Glycine receptor in rat hippocampal and spinal cord neurons as a molecular target for rapid actions of 17-β-estradiol

Glycine receptors (GlyRs) play important roles in regulating hippocampal neural network activity and spinal nociception. Here we show that, in cultured rat hippocampal (HIP) and spinal dorsal horn (SDH) neurons, 17-β-estradiol (E2) rapidly and reversibly reduced the peak amplitude of whole-cell glycine-activated currents (IGly). In outside-out membrane patches from HIP neurons devoid of nuclei, E2 similarly inhibited IGly, suggesting a non-genomic characteristic. Moreover, the E2 effect on IGly persisted in the presence of the calcium chelator BAPTA, the protein kinase inhibitor staurosporine, the classical ER (i.e. ERα and ERβ) antagonist tamoxifen, or the G-protein modulators, favoring a direct action of E2 on GlyRs. In HEK293 cells expressing various combinations of GlyR subunits, E2 only affected the IGly in cells expressing α2, α2β or α3β subunits, suggesting that either α2-containing or α3β-GlyRs mediate the E2 effect observed in neurons. Furthermore, E2 inhibited the GlyR-mediated tonic current in pyramidal neurons of HIP CA1 region, where abundant GlyR α2 subunit is expressed. We suggest that the neuronal GlyR is a novel molecular target of E2 which directly inhibits the function of GlyRs in the HIP and SDH regions. This finding may shed new light on premenstrual dysphoric disorder and the gender differences in pain sensation at the CNS level

Exploring 4D Quantum Hall Physics with a 2D Topological Charge Pump

The discovery of topological states of matter has profoundly augmented our understanding of phase transitions in physical systems. Instead of local order parameters, topological phases are described by global topological invariants and are therefore robust against perturbations. A prominent example thereof is the two-dimensional integer quantum Hall effect. It is characterized by the first Chern number which manifests in the quantized Hall response induced by an external electric field. Generalizing the quantum Hall effect to four-dimensional systems leads to the appearance of a novel non-linear Hall response that is quantized as well, but described by a 4D topological invariant - the second Chern number. Here, we report on the first observation of a bulk response with intrinsic 4D topology and the measurement of the associated second Chern number. By implementing a 2D topological charge pump with ultracold bosonic atoms in an angled optical superlattice, we realize a dynamical version of the 4D integer quantum Hall effect. Using a small atom cloud as a local probe, we fully characterize the non-linear response of the system by in-situ imaging and site-resolved band mapping. Our findings pave the way to experimentally probe higher-dimensional quantum Hall systems, where new topological phases with exotic excitations are predicted

Catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl compounds to nitroalkenes by a grinding method

Abstract An environmentally benign, fast and convenient protocol has been developed for the Michael addition of 1,3-dicarbonyl compounds to β-nitroalkenes in good to excellent yields by a grinding method under catalyst-and solvent-free conditions. 53

Biophysical and electrochemical studies of protein-nucleic acid interactions

This review is devoted to biophysical and electrochemical methods used for studying protein-nucleic acid (NA) interactions. The importance of NA structure and protein-NA recognition for essential cellular processes, such as replication or transcription, is discussed to provide background for description of a range of biophysical chemistry methods that are applied to study a wide scope of protein-DNA and protein-RNA complexes. These techniques employ different detection principles with specific advantages and limitations and are often combined as mutually complementary approaches to provide a complete description of the interactions. Electrochemical methods have proven to be of great utility in such studies because they provide sensitive measurements and can be combined with other approaches that facilitate the protein-NA interactions. Recent applications of electrochemical methods in studies of protein-NA interactions are discussed in detail

TFPI-2 is a putative tumor suppressor gene frequently inactivated by promoter hypermethylation in nasopharyngeal carcinoma

<p>Abstract</p> <p>Background</p> <p>Epigenetic silencing of tumor suppressor genes play important roles in NPC tumorgenesis. Tissue factor pathway inhibitor-2 (TFPI-2), is a protease inhibitor. Recently, <it>TFPI-2 </it>was suggested to be a tumor suppressor gene involved in tumorigenesis and metastasis in some cancers. In this study, we investigated whether <it>TFPI-2 </it>was inactivated epigenetically in nasopharyngeal carcinoma (NPC).</p> <p>Methods</p> <p>Transcriptional expression levels of <it>TFPI-2 </it>was evaluated by RT-PCR. Methylation status were investigated by methylation specific PCR and bisulfate genomic sequencing. The role of <it>TFPI-2 </it>as a tumor suppressor gene in NPC was addressed by re-introducing <it>TFPI-2 </it>expression into the NPC cell line CNE2.</p> <p>Results</p> <p><it>TFPI-2 </it>mRNA transcription was inactivated in NPC cell lines. <it>TFPI-2 </it>was aberrantly methylated in 66.7% (4/6) NPC cell lines and 88.6% (62/70) of NPC primary tumors, but not in normal nasopharyngeal epithelia. <it>TFPI-2 </it>expression could be restored in NPC cells after demethylation treatment. Ectopic expression of TFPI-2 in NPC cells induced apoptosis and inhibited cell proliferation, colony formation and cell migration.</p> <p>Conclusions</p> <p>Epigenetic inactivation of <it>TFPI-2 </it>by promoter hypermethylation is a frequent and tumor specific event in NPC. <it>TFPI-2 </it>might be considering as a putative tumor suppressor gene in NPC.</p

