Response characteristics and functional predictions of soil microorganisms to heavy metals, antibiotics, and their resistance genes originating from different animal farms amended with Herbaspirillum huttiense.

Current understanding is limited regarding technologies that use biochar and microorganisms to simultaneously treat soils contaminated with both veterinary antibiotics (VAs) and heavy metals (HMs) from different animal farms. The contributions of the keystone taxa and their similarities from different animal farms under VA and HM stresses before and after soil remediation should be further investigated as well. An innovative treatment of Herbaspirillum huttiense (HHS1) inoculated waste fungus chaff-based (WFCB) biochar was designed for immobilization of copper (Cu) and zinc (Zn), and the removal of oxytetracycline (OTC), enrofloxacin (ENR), and a subsequent reduction in their resistance genes in soils from pig, cow, and chicken farms. Roles of indigenous microorganisms which can treat soils contaminated with VAs and HMs were summarized. Results showed that available Cu and Zn were reduced by 19.5% and 28.1%, respectively, while 49.8% of OTC and 85.1% of ENR were removed by WFCB-HHS1. The decrease in ENR improved overall microbial community diversity, and the increases in genera HHS1, Pedobacter, Flavobacterium and Aequorivita, along with the decreases of genera Bacillus, Methylobacter, and Fermentimonas were indirectly favorable to treat HMs and VAs in soils from different animal farms. Bacterial communities in different animal farm soils were predominantly influenced by stochastic processes. The regulations of functional genes associated with metabolism and environmental information processing, which contribute to HM and VA defense, were altered when using WFCB-HHS1. Furthermore, the spread of their antibiotic resistance genes was restricted.

Associations between sarcopenia and circulating branched-chain amino acids: a cross-sectional study over 100,000 participants.

BACKGROUND: Emerging evidence suggests that alterations in BCAA metabolism may contribute to the pathogenesis of sarcopenia. However, the relationship between branched-chain amino acids (BCAAs) and sarcopenia is incompletely understood, and existing literature presents conflicting results. In this study, we conducted a community-based study involving > 100,000 United Kingdom adults to comprehensively explore the association between BCAAs and sarcopenia, and assess the potential role of muscle mass in mediating the relationship between BCAAs and muscle strength. METHODS: Multivariable linear regression analysis examined the relationship between circulating BCAAs and muscle mass/strength. Logistic regression analysis assessed the impact of circulating BCAAs and quartiles of BCAAs on sarcopenia risk. Subgroup analyses explored the variations in associations across age, and gender. Mediation analysis investigated the potential mediating effect of muscle mass on the BCAA-muscle strength relationship. RESULTS: Among 108,017 participants (mean age: 56.40 ± 8.09 years; 46.23% men), positive associations were observed between total BCAA, isoleucine, leucine, valine, and muscle mass (beta, 0.56-2.53; p < 0.05) and between total BCAA, leucine, valine, and muscle strength (beta, 0.91-3.44; p < 0.05). Logistic regression analysis revealed that increased circulating valine was associated with a 47% reduced sarcopenia risk (odds ratio = 0.53; 95% confidence interval = 0.3-0.94; p = 0.029). Subgroup analyses demonstrated strong associations between circulating BCAAs and muscle mass/strength in men and individuals aged ≥ 60 years. Mediation analysis suggested that muscle mass completely mediated the relationship between total BCAA, and valine levels and muscle strength, partially mediated the relationship between leucine levels and muscle strength, obscuring the true effect of isoleucine on muscle strength. CONCLUSION: This study suggested the potential benefits of BCAAs in preserving muscle mass/strength and highlighted muscle mass might be mediator of BCAA-muscle strength association. Our findings contribute new evidence for the clinical prevention and treatment of sarcopenia and related conditions involving muscle mass/strength loss.

Macular edema after siponimod treatment for multiple sclerosis: a case report and literature review.

BACKGROUND: As a modulator of the sphingosine 1-phosphate receptor, siponimod is administered as a therapeutic intervention for multiple sclerosis. A previous phase 3 study first reported siponimod-associated macular edema. Since that report, there were only few relevant reports in clinical settings. Here, we report a case of secondary progressive multiple sclerosis developed macular edema after siponimod treatment. We also review the progress of sphingosine 1-phosphate receptor modulators, elaborate on accepted mechanisms in treating multiple sclerosis, and discuss the causation of siponimod-associated macular edema. CASE PRESENTATION: A 38-year-old Chinese female patient with secondary progressive multiple sclerosis, who had recurrent numbness of the limbs and right leg fatigue, developed mild macular edema following 4 months of siponimod treatment. The macular edema resolved after discontinuing the medication, and did not recur after resuming siponimod. CONCLUSION: Although siponimod-associated macular edema may be rare, mild, transitory, and manageable, it cannot be ignored and requires ongoing vigilance.

