The alteration of age‐related molecules in the bone marrow microenvironment is one of the driving forces in osteoporosis. These molecules inhibit bone formation and promote bone resorption by ...regulating osteoblastic and osteoclastic activity, contributing to age‐related bone loss. Here, we observed that the level of microRNA‐31a‐5p (miR‐31a‐5p) was significantly increased in bone marrow stromal cells (BMSCs) from aged rats, and these BMSCs demonstrated increased adipogenesis and aging phenotypes as well as decreased osteogenesis and stemness. We used the gain‐of‐function and knockdown approach to delineate the roles of miR‐31a‐5p in osteogenic differentiation by assessing the decrease of special AT‐rich sequence‐binding protein 2 (SATB2) levels and the aging of BMSCs by regulating the decline of E2F2 and recruiting senescence‐associated heterochromatin foci (SAHF). Notably, expression of miR‐31a‐5p, which promotes osteoclastogenesis and bone resorption, was markedly higher in BMSCs‐derived exosomes from aged rats compared to those from young rats, and suppression of exosomal miR‐31a‐5p inhibited the differentiation and function of osteoclasts, as shown by elevated RhoA activity. Moreover, using antagomiR‐31a‐5p, we observed that, in the bone marrow microenvironment, inhibition of miR‐31a‐5p prevented bone loss and decreased the osteoclastic activity of aged rats. Collectively, our results reveal that miR‐31a‐5p acts as a key modulator in the age‐related bone marrow microenvironment by influencing osteoblastic and osteoclastic differentiation and that it may be a potential therapeutic target for age‐related osteoporosis.
The root of the eukaryote tree of life defines some of the most fundamental relationships among species. It is also critical for defining the last eukaryote common ancestor (LECA), the shared ...heritage of all extant species. The unikont-bikont root has been the reigning paradigm for eukaryotes for more than 10 years 1 but is becoming increasingly controversial 2–4. We developed a carefully vetted data set, consisting of 37 nuclear-encoded proteins of close bacterial ancestry (euBacs) and their closest bacterial relatives, augmented by deep sequencing of the Acrasis kona (Heterolobosea, Discoba) transcriptome. Phylogenetic analysis of these data produces a highly robust, fully resolved global phylogeny of eukaryotes. The tree sorts all examined eukaryotes into three megagroups and identifies the Discoba, and potentially its parent taxon Excavata 5, as the sister group to the bulk of known eukaryote diversity, the proposed Neozoa (Amorphea + Stramenopila+Alveolata+Rhizaria+Plantae SARP 6). All major alternative hypotheses are rejected with as little as ∼50% of the data, and this resolution is unaffected by the presence of fast-evolving alignment positions or distant outgroup sequences. This “neozoan-excavate” root revises hypotheses of early eukaryote evolution and highlights the importance of the poorly studied Discoba for understanding the evolution of eukaryotic diversity and basic cellular processes.
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•A new 37-protein data set produces a robust and rooted eukaryote tree•All examined eukaryotes form three megagroups: Amorphea, SARP, and Excavata•A new neozoan-excavate root is proposed with strong statistical support•Discoba (Excavata) has a long, unique, and largely unknown evolutionary history
He et al. developed a novel data set of 37 eukaryotic proteins of bacterial ancestry (euBacs) to explore the major radiations of eukaryotes. A neozoan-excavate root is found, with the little-known Discoba (and potentially its parent taxon Excavata) identified as sister group to the bulk of known eukaryote diversity.
Abstract
Study Objectives
Mounting evidence indicated the correlation between sleep and cerebral small vessel disease (CSVD). However, little is known about the exact causality between poor sleep and ...white matter injury, a typical signature of CSVD, as well as the underlying mechanisms.
Methods
Spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats were subjected to sleep fragmentation (SF) for 16 weeks. The effects of chronic sleep disruption on the deep white matter and cognitive performance were observed.
Results
SHR were validated as a rat model for CSVD. Fragmented sleep induced strain-dependent white matter abnormalities, characterized by reduced myelin integrity, impaired oligodendrocytes precursor cells (OPC) maturation and pro-inflammatory microglial polarization. Partially reversible phenotypes of OPC and microglia were observed in parallel following sleep recovery.
Conclusions
Long-term SF-induced pathological effects on the deep white matter in a rat model of CSVD. The pro-inflammatory microglial activation and the block of OPC maturation may be involved in the mechanisms linking sleep to white matter injury.
