Adenosine mediates the amelioration of social novelty deficits during rhythmic light treatment of 16p11.2 deletion female mice.

Non-invasive brain stimulation therapy for autism spectrum disorder (ASD) has shown beneficial effects. Recently, we and others demonstrated that visual sensory stimulation using rhythmic 40 Hz light flicker effectively improved cognitive deficits in mouse models of Alzheimer's disease and stroke. However, whether rhythmic visual 40 Hz light flicker stimulation can ameliorate behavioral deficits in ASD remains unknown. Here, we show that 16p11.2 deletion female mice exhibit a strong social novelty deficit, which was ameliorated by treatment with a long-term 40 Hz light stimulation. The elevated power of local-field potential (LFP) in the prefrontal cortex (PFC) of 16p11.2 deletion female mice was also effectively reduced by 40 Hz light treatment. Importantly, the 40 Hz light flicker reversed the excessive excitatory neurotransmission of PFC pyramidal neurons without altering the firing rate and the number of resident PFC neurons. Mechanistically, 40 Hz light flicker evoked adenosine release in the PFC to modulate excessive excitatory neurotransmission of 16p11.2 deletion female mice. Elevated adenosine functioned through its cognate A1 receptor (A1R) to suppress excessive excitatory neurotransmission and to alleviate social novelty deficits. Indeed, either blocking the A1R using a specific antagonist DPCPX or knocking down the A1R in the PFC using a shRNA completely ablated the beneficial effects of 40 Hz light flicker. Thus, this study identified adenosine as a novel neurochemical mediator for ameliorating social novelty deficit by reducing excitatory neurotransmission during 40 Hz light flicker treatment. The 40 Hz light stimulation warrants further development as a non-invasive ASD therapeutics.

TPMA: A two pointers meta-alignment tool to ensemble different multiple nucleic acid sequence alignments.

Accurate multiple sequence alignment (MSA) is imperative for the comprehensive analysis of biological sequences. However, a notable challenge arises as no single MSA tool consistently outperforms its counterparts across diverse datasets. Users often have to try multiple MSA tools to achieve optimal alignment results, which can be time-consuming and memory-intensive. While the overall accuracy of certain MSA results may be lower, there could be local regions with the highest alignment scores, prompting researchers to seek a tool capable of merging these locally optimal results from multiple initial alignments into a globally optimal alignment. In this study, we introduce Two Pointers Meta-Alignment (TPMA), a novel tool designed for the integration of nucleic acid sequence alignments. TPMA employs two pointers to partition the initial alignments into blocks containing identical sequence fragments. It selects blocks with the high sum of pairs (SP) scores to concatenate them into an alignment with an overall SP score superior to that of the initial alignments. Through tests on simulated and real datasets, the experimental results consistently demonstrate that TPMA outperforms M-Coffee in terms of aSP, Q, and total column (TC) scores across most datasets. Even in cases where TPMA's scores are comparable to M-Coffee, TPMA exhibits significantly lower running time and memory consumption. Furthermore, we comprehensively assessed all the MSA tools used in the experiments, considering accuracy, time, and memory consumption. We propose accurate and fast combination strategies for small and large datasets, which streamline the user tool selection process and facilitate large-scale dataset integration. The dataset and source code of TPMA are available on GitHub (https://github.com/malabz/TPMA).

Corrigendum: AMPA receptor-mediated regulation of a Gi-protein in cortical neurons.

This corrects the article DOI: 10.1038/39062.

Availability and threshold of the vasoactive-inotropic score for predicting early extubation in adults after rheumatic heart valve surgery: a single-center retrospective cohort study.