Systematic analysis of critical genes and pathways identified a signature of neuropathic pain after spinal cord injury.

Spinal cord injury (SCI) damages sensory systems, producing chronic neuropathic pain that is resistant to medical treatment. The specific mechanisms underlying SCI-induced neuropathic pain (SCI-NP) remain unclear, and protein biomarkers have not yet been integrated into diagnostic screening. To better understand the host molecular pathways involved in SCI-NP, we used the bioinformatics method, the PubMed database and bioinformatics methods to identify target genes and their associated pathways. We reviewed 2504 articles on the regulation of SCI-NP and used the text mining of PubMed database abstracts to determine associations among 12 pathways and networks. Based on this method, we identified two central genes in SCI-NP: interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). Adult male Sprague-Dawley rats were used to build the SCI-NP models. The threshold for paw withdrawal was significantly reduced in the SCI group, and TLR4 was activated in microglia after SCI. Enzyme-linked immunosorbent assay（ELISA) analysis of TNF-α and IL-6 levels was significantly higher in the SCI group than in the sham group. Western blot showed that expressions of the TLR4/MyD88/NF-κB inflammatory pathway protein increased dramatically in the SCI group. Using the TLR4 inhibitor TAK-242, the pain threshold and expressions of inflammatory factors and proteins of the proteins of the inflammatory signal pathway were reversed, TLR4 in microglia was suppressed, suggesting that SCI-NP was related to neuroinflammation mediated by the TLR4 signalling pathway. In conclusion, we found that TNF-α and IL-6 were the neuroinflammation-related genes involved in SCI-NP that can be alleviated by inhibiting the inflammatory pathway upstream of the TLR4/MyD88/NF-κB inflammatory pathway.

An ischemia-homing bioengineered nano-scavenger for specifically alleviating multiple pathogeneses in ischemic stroke.

BACKGROUND: Ischemic stroke is one of the most serious global public health problems. However, the performance of current therapeutic regimens is limited due to their poor target specificity, narrow therapeutic time window, and compromised therapeutic effect. To overcome these barriers, we designed an ischemia-homing bioengineered nano-scavenger by camouflaging a catalase (CAT)-loaded self-assembled tannic acid (TA) nanoparticle with a M2-type microglia membrane (TPC@M2 NPs) for ischemic stroke treatment. RESULTS: The TPC@M2 NPs can on-demand release TA molecules to chelate excessive Fe2+, while acid-responsively liberating CAT to synergistically scavenge multiple ROS (·OH, ·O2-, and H2O2). Besides, the M2 microglia membrane not only can be served as bioinspired therapeutic agents to repolarize M1 microglia into M2 phenotype but also endows the nano-scavenger with ischemia-homing and BBB-crossing capabilities. CONCLUSIONS: The nano-scavenger for specific clearance of multiple pathogenic elements to alleviate inflammation and protect neurons holds great promise for combating ischemic stroke and other inflammation-related diseases.

Remote ischemic preconditioning protects against cerebral ischemia injury in rats by upregulating miR-204-5p and activating the PINK1/Parkin signaling pathway.

Remote ischemic preconditioning (RiPC) is the process where preconditioning ischemia protects the organs against the subsequent index ischemia. RiPC is a protective method for brain damage. This study is to explore the effect and mechanism of RiPC in cerebral ischemia injury in rats through regulation of miR-204-5p/BRD4 expression. Middle cerebral artery occlusion (MCAO) rat model and glucose deprivation (OGD) neuron model were established. The effect of RiPC on neurological deficits, cerebral infarct size, autophagy marker, inflammatory cytokines and apoptosis was evaluated. miR-204-5p expression was analyzed using RT-qPCR, and then downregulated using miR-204-5p antagomir to estimate its effect on MCAO rats. The downstream mechanism of miR-204-5p was explored. RiPC promoted autophagy, reduced cerebral infarct volume and neurological deficit score, and alleviated apoptosis and cerebral ischemia injury in rats, with no significant effects on healthy rat brains. RiPC up-regulated miR-204-5p expression in MCAO rats. miR-204-5p knockdown partially reversed the effect of RiPC. RiPC promoted autophagy in OGD cells, and attenuated inflammation and apoptosis. miR-204-5p targeted BRD4, which partially reversed the effect of miR-204-5p on OGD cells. RiPC activated the PINK1/Parkin pathway via the miR-204-5p/BRD4 axis. In conclusion, RiPC activated the PINK1/Parkin pathway and prevented cerebral ischemia injury by up-regulating miR-204-5p and inhibiting BRD4.