Association between the Cytotoxic T-Lymphocyte Antigen 4 +49G > A polymorphism and cancer risk: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>As a key gene in the immunosurveillance of cell malignancy, Cytotoxic T-lymphocyte antigen 4 (CTLA-4 is an important negative regulator of T cell activation and proliferation. The CTLA-4 +49G > A polymorphism is one of the most commonly studied polymorphisms in this gene due to its association with cancer risks, but previous results have been conflicting.</p> <p>Methods</p> <p>We preformed a meta-analysis using 22 eligible case-control studies (including 32 datasets) with a total of 11,273 patients and 13,179 controls to summarize the existing data on the association between the <it>CTLA-4 </it>+49G > A polymorphism and cancer risk.</p> <p>Results</p> <p>Compared with the common <it>CTLA-4 </it>+49G > A GG genotype, the carriers of variant genotypes (<it>CTLA-4 </it>+49 GC/CC) had a 1.24-fold elevated risk of cancer (95% CI = 1.18-1.32, <it>P </it>< 0.05) under the dominant genetic model, as estimated using a fixed effect model. The effect of the <it>CTLA-4 </it>+49G > A polymorphism was further evaluated using stratification analysis. In four breast cancer studies, patients with the variant genotypes had a significantly increased risk of breast cancer (OR = 1.31, 95% CI = 1.17-1.48, <it>P </it>< 0.00001). A similar result was found in three skin cancer studies (OR = 1.30, 95% CI = 1.10-1.52, <it>P </it>= 0.001). In 26 solid tumor studies, subjects with the variant genotypes had a significantly higher risk of developing solid tumors (OR = 1.25, 95% CI = 1.18-1.33, <it>P </it>< 0.00001) compared with the 6 non-solid tumor studies (OR = 1.08, 95% CI = 0.79-1.48, <it>P </it>= 0.62). Patients with variant genotypes had significantly increased risk of non-epithelial tumors and epithelial tumors, with ORs of 1.23 (95% CI = 1.14-1.32, <it>P </it>< 0.00001) and 1.29 (95% CI = 1.17-1.41, <it>P </it>< 0.00001), respectively. It was also demonstrated that the increased risk of cancer associated with <it>CTLA-4 </it>+49G > A variant genotypes was more pronounced in Caucasians (OR = 1.29, 95% CI = 1.13-1.47, <it>P </it>= 0.0002), Asians (OR = 1.23, 95% CI = 1.16-1.32, <it>P </it>< 0.00001) and Chinese (OR = 1.23, 95% CI = 1.15-1.31, <it>P </it>< 0.00001).</p> <p>Conclusion</p> <p>Our meta-analysis suggests that the <it>CTLA-4 </it>+49G > A polymorphism genotypes (GA + AA) might be associated with an increased risk of cancer, especially in Caucasians and Chinese.</p

Analysis of Aurora kinase A expression in CD34+ blast cells isolated from patients with myelodysplastic syndromes and acute myeloid leukemia

Aurora kinase A, also known as aurora A, is a serine/threonine kinase that plays critical roles in mitosis entry, chromosome alignment, segregation, and cytokinesis. Overexpression of aurora A has been observed in many solid tumors and some hematopoietic neoplasms, but little is known about its expression in myeloid diseases. Because cytogenetic abnormalities play an essential role in the pathogenesis of myeloid malignancies, we hypothesized that aurora A deregulation may be involved in myelodysplastic syndromes and acute myeloid leukemia and contribute to the chromosomal instability observed in these diseases. We assessed aurora A mRNA levels in CD34+ bone marrow blasts from nine patients with acute myeloid leukemia, 20 patients with myelodysplastic syndromes, and five normal patients serving as controls. CD34+ blasts were isolated from bone marrow aspirate specimens using magnetic activated cell separation technology. RNA was extracted from purified CD34+ cells, and quantitative real-time reverse transcriptase polymerase chain reaction for aurora A was performed. Immunocytochemical analyses for total aurora A, phosphorylated aurora A, Ki-67, and activated caspase 3 were performed on cytospin slides made from purified CD34+ cells in myelodysplastic syndrome patients using standard methods. Aurora A mRNA and protein levels were correlated, as was aurora A mRNA level, with blast counts, cytogenetic abnormalities, and International Prognostic Scoring System score. We found that CD34+ cells in myelodysplastic syndromes and acute myeloid leukemia expressed aurora A at significantly higher levels (P = 0.01 and P = 0.01, respectively) than normal CD34+ cells. Aurora A mRNA levels correlated with total and phosphorylated protein levels (P = 0.0002 and P = 0.02, respectively). No significant correlation was found between aurora A mRNA level and blast count, blast viability, cytogenetic abnormalities, or the International Prognostic Scoring System score in patients with myelodysplastic syndromes. We conclude that aurora A is up-regulated in CD34+ blasts from myeloid neoplasms

Monoclonal antibody induced with inactived EV71-Hn2 virus protects mice against lethal EV71-Hn2 virus infection

<p>Abstract</p> <p>Background</p> <p>Enterovirus 71 (EV71) is a viral pathogen that belongs to the <it>Picornaviridae </it>family, EV71-infected children can develop severe neurological complications leading to rapid clinical deterioration and death.</p> <p>Results</p> <p>In this study, several monoclonal antibodies (MAbs) were produced by immunizing mice with the inactived EV71 Henan (Hn2) virus strain. The isolated MAbs were characterised by <it>in vitro </it>neutralizing analysis and peptide ELISA. ELISA assay showed that the neutralizing monoclonal antibody 4E8 specifically reacted with synthetic peptides which contain amino acid 240-250 and 250-260 of EV71 VP1. The <it>in vivo </it>protection assay showed that 4E8 can protect two-day-old BALB/c mice against the lethal challenge of EV71 virus.</p> <p>Conclusion</p> <p>The MAb 4E8 could be a promising candidate to be humanized and used for treatment of EV71 infection.</p