BACKGROUND: Early extubation (EEx) is defined as the removal of the endotracheal tube within 8 h postoperatively. The present study involved determining the availability and threshold of the vasoactive-inotropic score (VIS) for predicting EEx in adults after elective rheumatic heart valve surgery. METHODS: The present study was designed as a single-center retrospective cohort study which was conducted with adults who underwent elective rheumatic heart valve surgery with CPB. The highest VIS in the immediate postoperative period was used in the present study. The primary outcome, the availability of VIS for EEx prediction and the optimal threshold value were determined using ROC curve analysis. The gray zone analysis of the VIS was performed by setting the false negative or positive rate R = 0.05, and the perioperative risk factors for prolonged EEx were identified by multivariate logistic analysis. The postoperative complications and outcomes were compared between different VIS groups. RESULTS: Among the 409 patients initially screened, 379 patients were ultimately included in the study. The incidence of EEx was determined to be 112/379 (29.6%). The VIS had a good predictive value for EEx (AUC = 0.864, 95% CI: [0.828, 0.900], P < 0.001). The optimal VIS threshold for EEx prediction was 16.5, with a sensitivity of 71.54% (65.85-76.61%) and a specificity of 88.39% (81.15-93.09%). The upper and lower limits of the gray zone for the VIS were determined as (12, 17.2). The multivariate logistic analysis identified age (OR, 1.060; 95% CI: 1.017-1.106; P = 0.006), EF% (OR, 0.798; 95% CI: 0.742-0.859; P < 0.001), GFR (OR, 0.933; 95% CI: 0.906-0.961; P < 0.001), multiple valves surgery (OR, 4.587; 95% CI: 1.398-15.056; P = 0.012), and VIS > 16.5 (OR, 12.331; 95% CI: 5.015-30.318; P < 0.001) as the independent risk factors for the prolongation of EEx. The VIS ≤ 16.5 group presented a greater success rate for EEx, a shorter invasive ventilation support duration, and a lower incidence of complications than did the VIS > 16.5 group, while the incidence of reintubation was similar between the two groups. CONCLUSION: In adults, after elective rheumatic heart valve surgery, the highest VIS in the immediate postoperative period was a good predictive value for EEx, with a threshold of 16.5.

A functional near-infrared spectroscopy study on hemodynamic changes of patients with prolonged disorders of consciousness responding to different auditory stimuli.

Treating prolonged disorders of consciousness (pDoC) is challenging. Thus, accurate assessment of residual consciousness in patients with pDoC is important for the management and recovery of patients. Functional near-infrared spectroscopy (fNIRS) can be used to detect brain activity through changes of oxygenated hemoglobin/deoxygenated hemoglobin (HbO/HbR) concentrations changes and has recently gained increasing attention for its potential applications in assessing residual consciousness. However, the number of fNIRS studies assessing residual awareness in patients with pDoC is still limited. In this study, fNIRS was used to evaluate the brain function in 18 patients with pDoC, including 14 vegetative states (VS) and 4 minimally conscious states (MCS), and 15 healthy controls (HC). All participants accepted two types of external stimuli, i.e., active stimulation (motor imagery, MI) and passive stimulation (subject's own name, SON). The results showed that the mean concentrations of HbO/HbR in the prefrontal cortex of the HC during the passive stimulation were significantly lower than those of the active stimulation, and the fitting slope was high. However, the hemodynamic responses of the patients with pDoC were opposite to those of the HC. Additionally, the mean concentrations of HbO/HbR increased as the level of consciousness decreased during passive stimulation. Our findings suggest that the residual level of consciousness in pDoC patients can be assessed by measuring brain responses to different stimulations using fNIRS. The present study further demonstrates the feasibility and reliability of fNIRS in assessing residual consciousness in patients with pDoC, providing a basis for its expanded clinical application.

CAR-Modified Vγ9Vδ2 T Cells Propagated Using a Novel Bisphosphonate Prodrug for Allogeneic Adoptive Immunotherapy.