Association of neutrophil-to-lymphocyte ratio (NLR) with the prognosis of first attack neuromyelitis optica spectrum disorder (NMOSD): a retrospective cohort study.

BACKGROUND: To investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR) and prognosis after the first attack of optic neuromyelitis optica spectrum disorder (NMOSD). METHODS: In this retrospective study, we included the medical records of 324 patients with first episode NMOSD and collected data on clinical parameters. Follow-up extended disability status scale (EDSS) score and relapse rate were analyzed using logistic regression models to determine the independent effect of NLR on outcomes; receiver operating characteristic (ROC) curves were applied to analyze the predictive value of NLR for the prognosis of NMOSD. Interaction and stratification analyses were used to explore the association between NLR and prognosis of patients with NMOSD, and Kaplan-Meier analysis was used to investigate the relationship between NLR and outcome. The association between NLR level with relapse rate and poor recovery was assessed by a Cox regression analysis. RESULTS: Patients in the high-NLR group had significantly higher EDSS scores and relapse rates at follow-up (both, P < 0.001) than did those in the low-NLR group. Univariate analysis showed revealed that NLR was significantly associated with relapse (odds ratio [OR] = 1.28, 95% confidence interval [CI]: 1.16-1.41, P < 0.001) and poor recovery (OR = 1.32, 95% CI: 1.20-1.46, P < 0.001), and these associations remained significant, even after multifactorial analysis (OR = 1.33, 95% CI: 1.11-1.59, P = 0.002; OR = 1.23, 95% CI: 1.06-1.43, P = 0.007, respectively). Stratified analysis showed that sex, platelet-to-lymphocyte ratio (PLR) level, and lymphocyte-to-monocyte technical ratio (LMR) level were strongly associated with relapse owing to elevated NLR; Kaplan-Meier survival curve analysis showed that the median time to relapse was significantly lower in the high-NLR group than in the low-NLR group (P < 0.001). A multivariate analysis showed a significant relationship between NLR level with relapse (HR = 1.07, 95%CI: 1.03-1.10, P = 0.001) and poor recovery (HR = 1.08, 95%CI: 1.04-1.11, P = 0.001). CONCLUSIONS: NLR may be used as a prognostic indicator for first onset NMOSD, and a high NLR may be significantly associated with high relapse rates and poor recovery.

Lin28B regulates the fate of grafted mesenchymal stem cells and enhances their protective effects against Alzheimer's disease by upregulating IGF-2.

Mesenchymal stem cells (MSCs) transplantation has emerged as a potential therapeutic approach for Alzheimer's disease (AD). However, the poor proliferation capacity and low survival rate of engrafted MSCs in the hostile microenvironment of AD limit their therapeutic efficiency. Lin28B is a conserved RNA-binding protein associated with cell self-renewal and survival. The purpose of the present study was to explore whether lin28B might influence the functions of implanted MSCs and strengthen their neuroprotective potential in AD. A gain-of-function assay was used to upregulate lin28B expression in MSCs by lentiviral transfection. Our in vitro results indicated that lin28B promoted MSCs proliferation and migration, and protected MSCs against Aß1-42-induced cell death by upregulating insulin-like growth factor-2 (IGF-2). Blockage of IGF-2 partially abrogated the above effects of lin28B. After intracerebroventricular injection into amyloid precursor protein/presenilin 1 mice, implanted MSCs were monitored using bioluminescence imaging. We observed that administration of MSCs transfected with lin28B significantly stimulated their proliferation and prolonged cell retention after delivery. Moreover, administration of the transfected MSCs markedly mitigated cognitive deficits, promoted amyloid plaque clearance, decreased the activation of microglia, and reduced neuronal cell death. The data above confirmed our hypothesis that lin28B is a crucial modulator determining the fate of transplanted MSCs by regulating IGF-2-associated pathways and thereby enhancing their protective effects against AD.

Free thyroxine level is associated with both relapse rate and poor neurofunction in first-attack Neuromyelitis Optica Spectrum Disorder (NMOSD) patients.

