Inherent or acquired resistance to chemotherapeutic drugs is still an obstacle for the treatment of multiple myeloma (MM). MicroRNA dysregulation is related to the development of chemoresistance in cancers. However, its role in chemoresistance of MM is largely unknown. Here we demonstrated that miR-221/222 were upregulated in plasma cells from patients with MM, especially those with relapsed or refractory disease. Moreover, expression levels of miR-221/222 were inversely correlated with dexamethasone (Dex) sensitivity of human MM cell lines. Importantly, we found that Dex induced pro-death autophagy in MM cells and the inhibition of autophagy significantly decreased Dex-induced cell death. Mechanistically, autophagy-related gene 12 (ATG12) was identified as a novel target gene of miR-221/222, and miR-221/222 overexpression inhibited autophagy by directly targeting ATG12 and the p27kip (p27)-mammalian target of rapamycin (mTOR) pathway. Indeed, Dex treatment decreased the expression of miR-221/222, thereby activating the ATG12/p27-mTOR autophagy-regulatory axis and inducing cell death in Dex-sensitive MM cells. Furthermore, both in vitro and in vivo results showed that the inhibitions of miR-221/222 increased the expression of ATG12 and p27 and functionally induced extended autophagy and cell death of MM cells. In conclusion, our findings demonstrated the crucial role of the miR-221/222-ATG12/p27-mTOR autophagy-regulatory axis in Dex resistance of MM, and they suggest potential prediction and treatment strategies for glucocorticoid resistance.

Microorganism pollution in rivers is of great importance to the protection of watershed water quality and public health management. As a typical watershed of the Haihe River watershed, the Beiyun River was chosen as the study area, and the characteristics and health risk of microorganism pollution were assessed from a comprehensive perspective. The results showed that the microbial contamination of the fecal sources was serious during the wet season, and the microbial amount at most river sections was more than 105 MPN·L-1. During the normal season and dry season, the microbial amount was approximately 103-105 MPN·L-1. Therefore, no obvious change could be observed. The fecal pollution in the agricultural river sections was the most severe, and the water quality of over 60% of these river sections was below the state Grade V level. The fecal microbial biomass of some urban river sections increased from 103 MPN·L-1 to 106MPN·L-1 after the rainfall event, indicating an obvious change of fecal microbial pollution during the rainfall process. For the Beiyun River, the exposure risk of the fecal microbial biomass was mainly between 0.015-0.035, while the Lianhua River, Macao River, lower reaches of Qinghe River, and lower reaches of Wenyu River were hotspots for contamination. Greater attention should be paid to these areas.

Myocardial fibrosis (MF) can cause heart remodeling and it is an independent risk factor for malignant arrhythmias, sudden cardiac death, and other malignant cardiovascular events. It is often characterized by myocardial interstitial collagen deposition and hyperproliferation of cardiac fibroblasts (CFs). The transforming growth factor-β1 (TGF-β1) is the most influential profibrogenic factor. Resveratrol (RSV) is an active polyphenol substance that inhibits myocardial fibrosis. The mechanism of RSV-mediated inhibition of the proliferation of CFs at the microRNA level is not fully understood. We used TGF-β1 to induce CFs proliferation to simulate the pathogenesis of myocardial fibrosis. Neonatal rat CFs were treated with TGF-β1 in the presence or absence of resveratrol. Cell proliferation was measured using the CCK-8 and EdU assay. Collagen secretion was measured using hydroxyproline kit. Further, qPCR analysis was performed to determine microRNA levels after TGF-β1 or resveratrol treatment. To identify the target gene for miR-17, miR-17 was overexpressed or silenced, and the mRNA and protein levels of Smad7 were assessed. The effects of miR-17 silencing or Smad7 overexpression on cell proliferation and collagen secretion were also examined. Resveratrol treatment significantly decreased the TGF-β1-induced CF proliferation and collagen secretion. Resveratrol also decreased the levels of miR-17, miR-34a, and miR-181a in TGF-β1-treated CFs. Overexpression of miR-17 decreased the Smad7 mRNA and protein levels while silencing miR-17 increased them. Additionally, silencing miR-17 or overexpressing Smad7 decreased the TGF-β1-induced CFs proliferation and collagen secretion. In conclusion, resveratrol inhibits TGF-β1-induced CFs proliferation and collagen secretion. This inhibitory effect of resveratrol is orchestrated by the downregulation of miR-17 and the regulation of Smad7.