Graphical Abstract
Cumulative prospect theory (CPT) is a popular approach for modeling human preferences. It is based on probabilistic distortions and generalizes the expected utility theory. We bring the CPT to a ...stochastic optimization framework and propose algorithms for both estimation and optimization of CPT-value objectives. We propose an empirical distribution function-based scheme to estimate the CPT value, and then, use this scheme in the inner loop of a CPT-value optimization procedure. We propose both gradient based as well as gradient-free CPT-value optimization algorithms that are based on two well-known simulation optimization ideas: simultaneous perturbation stochastic approximation and model-based parameter search, respectively. We provide theoretical convergence guarantees for all the proposed algorithms and also illustrate the potential of CPT-based criteria in a traffic signal control application.
Dental laboratories require manpower resources for manufacturing prostheses and inventory management. In this paper, we developed an automated inventory management system for dental laboratories to ...improve the production efficiency. A sensing system was developed based on the framework of Internet of things to collect the information of cobalt-chromium disks both in the storage room and manufacturing area, and an expert system was developed to automatically conduct inventory management based on the established rules. The proposed system can reduce the time of recording data and also assist the manager in configuring and managing material orders. The experimental results showed that a large amount of working time is reduced, resulting in the benefits of saving money and improving efficiency in dental manufacturing.
Cholangiocarcinoma (CCA) is a severe malignancy usually producing a poor prognosis and high mortality rate. MicroRNAs (miRNAs) have been reported in association with CCA; however, the role miR‐329 ...plays in the CCA condition still remains unclear. Therefore, this study was conducted to explore the underlying mechanism of which miR‐329 is influencing the progression of CCA. This work studied the differential analysis of the expression chips of CCA obtained from the Gene Expression Omnibus database. Next, to determine both the expression and role of pituitary tumor transforming gene‐1 (PTTG1) in CCA, the miRNAs regulating PTTG1 were predicted. In the CCA cells that had been intervened with miR‐329 upregulation or inhibition, along with PTTG1 silencing, expression of miR‐329, PTTG1, p‐p38/p38, p‐ERK5/ERK5, proliferating cell nuclear antigen (PCNA), Cyclin D1, Bcl‐2‐associated X protein (Bax), B‐cell CLL/lymphoma 2 (Bcl‐2), and caspase‐3 were determined. The effects of both miR‐329 and PTTG1 on cell proliferation, cell‐cycle distribution, and apoptosis were also assayed. The miR‐329 was likely to affect the CCA development through regulation of the PTTG1‐mediated mitogen‐activated protein kinase (MAPK) signaling pathway. The miR‐329 targeted PTTG1, leading to inactivation of the MAPK signaling pathway. Upregulation of miR‐329 and silencing of PTTG1 inhibited the CCA cell proliferation, induced cell‐cycle arrest, and subsequently promoted apoptosis with elevations in Bax, cleaved caspase‐3, and total caspase‐3, but showed declines in PCNA, Cyclin D1, and Bcl‐2. Moreover, miR‐329 was also found to suppress the tumor growth by downregulation of PTTG1. To summarize, miR‐329 inhibited the expression of PTTG1 to inactivate the MAPK signaling pathway, thus suppressing the CCA progression, thereby providing a therapeutic basis for the CCA treatment.
To summarize, miR‐329 inhibited the expression of pituitary tumor transforming gene‐1 to inactivate the mitogen‐activated protein kinase signaling pathway, thus suppressing the cholangiocarcinoma (CCA) progression, thereby providing a therapeutic basis for CCA treatment.
Electrospinning is a simple and efficient method of fabricating a non-woven polymeric nanofiber matrix. However, using fluorinated alcohols as a solvent for the electrospinning of proteins often ...results in protein denaturation. TEM and circular dichroism analysis indicated a massive loss of triple-helical collagen from an electrospun collagen (EC) matrix, and the random coils were similar to those found in gelatin. Nevertheless, from mechanical testing we found the Young's modulus and ultimate tensile stresses of EC matrices were significantly higher than electrospun gelatin (EG) matrices because matrix stiffness can affect many cell behaviors such as cell adhesion, proliferation and differentiation. We hypothesize that the difference of matrix stiffness between EC and EG will affect intracellular signaling through the mechano-transducers Rho kinase (ROCK) and focal adhesion kinase (FAK) and subsequently regulates the osteogenic phenotype of MG63 osteoblast-like cells. From the results, we found there was no significant difference between the EC and EG matrices with respect to either cell attachment or proliferation rate. However, the gene expression levels of OPN, type I collagen, ALP, and OCN were significantly higher in MG63 osteoblast-like cells grown on the EC than in those grown on the EG. In addition, the phosphorylation levels of Y397-FAK, ERK1/2, BSP, and OPN proteins, as well as ALP activity, were also higher on the EC than on the EG. We further inhibited ROCK activation with Y27632 during differentiation to investigate its effects on matrix-mediated osteogenic differentiation. Results showed the extent of mineralization was decreased with inhibition after induction. Moreover, there is no significant difference between EC and EG. From the results of the protein levels of phosphorylated Y397-FAK, ERK1/2, BSP and OPN, ALP activity and mineral deposition, we speculate that the mechanism that influences the osteogenic differentiation of MG63 osteoblast-like cells on EC and EG is matrix stiffness and via ROCK-FAK-ERK1/2.