BACKGROUND: To investigate whether the serum free thyroxine (FT4) level is a prognostic factor for the first-attack neuromyelitis optica spectrum disorders (NMOSD). METHODS: This retrospective study enrolled 109 patients with first-attack NMOSD. The Expanded Disability Status Scale (EDSS) and the relapse rate were used to evaluate the outcomes. The logistic regression model was used to analyze the independent effects of FT4 on relapse and final EDSS. Kaplan-Meier analysis, scatter plot smoothing method, and two-phase piecewise linear regression model were used to investigate the relationship between the FT4 level and the relapse rate. RESULTS: Multivariate analysis revealed that serum FT4 level might be a risk factor for both final EDSS (ß = 0.17; 95% confidence interval: 0.03-0.32) and the relapse rate (HR = 1.18; 95% confidence interval: 1.05-1.32). Furthermore, 1400 days after the onset, nearly 100% of patients in the high-FT4 group relapsed, while only 40% of the patients in the low-FT4 group relapsed. Finally, we found that the relationship between the FT4 level and the NMOSD relapse rate was nonlinear. The risk of NMOSD relapse increased with the FT4 level up to the inflection point of 12.01 pmol/L (HR = 1.45; 95% confidence interval: 1.06-1.98). When the FT4 level was > 12.01 pmol/L, there was no correlation between the FT4 level and the risk of NMOSD relapse (HR = 1.05; 95% confidence interval: 0.78-1.41). CONCLUSION: Serum FT4 level may be a prognostic indicator for the first-attack in patients with NMOSD. High FT4 levels are associated with poor neurofunctions and a high relapse rate in patients with the first-attack in patients with NMOSD.

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury.

BACKGROUND/AIMS: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. METHODS: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. RESULTS: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1ß, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. CONCLUSION: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously.

MicroRNA let-7f-5p regulates neuronal differentiation of rat bone marrow mesenchymal stem cells by targeting Par6α.

Par6α (partitioning defective 6 homologue alpha), a component of the Par3/Par6/aPKC complex, was recently shown to be essential for axon specification during neuronal development. However, the biological functions and regulatory mechanisms of Par6α in the mesenchymal stem cell (MSC) differentiation process have not been investigated. In this study, we found that the expression of let-7f-5p was downregulated during differentiation of bone marrow-derived MSCs to neuron-like cells. Interestingly, Par6α was predicted to be a target gene of let-7f-5p by computerized analysis and the luciferase reporter assay. Using gain- and loss-of-function approaches, we found that expression of Par6α was inversely correlated with let-7f-5p levels during differentiation (p < 0.05). By silencing Par6α using siRNAs, we demonstrated that Par6α was necessary for MSC neuronal differentiation. Altogether, our studies proved that inhibition of let-7f-5p facilitates induction of MSCs into neuron-like cells by directly targeting Par6α.

High-Dose Tanshinone IIA Suppresses Migration and Proliferation While Promoting Apoptosis of Astrocytoma Cells Via Notch-1 Pathway.

Malignant astrocytoma is the most common malignant tumor with strong invasion in the central nervous system. Tanshinone IIA is an effective compound to suppress cell proliferation and promote cell apoptosis. However, there is little research about the role of tanshinone IIA in the treatment of astrocytoma. This study aimed to investigate the effect of tanshinone IIA on migration, proliferation and apoptosis of astrocytoma cells. The efficacy of tanshinone IIA on migration, proliferation and apoptosis of astrocytoma cells were evaluated by flow cytometry and the assays of plate clone formation, CCK-8, wound healing and transwell migration. The protein molecule and signaling pathway were detected by western blot. High-dose tanshinone IIA suppressed migration and proliferation of astrocytoma cells while promoting apoptosis of astrocytoma cells. The western blot results showed that there were high Notch-1 protein expression and low c-Myc, MMP-9 and Bcl-2 activation in the high-dose tanshinone IIA group compared with the control group. High-dose tanshinone IIA suppresses astrocytoma cell proliferation, migration while promoting apoptosis through Notch-1 pathway. Tanshinone IIA may be used to develop new drugs for the treatment of astrocytoma.

Neuroprotective effects of α-melanocyte-stimulating hormone against the neurotoxicity of 1-methyl-4-phenylpyridinium.