Long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which can largely influence on tumorigenesis and tumor progression. However, the role of lncRNA-mediated ceRNAs in cholangiocarcinoma (CCA) remains unknown. This study aimed to develop novel lncRNAs as well as their action mechanisms in CCA.

Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in numerous kinds of cardiovascular diseases, and their vital role in regulating cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA X-inactive specific transcript (XIST) was upregulated in hypertrophic cardiac of mice and phenylephrine (PE)-treated cardiomyocytes. Next, we observed that inhibition of XIST induced hypertrophic response of cardiomyocyte and overexpression of XIST attenuated cardiomyocyte hypertrophy induced by PE. Furthermore, through online predictive tools and functional experiments, we demonstrated that XIST and S100B were targets of miR-330-3p. XIST and miR-330-3p suppressed each other in a reciprocal way in cardiomyocytes. Additionally, XIST promoted S100B expression through harboring the complementary binding sites with miR-330-3p, eventually prevented cardiac hypertrophy. In conclusion, our findings revealed a novel molecular mechanism that XIST/miR-330-3p/S100B pathway modulates the progression of cardiomyocyte hypertrophy.

Porcine reproductive and respiratory syndrome is an infectious disease that causes serious economic losses to the swine industry worldwide. To better understand the pathogenesis of the porcine reproductive and respiratory syndrome virus (PRRSV), three PRRSV strains with different molecular markers and virulence were used to infect MARC-145 cells. A total of 1804 proteins were identified, and 233 altered proteins and 72 signaling pathways involved in the proteomic profiling of virus-infected MARC-145 cells increased with the virulence of the PRRSV strain. The three types of viral strains shared a common pathway-the electron transport reaction in mitochondria-in the infected-MARC-145 cells. Moreover, the antisense pathway was the most variable of all significant signaling pathways for the highly virulent SX-1 strain, indicating that this unique pathway may be connected to the high virulence of the SX-1 strain. Our study is the first attempt to provide a proteome profile of MARC-145 cells infected with PRRSV strains with different virulence, and these findings will facilitate a deep understanding of the interactions between this virus and its host.

The relationship between the gut microbiota and the central nervous system has been gradually recognized while whether microbiome plays a role in the pathogenesis of drug-resistant epilepsy is still unknown. The aim of our work was to explore whether dysbiosis is involved in the mechanism of drug-resistant epilepsy.

This study was to evaluate the fermentation dynamics, structural and nonstructural carbohydrate composition and in vitro gas production of rice straw ensiled with lactic acid bacteria and molasses.

Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4-CD8- double negative (DN) stages but not at the CD4+CD8+ double positive (DP) or later stages. Notably, Sin1-deficient DN thymocytes show markedly reduced proliferation and glycolysis. Importantly, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sin1 effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sin1-mTORC2 controls PKM2 expression through an AKT-dependent PPAR-γ nuclear translocation. Together, our study unravels a novel mTORC2-PPAR-γ-PKM2 pathway in immune-metabolic regulation of early thymocyte development.

To analyse the factors predicting uncontrolled seizures in epilepsy with auditory features (EAF).

The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.

