Pathologically Activated Neuroprotection via Uncompetitive Blockade of \u3cem\u3eN\u3c/em\u3e-Methyl-d-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin

Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and γ-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [3H]MK-801 with a Ki value of 0.27 μm, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation

MicroRNA-214 Protects Against Hypoxia/Reoxygenation Induced Cell Damage and Myocardial Ischemia/Reperfusion Injury via Suppression of PTEN and Bim1 Expression

Background: Myocardial apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Activation of PI3K/Akt signaling protects the myocardium from I/R injury. This study investigated the role of miR-214 in hypoxia/ reoxygenation (H/R)-induced cell damage in vitro and myocardial I/R injury in vivo. Methods and Results: H9C2 cardiomyoblasts were transfected with lentivirus expressing miR-214 (LmiR-214) or lentivirus expressing scrambled miR-control (LmiR-control) respectively, to establish cell lines of LmiR-214 and LmiR-control. The cells were subjected to hypoxia for 4 h followed by reoxygenation for 24 h. Transfection of LmiR-214 suppresses PTEN expression, significantly increases the levels of Akt phosphorylation, markedly attenuates LDH release, and enhances the viability of the cells subjected to H/R. In vivo transfection of mouse hearts with LmiR-214 significantly attenuates I/R induced cardiac dysfunction and reduces I/Rinduced myocardial infarct size. LmiR-214 transfection significantly attenuates I/Rinduced myocardial apoptosis and caspase-3/7 and caspase-8 activity. Increased expression of miR-214 by transfection of LmiR-214 suppresses PTEN expression, increases the levels of phosphorylated Akt, represses Bim1 expression and induces Bad phosphorylation in the myocardium. In addition, in vitro data shows transfection of miR-214 mimics to H9C2 cells suppresses the expression and translocation of Bim1 from cytosol to mitochondria and induces Bad phosphorylation. Conclusions: Our in vitro and in vivo data suggests that miR-214 protects cells from H/R induced damage and attenuates I/R induced myocardial injury. The mechanisms involve activation of PI3K/Akt signaling by targeting PTEN expression, induction of Bad phosphorylation, and suppression of Bim1 expression, resulting in decreases in I/R-induced myocardial apoptosis

Study on the correlation between pre-treatment Glasgow score and blood inflammatory markers and prognosis of nasopharyngeal carcinoma patients

Objective To investigate the correlation between Glasgow score and blood inflammatory markers before treatment with the efficacy of nasopharyngeal carcinoma. Methods Cases from the two clinical centers were divided into training set and validation set， and the clinical characteristics of the two groups were compared to be balanced. To search the independent prognostic risk factors of nasopharyngeal carcinoma and then the prognostic index of each patient was calculated， and the patients were divided into high-risk， intermediate-risk and low-risk groups. Further validation in the validation set. Results Cox multivariate analysis of the training set showed that age >50， T3-T4， N2-N3， GPS score of 1-2， NLR>2.5， and LMR≤2.35 before treatment were poor prognostic factors affecting the 5-year disease-specific survival rate of patients with nasopharyngeal carcinoma. Conclusion The combination of GPS， NLR， LMR and age， TNM staging may provide a new way for the prognosis evaluation of patients with nasopharyngeal carcinoma before treatment