The benefits of CAR-T therapy could be expanded to the treatment of solid tumors through the use of derived autologous αß T cell, but clinical trials of CAR-T therapy for patients with solid tumors have so far been disappointing. CAR-T therapy also faces hurdles due to the time and cost intensive preparation of CAR-T cell products derived from patients as such CAR-T cells are often poor in quality and low in quantity. These inadequacies may be mitigated through the use of third-party donor derived CAR-T cell products which have a potent anti-tumor function but a constrained GVHD property. Vγ9Vδ2 TCR have been shown to exhibit potent antitumor activity but not alloreactivity. Therefore, in this study, CAR-T cells were prepared from Vγ9Vδ2 T (CAR-γδ T) cells which were expanded by using a novel prodrug PTA. CAR-γδ T cells suppressed tumor growth in an antigen specific manner but only during a limited time window. Provision of GITR co-stimulation enhanced anti-tumor function of CAR-γδ T cells. Our present results indicate that, while further optimization of CAR-γδ T cells is necessary, the present results demonstrate that Vγ9Vδ2 T cells are potential source of 'off-the-shelf' CAR-T cell products for successful allogeneic adoptive immunotherapy.

A spray-as-you-go airway topical anesthesia attenuates cardiovascular responses for double-lumen tube tracheal intubation.

BACKGROUND: Spray-as-you-go (SAYGo) airway topical anesthesia and nerve block are common techniques used during awake tracheal intubation. However, their effects have not been described during double-lumen tube intubation. We report on a prospective randomized study that aimed to compare the intubation effects of SAYGo and nerve block patients undergoing thoracic surgery. METHODS: Sixty-six American Society of Anesthesiologists (ASA) physical status I and II patients were scheduled to undergo double-lumen tube (DLT) tracheal intubation for thoracic surgery. The patients were randomly assigned into control (Group C), ultrasound (Group U), and flexible intubation scope (Group F) groups with 22 cases in each group. Patients in Group C were induced with a standard anesthetic regimen. Patients in Groups U and F were treated with superior laryngeal nerve (SLN) block combined with transtracheal injection (TTI) and given a SAYGo airway topical anesthesia before intubation. Hemodynamic variables during intubation process were recorded as the primary outcome. Additional patient data were recorded including the occurrence of adverse events, the level of hoarseness, the occurrence of sore throats, memory function and the level of patient satisfaction with anesthesia. RESULTS: The blood pressure (BP) and heart rate (HR) of patients in group C was significantly increased 1 min after tracheal intubation (P < 0.05) compared to before anesthesia. The BP and HR of patients in Groups U and F remained stable. 10 cases of hypertension were observed in Group C, 6 cases in Group U and 1 case in Group F. In Group C, tachycardia was observed in 9 patients along with 9 cases in Group U and 4 cases in Group F. In Group U, 4 patients experienced puncture and bleeding were and 8 patients had a poor memory of TTI. No significant differences were found in the incidence of hoarseness, sore throats, and satisfaction with anesthesia in postoperative follow-up. CONCLUSIONS: SAYGo airway topical anesthesia and SLN block combined with the TTI technique can inhibit the cardiovascular response during DLT tracheal intubation. The SAYGo technique has fewer complications and more advantages compared to other approaches.

The Generation and Modulation of Distinct Gamma Oscillations with Local, Horizontal, and Feedback Connections in the Primary Visual Cortex: A Model Study on Large-Scale Networks.