MicroRNAs (miRNAs) are important regulators of tumor formation, progression and metastasis. The present study characterized a novel miRNA (miR)-888, as a potent oncomiR in human colorectal cancer (CRC). The clinicopathological investigation on 126 cases of CRC patients demonstrated that the expression level of miR-888 was significantly upregulated in tumors compared with adjacent healthy tissue, and was associated with tumor stage and histological differentiation. A Kaplan-Meier analysis and log-rank test demonstrated that CRC patients with increased miR-888 expression exhibited a decreased overall survival (OS) and disease-free survival (DFS) compared with patients with low miR-888 expression. Further univariate and multivariate analyses identified miR-888 as an independent prognostic factor for poor survival outcome in CRC patients. To determine the biological role of miR-888 in human CRC, in vitro Cell Counting kit-8, wound healing and transwell assays were performed and demonstrated that miR-888 contributed greatly to CRC cell proliferation, invasion and metastasis. Furthermore, potential targets of miR-888 were investigated using a luciferase reporter assay, followed by polymerase chain reaction and western blot analysis. The findings revealed that miR-888 directly bound to the 3'-untranslated region of mothers against decapentaplegic-4 and thus inhibited its expression and promoted the tumor growth factor-1-induced cancer metastasis signaling. The results of the present study identified miR-888 as an oncogenic miRNA in CRC and provide a foundation for promising research in the future regarding this predictive and prognostic biomarker.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal fibrotic lung disease characterized by profound changes in stem cell differentiation, epithelial cell phenotypes and fibroblast proliferation. In our study, we found that miR-497-5p was significantly upregulated both during myofibroblast differentiation of lung resident mesenchymal stem cells (LR-MSCs) and in the lung tissues of a pulmonary fibrosis model. In addition, as determined by luciferase assays and Western blot analysis, reversion-inducing cysteine-rich protein with kazal motifs (Reck) was identified to be one of the target genes of miR-497-5p, and Reck could suppress the expression of matrix metalloproteinase-2 (Mmp2) and Mmp9, which could activate latent transforming growth factor-β1 (TGF-β1). To test the potential therapeutic significance of this miRNA, we modulated the expression of miR-497-5p in LR-MSCs and relevant animal models. The results demonstrated that upregulation of miR-497-5p could induce LR-MSCs to differentiate into myofibroblasts and promote pulmonary fibrogenesis, while inhibition of its expression could effectively retard these processes. In conclusion, our work supports that controlling pulmonary fibrogenesis via inhibition of miR-497-5p expression may provide a potential therapeutic strategy for IPF.

The present study aimed to investigate the effects of diabetes mellitus (DM) on the generation of experimental corneal neovascularization (CrNV) and choroidal neovascularization (ChNV). Diabetes was induced in mice by intraperitoneal injection of streptozotocin (STZ). Experimental CrNV and ChNV were induced by alkali injury and laser photocoagulation, respectively. CrNV and ChNV were compared between the STZ‑induced diabetic mice and control mice two weeks after injury. Relative expression of angiogenic factors was quantified by reverse transcription‑quantitative polymerase chain reaction, and progenitor cell or macrophage accumulation in the early phase following injury was examined by flow cytometric analysis. Compared with the alkali‑injured normal mice, the alkali‑injured diabetic mice (STZ‑induced) exhibited no significant difference in CrNV occurrence, whereas the laser‑injured diabetic mice exhibited significantly reduced levels of ChNV compared with those of the laser‑injured control animals. The laser‑induced intrachoroidal mRNA expression levels of angiogenic factors, including vascular endothelial growth factor, hypoxia‑induced factor‑1α, chemokine (C‑C motif) ligand 3, and stromal cell‑derived factor‑1α, were reduced in the laser‑injured diabetic mice when compared with laser‑injured control mice. Furthermore, the laser‑induced intrachoroidal infiltration of c‑Kit+ progenitor cells was impaired in the laser‑injured diabetic mice compared with the laser‑injured control mice. Overall, diabetes did not exert a significant effect on the generation of experimental CrNV. However, diabetes reduced laser‑induced ChNV through downregulation of intrachoroidal progenitor cell infiltration and angiogenic factor expression.