Properties and structural features of iron doped BABAL glasses

Temporal-Spatial of dengue virus (DENV) analyses have been performed in previous epidemiological studies in mainland China, but few studies have examined the whole genome of the DENV. Herein, 40 whole genome sequences of DENVs isolated from mainland China were downloaded from GenBank. Phylogenetic analyses and evolutionary distances of the dengue serotypes 1 and 2 were calculated using 14 maximum likelihood trees created from individual genes and whole genome. Amino acid variations were also analyzed in the 40 sequences that included dengue serotypes 1, 2, 3 and 4, and they were grouped according to temporal and spatial differences. The results showed that none of the phylogenetic trees created from each individual gene were similar to the trees created using the complete genome and the evolutionary distances were variable with each individual gene. The number of amino acid variations was significantly different (p = 0.015) between DENV-1 and DENV-2 after 2001; seven mutations, the N290D, L402F and A473T mutations in the E gene region and the R101K, G105R, D340E and L349M mutations in the NS1 region of DENV-1, had significant substitutions, compared to the amino acids of DENV-2. Based on the spatial distribution using Guangzhou, including Foshan, as the indigenous area and the other regions as expanding areas, significant differences in the number of amino acid variations in the NS3 (p = 0.03) and NS1 (p = 0.024) regions and the NS2B (p = 0.016) and NS3 (p = 0.042) regions were found in DENV-1 and DENV-2. Recombination analysis showed no inter-serotype recombination events between the DENV-1 and DENV-2, while six and seven breakpoints were found in DENV-1 and DENV-2. Conclusively, the individual genes might not be suitable to analyze the evolution and selection pressure isolated in mainland China; the mutations in the amino acid residues in the E, NS1 and NS3 regions may play important roles in DENV-1 and DENV-2 epidemics

Validation of a Disability Assessment Tool Based on the International Classification of Functioning, Disability, and Health in the Chinese Context

Background:The common standards of disability assessment for long-term care (LTC) insurance are currently absent. The International Classification of Functioning, Disability and Health (ICF) was designed for a better description of health and functioning, which could fill the demand gap for the standards of disability assessment and be a promising tool for the development of LTC insurance system.ObjectivesTo validate a disability assessment scale for disabled elderly individuals based on the ICF for LTC in the Chinese context.MethodsThe present study is a cross-sectional study. A disability assessment tool based on the ICF was developed by referring to other assessment tools and an expert consensus meeting in the initial phase of the study. The developed tool was used to evaluate 1,610 elderly individuals in the LTC institutions. The Cronbach's α coefficient and split-half reliability were applied to test the internal consistency of the tool, while the Interclass correlation coefficients (ICCs) were used to evaluate the interrater reliability (IRR). Factor analysis was performed to verify the construct validity of the tool. The scores from the Medical Outcomes Short Form-12 (SF-12) were correlated with that from the disability assessment tool, to assess the criterion-related validity.ResultsThe Cronbach's α coefficient and split-half reliability of the disability assessment tool were 0.969 and 0.877, respectively. The ICCs of the sum scale was 0.85, and the ICCs of each of the 20 items in the scale ranged from 0.78 to 0.94. The items were divided into three factors through analysis, which is consistent with the structure expectation. The scores of each item and the sum score of the disability assessment scale were negatively correlated with the scores of the physical and psychological fields in SF-12 (p < 0.001). Overall, the data indicated that the tool was characterized by good internal consistency, IRR, construct validity, and criterion-related validity.ConclusionsThe disability assessment tool based on the ICF is a reliable and valid tool for the collection of information on functioning across various LTC settings. The information of disability provided evidence for the distribution of LTC service and guided the development of LTC insurance standards

All-Trans Retinoic Acid Promotes TGF-β-Induced Tregs via Histone Modification but Not DNA Demethylation on Foxp3 Gene Locus

It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4(+)Foxp3(+) regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs.Addition of atRA to naïve CD4(+)CD25(-) cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+) iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+) cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+) cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+) cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+) cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered.We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation

Peregrine and saker falcon genome sequences provide insights into evolution of a predatory lifestyle

As top predators, falcons possess unique morphological, physiological and behavioral adaptations that allow them to be successful hunters: for example, the peregrine is renowned as the world's fastest animal. To examine the evolutionary basis of predatory adaptations, we sequenced the genomes of both the peregrine (Falco peregrinus) and saker falcon (Falco cherrug), and we present parallel, genome-wide evidence for evolutionary innovation and selection for a predatory lifestyle. The genomes, assembled using Illumina deep sequencing with greater than 100-fold coverage, are both approximately 1.2 Gb in length, with transcriptome-assisted prediction of approximately 16,200 genes for both species. Analysis of 8,424 orthologs in both falcons, chicken, zebra finch and turkey identified consistent evidence for genome-wide rapid evolution in these raptors. SNP-based inference showed contrasting recent demographic trajectories for the two falcons, and gene-based analysis highlighted falcon-specific evolutionary novelties for beak development and olfaction and specifically for homeostasis-related genes in the arid environment–adapted saker