Gamma oscillation (GAMMA) in the local field potential (LFP) is a synchronized activity commonly found in many brain regions, and it has been thought as a functional signature of network connectivity in the brain, which plays important roles in information processing. Studies have shown that the response property of GAMMA is related to neural interaction through local recurrent connections (RC), feed-forward (FF), and feedback (FB) connections. However, the relationship between GAMMA and long-range horizontal connections (HC) in the brain remains unclear. Here, we aimed to understand this question in a large-scale network model for the primary visual cortex (V1). We created a computational model composed of multiple excitatory and inhibitory units with biologically plausible connectivity patterns for RC, FF, FB, and HC in V1; then, we quantitated GAMMA in network models at different strength levels of HC and other connection types. Surprisingly, we found that HC and FB, the two types of large-scale connections, play very different roles in generating and modulating GAMMA. While both FB and HC modulate a fast gamma oscillation (around 50-60 Hz) generated by FF and RC, HC generates a new GAMMA oscillating around 30 Hz, whose power and peak frequency can also be modulated by FB. Furthermore, response properties of the two GAMMAs in a network with both HC and FB are different in a way that is highly consistent with a recent experimental finding for distinct GAMMAs in macaque V1. The results suggest that distinct GAMMAs are signatures for neural connections in different spatial scales and they might be related to different functions for information integration. Our study, for the first time, pinpoints the underlying circuits for distinct GAMMAs in a mechanistic model for macaque V1, which might provide a new framework to study multiple gamma oscillations in other cortical regions.

Soil Threshold Values for Zn Based on Soil-Rice System and Health Risk Assessment in a Typical Carbonate Area of Guangxi.

Zinc (Zn) is enriched in carbonate area related to geological genesis. To ensure safety of rice, soil threshold values of Zn in soil-rice systems were assessed based on analysis of soil-rice Zn concentration in relation to human health risk. Models for the prediction of Zn concentration of early-season and late-season rice grain were accurately established on the basis of significant partial correlations between log10 (BAFs) and log10 (soil properties). The rice threshold value ranged from 10.67 to 37.90 mg/kg, which might not suitable for male and urban residents. The soil safety threshold of early-season rice and late-season rice in carbonate area ranged from 148-200 mg/kg, 119-200 mg/kg with pH below 6.5, 148-250 mg/kg, 119-250 mg/kg with pH ranging from 6.5 to 7.5; 148-300 mg/kg, 119-300 mg/kg with pH above 7.5, respectively.

Regulatory network of miRNA on its target: coordination between transcriptional and post-transcriptional regulation of gene expression.

MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that participate in a majority of biological processes via regulating target gene expression. The post-transcriptional repression through miRNA seed region binding to 3' UTR of target mRNA is considered as the canonical mode of miRNA-mediated gene regulation. However, emerging evidence suggests that other regulatory modes exist beyond the canonical mechanism. In particular, the function of intranuclear miRNA in gene transcriptional regulation is gradually revealed, with evidence showing their contribution to gene silencing or activating. Therefore, miRNA-mediated regulation of gene transcription not only expands our understanding of the molecular mechanism underlying miRNA regulatory function, but also provides new evidence to explain its ability in the sophisticated regulation of many bioprocesses. In this review, mechanisms of miRNA-mediated gene transcriptional and post-transcriptional regulation are summarized, and the synergistic effects among these actions which form a regulatory network of a miRNA on its target are particularly elaborated. With these discussions, we aim to emphasize the importance of miRNA regulatory network on target gene regulation and further highlight the potential application of the network mode in the achievement of a more effective and stable modulation of the target gene expression.

MiR-1254 suppresses HO-1 expression through seed region-dependent silencing and non-seed interaction with TFAP2A transcript to attenuate NSCLC growth.

MicroRNAs (miRNAs) are a class of small non-coding RNAs, which direct post-transcriptional gene silencing (PTGS) and function in a vast range of biological events including cancer development. Most miRNAs pair to the target sites through seed region near the 5' end, leading to mRNA cleavage and/or translation repression. Here, we demonstrated a miRNA-induced dual regulation of heme oxygenase-1 (HO-1) via seed region and non-seed region, consequently inhibited tumor growth of NSCLC. We identified miR-1254 as a negative regulator inhibiting HO-1 translation by directly targeting HO-1 3'UTR via its seed region, and suppressing HO-1 transcription via non-seed region-dependent inhibition of transcriptional factor AP-2 alpha (TFAP2A), a transcriptional activator of HO-1. MiR-1254 induced cell apoptosis and cell cycle arrest in human non-small cell lung carcinoma (NSCLC) cells by inhibiting the expression of HO-1, consequently suppressed NSCLC cell growth. Consistently with the in vitro studies, mouse xenograft studies validated that miR-1254 suppressed NSCLC tumor growth in vivo. Moreover, we found that HO-1 expression was inversely correlated with miR-1254 level in human NSCLC tumor samples and cell lines. Overall, these findings identify the dual inhibition of HO-1 by miR-1254 as a novel functional mechanism of miRNA, which results in a more effective inhibition of oncogenic mRNA, and leads to a tumor suppressive effect.