Stem cell transplantation has been considered a promising therapeutic approach for premature ovarian failure (POF). However, to date, no quantitative data analysis of stem cell therapy for POF has been performed. Therefore, the present study performed a meta-analysis to assess the efficacy of stem cell transplantation in improving ovarian function in animal models of POF. In addition, a case report of a patient with POF subjected to stem cell treatment was included to demonstrate that stem cell therapy also contributes to the recovery of ovarian function in patients. Published studies were identified by a systematic review of the PubMed, Embase, and Cochrane's library databases, and references cited in associated reviews were also considered. Data regarding follicle-stimulating hormone (FSH), estradiol (E2), ovarian weight, follicle count, the number of pregnancies and other parameters, including delivery route and cell type, were extracted. Pooled analysis, sensitivity analyses, subgroup analyses and meta-regression were performed. In the case of POF, transvaginal ultrasound (TVS), abdominal ultrasound (TAS) and color Doppler flow imaging (CDFI) were performed to observe the endometrial morphology and blood flow signals in the patient. Overall, pooled results from 16 pre-clinical studies demonstrated that stem cell-based therapy significantly improved FSH levels [standardized mean difference (SMD)=-1.330; 95% confidence interval (CI), -(2.095-0.565); P=0.001], E2 levels (SMD=2.334; 95% CI, 1.350-3.319; P<0.001), ovarian weight (SMD=1.310; 95% CI, 0.157-2.463; P=0.026), follicle count (SMD=1.871; 95% CI, 1.226-2.516; P<0.001), and the number of pregnancies (risk ratio=1.715, 95% CI, 1.213-2.424; P=0.002). The results of TVS and TAS demonstrated improved ovarian size and endometrial thickness in the patient with POF after MSC treatment. Of note, a rich blood flow signal in the endometrium was observed on CDFI. It appeared that stem cell-based therapy may be an effective method for the resumption of ovarian function in a patient and in animal models of POF; however, large-scale and high-quality future studies are required to confirm the present findings due to heterogeneity.

γδ T cells recognize a wide variety of ligands in mammals, among them members of the butyrophilin (BTN) family. Nothing is known about γδ T cell ligands in chickens, despite there being many such cells in blood and lymphoid tissues, as well as in mucosal surfaces. The major histocompatibility complex (MHC) of chickens was discovered because of polymorphic BG genes, part of the BTN family. All but two BG genes are located in the BG region, oriented head-to-tail so that unequal crossing-over has led to copy number variation (CNV) as well as hybrid (chimeric) genes, making it difficult to identify true alleles. One approach is to examine BG genes expressed in particular cell types, which likely have the same functions in different BG haplotypes and thus can be considered "functional alleles." We cloned nearly full-length BG transcripts from peripheral T cells of four haplotypes (B2, B15, B19, and B21), and compared them to the BG genes of the B12 haplotype that previously were studied in detail. A dominant BG gene was found in each haplotype, but with significant levels of subdominant transcripts in three haplotypes (B2, B15, and B19). For three haplotypes (B15, B19, and B21), most sequences are closely-related to BG8, BG9, and BG12 from the B12 haplotype. We found that variation in the extracellular immunoglobulin-variable-like (Ig-V) domain is mostly localized to the membrane distal loops but without evidence for selection. However, variation in the cytoplasmic tail composed of many amino acid heptad repeats does appear to be selected (although not obviously localized), consistent with an intriguing clustering of charged and polar residues in an apparent α-helical coiled-coil. By contrast, the dominantly-expressed BG gene in the B2 haplotype is identical to BG13 from the B12 haplotype, and most of the subdominant sequences are from the BG5-BG7-BG11 clade. Moreover, alternative splicing leading to intron read-through results in dramatically truncated cytoplasmic tails, particularly for the dominantly-expressed BG gene of the B2 haplotype. The approach of examining "functional alleles" has yielded interesting data for closely-related genes, but also thrown up unexpected findings for at least one haplotype.

To explore the potential molecular mechanism of low-intensity pulsed ultrasound (LIPUS) in the treatment of temporomandibular joint osteoarthritis (TMJ-OA), and identify the target genes for therapy of TMJ-OA.

Hypertension is the most important risk factor for cardiovascular and cerebrovascular diseases. The study found that CXCL12 and CNNM2 gene affects the risk of coronary heart disease, but the relationship with hypertension is unclear. The aim of this research is to explore the association between CXCL12 and CNNM2 gene and hypertension in Chinese Han population.

YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.

Understanding virus assembly mechanisms is important for developing therapeutic interventions. Nipah virus (NiV) is of interest because of its high mortality rate and efficient human-human transmissions. The current model for most enveloped viruses suggests that matrix proteins (M) recruit attachment glycoproteins (G) and fusion glycoproteins (F) to the assembly site at the plasma membrane. Here we report an assembly model that differs in many aspects from the current one. Examining NiV proteins on the cell plasma membrane using super-resolution microscopy reveals that clusters of F and G are randomly distributed on the plasma membrane regardless of the presence or absence of M. Our data suggests a model in which the M molecules assemble at the plasma membrane to form virus-like particles (VLPs), while the incorporation of F and G into the nascent VLPs is stochastic.