. Our work illustrates that an ultra-smooth ultra-thin solid-electrolyte interphase may be robust enough to suppress dendrite growth and thus serve as an initial layer for further improved protection of alkali metal anodes.
Cancer incidence is rising, and the efficacy of current available anticancer agents is limited by severe dose‐limiting toxicities and drug resistance problems. Nanoparticles are heralded as the next ...frontier in cancer treatment. Here, a pure physical method is used to efficiently fabricate very small silver particles even approaching the Ångstrom (Ång) dimension. Fructose is used as a dispersant and stabilizer to coat the Ång‐scale silver particles (AgÅPs). Functional and mechanistic studies demonstrate that fructose‐coated AgÅPs (F‐AgÅPs) can enter and accumulate in multiple cultured cancer cell lines to induce apoptotic death, whereas most normal cells are resistant to the efficacious dose of F‐AgÅPs; in vivo, intravenous administration of F‐AgÅPs potently inhibits the growth of pancreatic and lung cancer xenografts in nude mice, without inducing notable toxic effects on the healthy tissues. The results suggest the promising potential of F‐AgÅPs as a potent, safe, and broad‐spectrum agent for the cancer treatment.
Physical method‐fabricated fructose‐coated Ångstrom‐scale silver particles (F‐AgÅPs) have the ability to enter multiple cancer cells to induce apoptosis. Intravenous injection of F‐AgÅPs potently inhibits the growth of cancer xenograft models, without inducing notable toxic effects on healthy tissues. These results suggest that F‐AgÅPs have a great potential to be used as a potent, safe, and broad‐spectrum agent for cancer treatment.
The use of Monte‐Carlo (MC) p$$ p $$‐values when testing the significance of a large number of hypotheses is now commonplace. In large‐scale hypothesis testing, we will typically encounter at least ...some p$$ p $$‐values near the threshold of significance, which require a larger number of MC replicates than p$$ p $$‐values that are far from the threshold. As a result, some incorrect conclusions can be reached due to MC error alone; for hypotheses near the threshold, even a very large number (eg, 106$$ 1{0}^6 $$) of MC replicates may not be enough to guarantee conclusions reached using MC p$$ p $$‐values. Gandy and Hahn (GH)6‐8 have developed the only method that directly addresses this problem. They defined a Monte‐Carlo error rate (MCER) to be the probability that any decisions on accepting or rejecting a hypothesis based on MC p$$ p $$‐values are different from decisions based on ideal p$$ p $$‐values; their method then makes decisions by controlling the MCER. Unfortunately, the GH method is frequently very conservative, often making no rejections at all and leaving a large number of hypotheses “undecided”. In this article, we propose MERIT, a method for large‐scale MC hypothesis testing that also controls the MCER but is more statistically efficient than the GH method. Through extensive simulation studies, we demonstrate that MERIT controls the MCER while making more decisions that agree with the ideal p$$ p $$‐values than GH does. We also illustrate our method by an analysis of gene expression data from a prostate cancer study.
The rechargeable lithium-sulfur battery is regarded as a promising option for electrochemical energy storage systems owing to its high energy density, low cost and environmental friendliness. Further ...development of the Li-S battery, however, is still impeded by capacity decay and kinetic sluggishness caused by the polysulfide shuttle and electrode/electrolyte interface issues. Herein, a new type of metal-organic-framework-derived sulfur host containing cobalt and N-doped graphitic carbon (Co-N-GC) was synthesized and reported, in which the catalyzing for S redox, entrapping of polysulfides and an ideal electronic matrix were successfully achieved synchronously, leading to a significant improvement in the Li-S performance. The large surface area and uniform dispersion of cobalt nanoparticles within the N-doped graphitic carbon matrix contributed to a distinct enhancement in the specific capacity, rate performance and cycle stability for Li-S batteries. As a result of this multi-functional arrangement, cathodes with a high sulfur loading of 70 wt% could operate at 1C for over 500 cycles with nearly 100% coulombic efficiency and exhibited an outstanding high-rate response of up to 5C, suggesting that the SatCo-N-GC electrode was markedly improved by the proposed strategy, demonstrating its great potential for use in low-cost and high-energy Li-S batteries.
The application of blood plasma for soft tissue wound healing is receiving much more attention recently. Exosomes are critical paracrine mediators that can be obtained from biological fluids ...including plasma and be able to induce regenerative effects by transferring bioactive molecules such as microRNAs (miRNAs). This study aimed to investigate the effects of exosomes from human umbilical cord blood plasma (UCB-Exos) on wound healing and to elucidate the underlying mechanism.
UCB-Exos were isolated by ultracentrifugation and subcutaneously injected into full-thickness skin wounds in mice. The efficacy of UCB-Exos on wound healing was evaluated by measuring wound closure rates, histological analysis and immunofluorescence examinations.
, quantitative real-time PCR (qRT-PCR) analysis was performed to detect the expression levels of a class of miRNAs that have positive roles in regulating wound healing. The scratch wound assay, transwell assay and cell counting kit-8 analysis were conducted to assess the effects of UCB-Exos on migration and proliferation of human skin fibroblasts and endothelial cells. Tube formation assay was carried out to test the impact of UCB-Exos on angiogenic tube formation ability of endothelial cells. Meanwhile, by using specific RNA inhibitors or siRNAs, the roles of the candidate miRNA and its target genes in UCB-Exos-induced regulation of function of fibroblasts and endothelial cells were assessed.
The local transplantation of UCB-Exos into mouse skin wounds resulted in accelerated re-epithelialization, reduced scar widths, and enhanced angiogenesis.