Clinical diagnosis and mutation analysis of four Chinese families with succinic semialdehyde dehydrogenase deficiency.

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessively-inherited defect of γ-aminobutyric acid (GABA) metabolism. The absence of SSADH, which is encoded by aldehyde dehydrogenase family 5 member A1 (ALDH5A1) gene, leads to the accumulation of GABA and γ-hydroxybutyric acid (GHB). Few cases with SSADH deficiency were reported in China. CASE PRESENTATION: In this study, four Chinese patients were diagnosed with SSADH deficiency in Tianjin Children's Hospital. We conducted a multidimensional analysis with magnetic resonance imaging (MRI) of the head, semi quantitative detection of urine organic acid using gas chromatography-mass spectrometry, and analysis of ALDH5A1 gene mutations. Two of the patients were admitted to the hospital due to convulsions, and all patients were associated with developmental delay. Cerebral MRI showed symmetrical hyperintense signal of bilateral globus pallidus and basal ganglia in patient 1; hyperintensity of bilateral frontal-parietal lobe, widened ventricle and sulci in patient 2; and widened ventricle and sulci in patient 4. Electroencephalogram (EEG) revealed the background activity of epilepsy in patient 1 and the disappearance of sleep spindle in patient 2. Urine organic acid analysis revealed elevated GHB in all the patients. Mutational analysis, which was performed by sequencing the 10 exons and flanking the intronic regions of ALDH5A1 gene for all the patients, revealed mutations at five sites. Two cases had homozygous mutations with c.1529C > T and c.800 T > G respectively, whereas the remaining two had different compound heterozygous mutations including c.527G > A/c.691G > A and c.1344-2delA/c.1529C > T. Although these four mutations have been described previously, the homozygous mutation of c.800 T > G in ALDH5A1 gene is a novel discovery. CONCLUSION: SSADH deficiency is diagnosed based on the elevated GHB and 4, 5DHHA by urinary organic acid analysis. We describe a novel mutation p.V267G (c.800 T > G) located in the NAD binding domain, which is possibly crucial for this disease's severity. Our study expands the mutation spectrum of ALDH5A1 and highlights the importance of molecular genetic evaluation in patients with SSADH deficiency.

JNK-mediated microglial DICER degradation potentiates inflammatory responses to induce dopaminergic neuron loss.

BACKGROUND: Amplified inflammation is important for the progression of Parkinson's disease (PD). However, how this enhanced inflammation is regulated remains largely unknown. Deletion of DICER leads to progressive dopamine neuronal loss and induces gliosis. We hypothesized that the homeostasis of microglial DICER would be responsible for the amplified inflammation in the mouse model of PD. METHODS: The microglia or C57BL/6 mice were treated or injected with l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+), respectively, for the model establishment. Microglia and astrocytes sorted by fluorescence-activated cell sorter (FACS) were assayed by quantitative real-time PCR, Western blotting, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), immunohistofluorescence, and mass spectrometry. RESULTS: Microglial DICER was phosphorylated at serine 1456 by c-jun N-terminal kinase (JNK) and downregulated in response to 1-methyl-4-phenylpyridinium (MPP+), a causative agent in PD. Inhibition of JNK phosphorylation of DICER at serine 1456 rescued the MPP+-induced DICER degradation, suppressed microglial inflammatory process, and prevented the loss of tyrosine hydroxylase-expressing neurons in the mouse MPTP model. CONCLUSIONS: JNK-mediated microglial DICER degradation potentiates inflammation to induce dopaminergic neuronal loss. Thus, preventing microglial DICER degradation could be a novel strategy for controlling neuroinflammation in PD.