Development of an Infectious Cell Culture System for Hepatitis C Virus Genotype 6a Clinical Isolate Using a Novel Strategy and Its Sensitivity to Direct-Acting Antivirals

Hepatitis C virus (HCV) is classified into seven major genotypes, and genotype 6 is commonly prevalent in Asia, thus reverse genetic system representing genotype 6 isolates in prevalence is required. Here, we developed an infectious clone for a Chinese HCV 6a isolate (CH6a) using a novel strategy. We determined CH6a consensus sequence from patient serum and assembled a CH6a full-length (CH6aFL) cDNA using overlapped PCR product-derived clones that shared the highest homology with the consensus. CH6aFL was non-infectious in hepatoma Huh7.5 cells. Next, we constructed recombinants containing Core-NS5A or 5′UTR-NS5A from CH6a and the remaining sequences from JFH1 (genotype 2a), and both were engineered with 7 mutations identified previously. However, they replicated inefficiently without virus spread in Huh7.5 cells. Addition of adaptive mutations from CH6a Core-NS2 recombinant, with JFH1 5′UTR and NS3-3′UTR, enhanced the viability of Core-NS5A recombinant and acquired replication-enhancing mutations. Combination of 22 mutations in CH6a recombinant with JFH1 5′UTR and 3′UTR (CH6aORF) enabled virus replication and recovered additional four mutations. Adding these four mutations, we generated two efficient recombinants containing 26 mutations (26m), CH6aORF_26m and CH6aFL_26m (designated “CH6acc”), releasing HCV of 104.3–104.5 focus-forming units (FFU)/ml in Huh7.5.1-VISI-mCherry and Huh7.5 cells. Seven newly identified mutations were important for HCV replication, assembly, and release. The CH6aORF_26m virus was inhibited in a dose- and genotype-dependent manner by direct-acting-antivirals targeting NS3/4A, NS5A, and NS5B. The CH6acc enriches the toolbox of HCV culture systems, and the strategy and mutations applied here will facilitate the culture development of other HCV isolates and related viruses

Performance Improvement on Nonorthogonal Multiple Access without CSIT

In this paper, a downlink virtual-channel-optimization nonorthogonal multiple access (VNOMA) without channel state information at the transmitter (CSIT) is proposed. The novel idea is to construct multiple complex virtual channels by jointly adjusting the amplitudes and phases to maximize the minimum Euclidean distance (MED) among the superposed constellation points. The optimal solution is derived in the absence of CSIT. Considering practical communications with finite input constellations in which symbols are uniformly distributed, we resort to the sum constellation constrained capacity (CCC) to evaluate the performance. For MED criterion, the maximum likelihood (ML) decoder is expected at the receiver. To decrease the computational cost, we propose a reduced-complexity bitwise ML (RBML) decoder. Experimental results are presented to validate the superior of our proposed scheme

Performance Optimization for Overloaded MIMO Systems with Virtual Channel Approach

In this letter, we propose a virtual channel (VC) optimization approach with a closed-loop and adaptive scheme for overloaded MIMO systems. With this approach, each input data stream goes through a VC which is generated at the transmitter; then it is transmitted to a receiver through the actual wireless channels. The VCs are concatenated with the actual wireless channels. Through VC optimization, the values of which can be adjusted to reduce the channel correlation, leading to a much improved system performance. Compared to the conventional overloaded MIMO systems, the overloaded MIMO systems with this approach can achieve significantly better performances in terms of the system capacity and symbol error rate (SER). The method that uses genetic algorithm (GA) for finding the optimal VC vector is described. Simulation results illustrate the effectiveness of the proposed approach