Parkinson's disease (PD) is the second most common neurodegenerative disease in humans. The hormone α-melanocyte-stimulating hormone (α-MSH) has been reported to be neuroprotective in previous studies. The aim of this study is to investigate the neuroprotective effects of α-MSH against the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+). Our results indicated that treatment with α-MSH in M17 cells attenuated MPP+-induced oxidative stress, embodied by exacerbated reactive oxygen species and protein carbonyls. In addition, we found that α-MSH could improve mitochondrial function in M17 cells through increasing the level of adenosine triphosphate and mitochondrial membrane potential. Furthermore, treatment with α-MSH restored the reduction of cell viability and the induction of lactate dehydrogenase release induced by α-MSH. Importantly, Hoechst staining results indicated that α-MSH treatment significantly reduces the number of apoptotic cells after treatment with MPP+. Mechanically, we found that α-MSH prevented apoptosis signals through reducing the level of cleaved caspase-3 and attenuating cytochrome c release. All these data imply that α-MSH produces a protective effect in PD. © 2015 IUBMB Life, 69(5):315-320, 2017.

Let-7f Regulates the Hypoxic Response in Cerebral Ischemia by Targeting NDRG3.

microRNAs are a class of non-coding RNAs including approximately 22 nucleotides in length and play a pivotal role in post-transcriptional gene regulation. Currently, the role of miRNAs in the pathophysiology of ischemic stroke has been the subject of recent investigations. In particular, antagomirs to microRNA (miRNA) let-7f have been found to be neuroprotective in vivo, although the detailed function of let-7f during cerebral ischemia has not been fully illustrated. NDRG3 is an N-myc downstream-regulated gene (NDRG) family member that has been observed in the nuclei in most brain cells. Recently, a NDRG3-mediated lactate signaling, in which stabilized NDRG3 protein can promote angiogenesis and cell growth by activating the Raf-ERK pathway in hypoxia was discovered. In this study, we preliminarily explored the change in the expression of the NDRG3 protein which indicated that NDRG3 protein is an oxygen-regulated protein in neurons in rat cerebral ischemia in vivo and in vitro. We further identified let-7f as an upstream regulator of NDRG3 by the lentiviral transfection of rat cortical neurons and the dual luciferase analysis of human genes. In addition, a dual-color fluorescence in situ hybridization assay showed that when the expression of let-7f was elevated, the expression of NDRG3 mRNA was accordingly reduced in rat cerebral ischemia. Taken together, our results identify a new regulatory mechanism of let-7f on NDRG3 expression in the hypoxic response of cerebral ischemia and raise the possibility that the let-7f/NDRG3 pathway may serve as a potential target for the treatment of ischemic stroke.

Circular RNA: a new star in neurological diseases.

Circular RNAs (circRNAs) are novel endogenous non-coding RNAs characterized by the presence of a covalent bond linking the 3' and 5' ends generated by backsplicing. In this review, we summarize a number of the latest theories regarding the biogenesis, properties and functions of circRNAs. Specifically, we focus on the advancing characteristics and functions of circRNAs in the brain and neurological diseases. CircRNAs exhibit the characteristics of species conservation, abundance and tissue/developmental-stage-specific expression in the brain. We also describe the relationship between circRNAs and several neurological diseases and highlight their functions in neurological diseases.

Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy.

There is a significant unmet need in the treatment of primary biliary cirrhosis (PBC) despite significant data on the effector pathways that lead to biliary duct damage. We focused attention on a murine model of PBC, the dominant negative transforming growth factor ß receptor II (Tg) mice. To further define the pathways that lead to biliary pathology in these mice, we developed Tg mice deleted of CD4 cells (CD4(-/-)Tg). Interestingly, these mice developed more severe cholangitis than control Tg mice. These mice, which lack CD4 cells, manifested increased levels of IFN-γ produced by effector CD8 cells. It appears that increased cholangitis is due to the absence of CD4 Treg cells. Based on these data, we parabiosed CD4(-/-)Tg mice with established disease at 8-9 weeks of age with C57BL/6 control mice. Such parabiotic "twins" had a significant reduction in autoimmune cholangitis, even though they had established pathology at the time of surgery. We prepared mixed bone marrow chimera mice constructed from CD4(-/-)Tg and CD8(-/-) mice and not only was cholangitis improved, but a decrease in terminally differentiated CD8(+) T effector cells in the presence of wild type CD4 cells was noted. In conclusion, "correcting" the CD4 T cell subset, even in the presence of pathogenic CD8 T cells, is effective in treating autoimmune cholangitis.

Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis.