Sonic hedgehog is a regulator of extracellular glutamate levels and epilepsy.

Sonic hedgehog (Shh), both as a mitogen and as a morphogen, plays an important role in cell proliferation and differentiation during early development. Here, we show that Shh inhibits glutamate transporter activities in neurons, rapidly enhances extracellular glutamate levels, and affects the development of epilepsy. Shh is quickly released in response to epileptic, but not physiological, stimuli. Inhibition of neuronal glutamate transporters by Shh depends on heterotrimeric G protein subunit Gαi and enhances extracellular glutamate levels. Inhibiting Shh signaling greatly reduces epileptiform activities in both cell cultures and hippocampal slices. Moreover, pharmacological or genetic inhibition of Shh signaling markedly suppresses epileptic phenotypes in kindling or pilocarpine models. Our results suggest that Shh contributes to the development of epilepsy and suppression of its signaling prevents the development of the disease. Thus, Shh can act as a modulator of neuronal activity, rapidly regulating glutamate levels and promoting epilepsy.

Correction to: Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China.

The original version of this article unfortunately contained an error.

Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China.

PURPOSE: Neural tube defects (NTDs) are one of the most prevalent and the most severe congenital malformations worldwide. Studies have confirmed that folic acid supplementation could effectively reduce NTDs risk, but the genetic mechanism remains unclear. In this study, we explored association of single nucleotide polymorphisms (SNP) within folate metabolic pathway genes with NTDs in Han population of Northern China. METHODS: We performed a case-control study to compare genotype and allele distributions of SNPs in 152 patients with NTDs and 169 controls. A total of 16 SNPs within five genes were genotyped by the Sequenom MassARRAY assay. RESULTS: Our results indicated that three SNPs associated significantly with NTDs (P<0.05). For rs2236225 within MTHFD1, children with allele A or genotype AA had a high NTDs risk (OR=1.500, 95%CI=1.061~2.120; OR=2.862, 95%CI=1.022~8.015, respectively). For rs1801133 within MTHFR, NTDs risk markedly increased in patients with allele T or genotype TT (OR=1.552, 95%CI=1.130~2.131; OR=2.344, 95%CI=1.233~4.457, respectively). For rs1801394 within MTRR, children carrying allele G and genotype GG had a higher NTDs risk (OR=1.533, 95%CI=1.102~2.188; OR=2.355, 95%CI=1.044~5.312, respectively). CONCLUSIONS: Our results suggest that rs2236225 of MTHFD1 gene, rs1801133 of MTHFR gene and rs1801394 of MTRR gene were associated with NTDs in Han population of Northern China.

Association of neural tube defects with gene polymorphisms in one-carbon metabolic pathway.

PURPOSE: Neural tube defects (NTDs) are common congenital malformations. In this study, we aimed to explore the association between single nucleotide polymorphisms (SNPs) related to one-carbon metabolism (OCM) and NTDs in Han population of Northern China. METHODS: A case-control study was conducted in 152 children with NTDs and 169 controls. Twenty-nine SNPs in five genes were genotyped by Sequenom MassARRAY technology, and haplotype analysis was done by Haploview4.2 software. RESULTS: The allele frequency of rs3733890 in betaine-homocysteine methyltransferase (BHMT) gene was statistically different between NTDs and control groups (P = 0.041), and the children with A allele had higher risk for NTDs than G allele (OR = 1.408, 95%CI 1.013-1.956). In addition, there was a statistical difference in the allele and genotype frequencies of rs1051266 in reduced folate carrier1 (RFC1) gene between cases and controls (P = 0.013, 0.034), and the risk for NTDs was also higher in children with G allele and GG genotype, compared with A allele and AA genotype, respectively (OR = 1.492, 95%CI 1.089-2.044; OR = 2.020, 95%CI 1.081-3.780). The statistical significant difference was also found in allele frequency of rs1805087 in methionine synthetase (MTR) gene between cases and controls (P = 0.031), and the children with G allele were associated with an increased NTDs risk, compared with A allele (OR = 1.664, 95%CI 1.045-2.647). Meanwhile, haplotype analysis showed C-A-A-A haplotype of BHMT, and G-G-G-T haplotype of RFC1 was correlated with an increased risk of NTDs, but C-G-A-A haplotype of BHMT and G-G-C-A haplotype of MTR might decrease the risk of NTDs. CONCLUSIONS: The BHMT gene rs3733890, RFC1 gene rs1051266 and MTR gene rs1805087 were associated with the occurrence of NTDs in Han population of Northern China. It was confirmed that the gene variation related to OCM was one of the susceptibility factors for NTDs.