Aim
Noninvasive evaluation of hypoxia in rabbit VX2 lung transplant tumors using spectral CT parameters and texture analysis.
Materials and methods
Twenty-five VX2 lung transplant tumors of ...twenty-two rabbits were included in the study. Contrast-enhanced spectral CT scanning in the arterial phase (AP) and venous phase (VP) was performed. Tumors were divided into strong and weak hypoxic groups by hypoxic probe staining results. Spectral CT image-related parameters 70 keV CT value, normalized iodine concentration (NIC), slope of spectral HU curve (λ
HU
) were measured and the texture analysis on the monochromatic images was performed. Imaging parameters and texture features between tumors with different hypoxic degrees were compared and their diagnostic efficacies for predicting hypoxia in lung cancers were analyzed using receiver operating characteristic (ROC) curve.
Results
NIC in VP and λ
HU
in VP of the strong hypoxic group were significantly higher than those in the weak hypoxic group (
p
< 0.05). For the texture features, entropy in VP and kurtosis in AP were significantly different between the two hypoxic groups. According to ROC analysis, λ
HU
in VP had a better diagnostic ability for predicting hypoxia in tumors Area Under Curve (AUC): 0.883, sensitivity: 85.7%, specificity: 100%. The combination of four features improved AUC to 0.955.
Conclusion
NIC in VP, λ
HU
in VP, entropy in VP and kurtosis in AP have certain values in predicting tumor hypoxia and a combination of image parameters and texture features improves diagnostic efficiency.
Cisplatin, a commonly used chemotherapy drug, can increase the survival rate of cancer patients. However, it often causes various side effects, including neuronal deficit-induced cognitive ...impairment. Considering that curcumin is effective in neuronal protection, the action of curcumin on cognitive improvement was evaluated in cisplatin-treated C57BL/6 mice in the present study. Our results first showed that curcumin restored impaired cognitive behaviors. Consistent with this, neurogenesis and synaptogenesis were improved by curcumin. In addition, cisplatin-induced dysfunction of apoptosis-related proteins was partly reversed by curcumin. Moreover, cisplatin-induced autophagy was enhanced by curcumin. Our results also indicated that cisplatin induced autophagy through the endoplasmic reticulum (ER) stress-mediated ATF4-Akt-mTOR signaling pathway. Curcumin activated AMPK-JNK signaling, which mediated both mTOR inhibition and Bcl-2 upregulation and in turn enhanced autophagy and suppressed apoptosis, respectively. In contrast, pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) completely abolished the effects of curcumin on cognitive improvement and improved neurogenesis, synaptogenesis and autophagy. Our results show that cognitive improvement induced by curcumin during chemotherapy is mediated by the enhancement of hippocampal autophagy.
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•Curcumin attenuates the impaired cognition induced by cisplatin.•Curcumin promotes neurogenesis and synaptogenesis in the hippocampus.•Curcumin enhances autophagy in the hippocampus.•The autophagy enhanced by curcumin is mediated by AMPK-JNK signaling.•3-MA blocks the effects of curcumin on cognitive improvement in chemotherapy.
Cell separation is one of the key limiting factors for precise analysis of non-axenic microbial lab cultures or environmental samples, and it remains a challenge to isolate target cells with high ...purity and viability
high-throughput cell sorting. During the past decade, hydrodynamic microfluidic platforms have attracted great attention in cell preparation for their high efficiency, robust performance and low cost. Here, we employ the use of a low-velocity sheath flow with high viscosity near the wall and a high-velocity sheath flow with low viscosity on the other side of the sample flow in a soft inertial separation chip. This not only prevents hard interactions between cells and chip walls but, in comparison to previous inertial separation methods, generates a significant increase in deflection of large cells while keeping the small ones in the original flow. We first conducted experiments on a mixture of small and large fluorescent particles (1.0 and 9.9 μm, respectively) and removed over 99% of the small particles. The separation efficiency was then tested on a culture of a bacterivorous jakobid flagellate,
fed on the live bacterium,
sp. Using our microfluidic chip, over 94% of live bacteria were removed while maintaining high jakobid cell viability. For comparison, we also conducted size-based cell sorting of the same culture using flow cytometry, which is widely used as a rapid and automated separation tool. Compared with the latter, our chip showed more than 40% higher separation efficiency. Thus, our device provides high purity and viability for cell separation of a sensitive cell sample (jakobid cells). Potentially, the method can be further used for applications in diagnostics, biological analyses and environmental assessment of mixed microbial samples.
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