CD4(+)Foxp3(+) regulatory T cells (Tregs) play a non-redundant role in control of excessive immune responses, and defects in Tregs have been shown both in patients and murine models of primary biliary cirrhosis (PBC), a progressive autoimmune biliary disease. Herein, we took advantage of a murine model of PBC, the dominant negative transforming growth factor ß receptor II (dnTGFßRII) mice, to assess Treg genetic defects and their functional effects in PBC. By using high-resolution microarrays with verification by PCR and protein expression, we found profound and wide-ranging differences between dnTGFßRII and normal, wild type Tregs. Critical transcription factors were down-regulated including Eos, Ahr, Klf2, Foxp1 in dnTGFßRII Tregs. Functionally, dnTGFßRII Tregs expressed an activated, pro-inflammatory phenotype with upregulation of Ccl5, Granzyme B and IFN-γ. Genetic pathway analysis suggested that the primary effect of loss of TGFß pathway signaling was to down regulate immune regulatory processes, with a secondary upregulation of inflammatory processes. These findings provide new insights into T regulatory genetic defects; aberrations of the identified genes or genetic pathways should be investigated in human PBC Tregs. This approach which takes advantage of biologic pathway analysis illustrates the ability to identify genes/pathways that are affected both independently and dependent on abnormalities in TGFß signaling. Such approaches will become increasingly useful in human autoimmunity.

Elevated Serum MicroRNA Let-7c in Moyamoya Disease.

BACKGROUND: Few studies have examined the relationship between mircroRNAs and moyamoya disease (MMD). We performed a study of the significance of let-7c expression in the serum of MMD patients. METHODS: The experimental group includes 49 MMD patients, and the control group consists of 30 normal people, 20 cerebral hemorrhage patients, 20 massive cerebral infarction patients, 20 nonmassive cerebral infarction patients, and 20 neurological autoimmune disease patients. Let-7 family levels were determined by polymerase chain reaction. A dual luciferase assay was used to test whether let-7c recognized the 3'UTR of RNF213. RESULTS: The expression level of let-7c in MMD patients is higher than that observed in the control groups (P < .001). The luciferase assay results indicated that hsa-let-7c could diminish luciferase activity from a reporter vector containing the 3'-UTR of RNF213 (P < .05). The suppression of luciferase activity is not found in mutRNF213 (P > .05). CONCLUSIONS: Increased expression of let-7c in MMD patients may contribute to MMD pathogenesis by targeting RNF213. Thus, let-7c may be a potential biomarker for the diagnosis of MMD.

Role of autophagy and mTOR signaling in neural differentiation of bone marrow mesenchymal stem cells.

Autophagy is involved in cell differentiation. We present evidence that autophagy is activated during ß-mercaptoethanol (ß-ME)-induced neuronal differentiation of bone marrow mesenchymal stem cells (MSCs), in which mammalian target of rapamycin (mTOR) signaling is important. mTOR activity declined after being transported from the nucleus to the cytoplasm. Using 3-methyladenine (3-MA) and rapamycin to regulate the activity of mTOR, it was found that the efficiency of neuronal differentiation was affected.

[A preliminary study of plasma microRNA levels in children with methylmalonic acidemia].

OBJECTIVE: To screen out differentially expressed microRNAs (miRNAs) in the plasma of children with methylmalonic acidemia (MMA), to determine the expression of miR-9-1 in plasma and to preliminarily evaluate the significance of miR-9-1 as a biomarker in MMA. METHODS: Plasma was obtained from 17 MMA children, 10 hyperhomocysteinemia (HHcy) children without MMA (HHcy group), and 10 normal controls. Of 17 MMA children, 12 had HHcy (MMA+HHcy group), and 5 had no HHcy (MMA group). The differentially expressed miRNAs were screened out by miRNA microarray. Differentially expressed miR-9-1 was selected, and plasma miR-9-1 levels were determined by RT-PCR. Urine was collected from MMA patients who received vitamin B12 treatment, and plasma miR-9-1 levels were determined by RT-PCR after treatment. RESULTS: The miRNA microarray analysis showed that 26 miRNAs were differentially expressed, among which 16 miRNAs (including miR-9-1) were down-regulated over 2 times, while 10 miRNAs were up-regulated over 2 times. The MMA+HHcy , MMA and HHcy groups had significantly down-regulated miR-9-1 compared with the normal control group (P<0.01). The patients who showed a good response to vitamin B12 treatment had significantly increased plasma miR-9-1 levels, without significant difference compared with the normal control group. CONCLUSIONS: Plasma miR-9-1 is significantly down-regulated in MMA patients, but it is significantly up-regulated after vitamin B12 treatment, suggesting that miR-9-1 may act as a biomarker in monitoring the progression of MMA.