A dual inhibition: microRNA-552 suppresses both transcription and translation of cytochrome P450 2E1.

MicroRNAs (miRNAs) can direct post-transcriptional or transcriptional gene silencing. Here, we report that miR-552 is in the nucleus and cytosol and inhibits human cytochrome P450 (CYP) 2E1 expression at both transcriptional and post-transcriptional levels. MiR-552 via its non-seed sequence forms hybrids with a loop hairpin of the cruciform structure in CYP2E1 promoter region to inhibit SMARCE1 and RNA polymerase II binding to the promoter and CYP2E1 transcription. Expressing SMARCE1 reverses the inhibitory effects of miR-552 on CYP2E1 mRNA expression. MiR-552 with mutations in non-seed region losses its transcriptional, but retains its post-transcriptional repression to CYP2E1. In contrast, mutation in miR-552 seed sequence suppresses its inhibitory effects on CYP2E1 expression at protein, but not at mRNA, levels. Our results suggest that miR-552 is a miRNA with a dual inhibitory ability at transcriptional and post-transcriptional levels leading to an effective inhibition.

Downregulation of miR-7116-5p in microglia by MPP+ sensitizes TNF-α production to induce dopaminergic neuron damage.

Activation of microglia resulting in exacerbated inflammation expression plays an important role in degeneration of dopaminergic (DA) neurons in the pathogenesis of Parkinson's disease (PD). However, how this enhanced inflammation is induced in microglia remains largely unclear. Here, in the mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine (MPTP), we found that miR-7116-5p in microglia has a crucial role in this inflammation. 1-methyl-4-phenylpyridinium (MPP+ ) is uptaken by microglia through organic cation transporter 3 (OCT3) to downregulate miR-7116-5p, an miRNA found to target tumor necrosis factor alpha (TNF-α). Production of TNF-α in microglia is specifically potentiated by MPP+ via downregulation of miR-7116-5p to elicit subsequent inflammatory responses. Furthermore, enhancement of miR-7116-5p expression in microglia in mice inhibits the production of TNF-α and the activation of glia, and further prevents loss of DA neurons. Together, our studies suggest that MPP+ suppresses miR-7116-5p level in microglia and potentiates TNF-α production and inflammatory responses to contribute to DA neuron damage.

TRPC6 expression in neurons is differentially regulated by NR2A- and NR2B-containing NMDA receptors.

The expression of transient receptor potential canonical 6 (TRPC6) in central nervous system (CNS) is important for neuronal functions and certain neural disorders. However, the regulatory mechanism of TRPC6 expression in neurons is still obscure. In this study, we show that TRPC6 expression in the primary cultured cortical neurons is bidirectionally regulated by glutamate. Activation of NR2A-containing NMDARs induces TRPC6 transcription through a calcineurin-dependent pathway. In contrast, activation of NR2B-containing NMDARs causes TRPC6 degradation through calpain. Thus, TRPC6 expression in neurons is regulated by glutamate in a bidirectional manner that is dependent on NR2A and NR2B.