, UCB-Exos could promote the proliferation and migration of fibroblasts, and enhance the angiogenic activities of endothelial cells. Notably, miR-21-3p was found to be highly enriched in UCB-Exos and served as a critical mediator in UCB-Exos -induced regulatory effects through inhibition of phosphatase and tensin homolog (PTEN) and sprouty homolog 1 (SPRY1).
Our results suggest that UCB-Exos are important effectors of plasma activity and can be used as a novel promising strategy for soft tissue wound healing.
Summary
Rice (Oryza sativa L.) has two ecotypes, upland and lowland rice, that have been observed to show different tolerance levels under flooding stress. In this study, two rice cultivars, upland ...(Up221, flooding‐intolerant) and lowland (Low88, flooding‐tolerant), were initially used to study their molecular mechanisms in response to flooding germination. We observed that variations in the OsCBL10 promoter sequences in these two cultivars might contribute to this divergence in flooding tolerance. Further analysis using another eight rice cultivars revealed that the OsCBL10 promoter could be classified as either a flooding‐tolerant type (T‐type) or a flooding‐intolerant type (I‐type). The OsCBL10 T‐type promoter only existed in japonica lowland cultivars, whereas the OsCBL10 I‐type promoter existed in japonica upland, indica upland and indica lowland cultivars. Flooding‐tolerant rice cultivars containing the OsCBL10 T‐type promoter have shown lower Ca2+ flow and higher α‐amylase activities in comparison to those in flooding‐intolerant cultivars. Furthermore, the OsCBL10 overexpression lines were sensitive to both flooding and hypoxic treatments during rice germination with enhanced Ca2+ flow in comparison to wild‐type. Subsequent findings also indicate that OsCBL10 may affect OsCIPK15 protein abundance and its downstream pathways. In summary, our results suggest that the adaptation to flooding stress during rice germination is associated with two different OsCBL10 promoters, which in turn affect OsCBL10 expression in different cultivars and negatively affect OsCIPK15 protein accumulation and its downstream cascade.
Significance Statement
This study identifies that OsCBL10 is able to communicate with upstream calcium signaling and downstream flooding responses by affecting OsCIPK15 protein accumulation or stability. The variation in OsCBL10 promoter regions could be a general mechanism in Sub1A‐deficient lowland japonica cultivars in response to flooding germination.
To identify operational taxonomy units (OTUs) signaling disease onset in an observational study, a powerful strategy was selecting participants by matched sets and profiling temporal metagenomes, ...followed by trajectory analysis. Existing trajectory analyses modeled individual OTU or microbial community without adjusting for the within-community correlation and matched-set-specific latent factors.
We proposed a joint model with matching and regularization (JMR) to detect OTU-specific trajectory predictive of host disease status. The between- and within-matched-sets heterogeneity in OTU relative abundance and disease risk were modeled by nested random effects. The inherent negative correlation in microbiota composition was adjusted by incorporating and regularizing the top-correlated taxa as longitudinal covariate, pre-selected by Bray-Curtis distance and elastic net regression. We designed a simulation pipeline to generate true biomarkers for disease onset and the pseudo biomarkers caused by compositionality. We demonstrated that JMR effectively controlled the false discovery and pseudo biomarkers in a simulation study generating temporal high-dimensional metagenomic counts with random intercept or slope. Application of the competing methods in the simulated data and the TEDDY cohort showed that JMR outperformed the other methods and identified important taxa in infants' fecal samples with dynamics preceding host disease status.
Our method JMR is a robust framework that models taxon-specific trajectory and host disease status for matched participants without transformation of relative abundance, improving the power of detecting disease-associated microbial features in certain scenarios. JMR is available in R package mtradeR at https://github.com/qianli10000/mtradeR.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's disease (AD) is currently ranked as the third leading cause of death for eldly people, just behind heart disease and cancer. Autophagy is declined with aging. Our study determined the ...biphasic changes of miR-331-3p and miR-9-5p associated with AD progression in APPswe/PS1dE9 mouse model and demonstrated inhibiting miR-331-3p and miR-9-5p treatment prevented AD progression by promoting the autophagic clearance of amyloid beta (Aβ).
The biphasic changes of microRNAs were obtained from RNA-seq data and verified by qRT-PCR in early-stage (6 months) and late-stage (12 months) APPswe/PS1dE9 mice (hereinafter referred to as AD mice). The AD progression was determined by analyzing Aβ levels, neuron numbers (MAP2
) and activated microglia (CD68
IBA1
) in brain tissues using immunohistological and immunofluorescent staining. MRNA and protein levels of autophagic-associated genes (
) were tested to determine the autophagic activity. Morris water maze and object location test were employed to evaluate the memory and learning after antagomirs treatments in AD mice and the Aβ in the brain tissues were determined.
MiR-331-3p and miR-9-5p are down-regulated in early-stage of AD mice, whereas up-regulated in late-stage of AD mice. We demonstrated that miR-331-3p and miR-9-5p target autophagy receptors Sequestosome 1 (
) and Optineurin (
), respectively. Overexpression of miR-331-3p and miR-9-5p in SH-SY5Y cell line impaired autophagic activity and promoted amyloid plaques formation. Moreover, AD mice had enhanced Aβ clearance, improved cognition and mobility when treated with miR-331-3p and miR-9-5p antagomirs at late-stage.
Our study suggests that using miR-331-3p and miR-9-5p, along with autophagic activity and amyloid plaques may distinguish early versus late stage of AD for more accurate and timely diagnosis. Additionally, we further provide a possible new therapeutic strategy for AD patients by inhibiting miR-331-3p and miR-9-5p and enhancing autophagy.
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