Targeting Acid-Sensing Ion Channels by Peptide Toxins

Acid-sensing ion channels (ASICs) are proton-gated ion channels that are highly expressed in the nervous system and play important roles in physiological and pathological conditions. They are also expressed in non-neuronal tissues with different functions. The ASICs rapidly respond to a reduction in extracellular pH with an inward current that is quickly inactivated despite the continuous presence of protons. Recently, protons have been identified as neurotransmitters in the brain. Until now, six different isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) in rodents have been discovered and they can be assembled into homotrimers or heterotrimers to form an ion channel. Peptide toxins targeting ASICs have been found from the venoms of spider Psalmotoxin-1 (PcTx1), sea anemones (APETx2 and PhcrTx1) and snakes (MitTx and mambalgins). They reveal different pharmacological properties and are selective blockers of ASICs, except for MitTx, which is a potent activator of ASICs. In this mini review, the structure, pharmacology and effects of peptide toxins on ASICs will be introduced and their therapeutic potentials for neurological and psychological diseases will be discussed

The LAMOST Survey of Background Quasars in the Vicinity of the Andromeda and Triangulum Galaxies -- II. Results from the Commissioning Observations and the Pilot Surveys

We present new quasars discovered in the vicinity of the Andromeda and Triangulum galaxies with the LAMOST during the 2010 and 2011 observational seasons. Quasar candidates are selected based on the available SDSS, KPNO 4 m telescope, XSTPS optical, and WISE near infrared photometric data. We present 509 new quasars discovered in a stripe of ~135 sq. deg from M31 to M33 along the Giant Stellar Stream in the 2011 pilot survey datasets, and also 17 new quasars discovered in an area of ~100 sq. deg that covers the central region and the southeastern halo of M31 in the 2010 commissioning datasets. These 526 new quasars have i magnitudes ranging from 15.5 to 20.0, redshifts from 0.1 to 3.2. They represent a significant increase of the number of identified quasars in the vicinity of M31 and M33. There are now 26, 62 and 139 known quasars in this region of the sky with i magnitudes brighter than 17.0, 17.5 and 18.0 respectively, of which 5, 20 and 75 are newly-discovered. These bright quasars provide an invaluable collection with which to probe the kinematics and chemistry of the ISM/IGM in the Local Group of galaxies. A total of 93 quasars are now known with locations within 2.5 deg of M31, of which 73 are newly discovered. Tens of quasars are now known to be located behind the Giant Stellar Stream, and hundreds behind the extended halo and its associated substructures of M31. The much enlarged sample of known quasars in the vicinity of M31 and M33 can potentially be utilized to construct a perfect astrometric reference frame to measure the minute PMs of M31 and M33, along with the PMs of substructures associated with the Local Group of galaxies. Those PMs are some of the most fundamental properties of the Local Group.Comment: 26 pages, 6 figures, AJ accepte

Genomewide association study of leprosy.

BACKGROUND: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS: We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS: We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS: Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae

Modulation of Ionotropic Glutamate Receptors and Acid-Sensing Ion Channels by Nitric Oxide

Ionotropic glutamate receptors (iGluR) are ligand-gated ion channels and are densely expressed in broad areas of mammalian brains. Like iGluRs, acid-sensing ion channels (ASIC) are ligand (H+)-gated channels and are enriched in brain cells and peripheral sensory neurons. Both ion channels are enriched at excitatory synaptic sites, functionally coupled to each other, and subject to the modulation by a variety of signaling molecules. Central among them is a gasotransmitter, nitric oxide (NO). Available data show that NO activity-dependently modulates iGluRs and ASICs via either a direct or an indirect pathway. The former involves a NO-based and cGMP-independent post-translational modification (S-nitrosylation) of extracellular cysteine residues in channel subunits or channel-interacting proteins. The latter is achieved by NO activation of soluble guanylyl cyclase, which in turn triggers an intracellular cGMP-sensitive cascade to indirectly modulate iGluRs and ASICs. The NO modification is usually dynamic and reversible. Modified channels undergo significant, interrelated changes in biochemistry and electrophysiology. Since NO synthesis is enhanced in various neurological disorders, the NO modulation of iGluRs and ASICs is believed to be directly linked to the pathogenesis of these disorders. This review summarizes the direct and indirect modifications of iGluRs and ASICs by NO and analyzes the role of the NO-iGluR and NO-ASIC coupling in cell signaling and in the pathogenesis of certain related neurological diseases

Genetic diversity and population structure of Kudouzi (Sophora alopecuroides) in Northwest China revealed by SNP markers and seed phenotypic traits

IntroductionSophora alopecuroides L., a perennial leguminous herb native to northwest China, holds medicinal, ecological, and forage value. However, intensified human activities have caused a sharp decline in its wild populations and genetic diversity.MethodsTo assess its genetic structure and diversity, we analyzed 65 wild populations using SNP markers and seed phenotypic traits.ResultsThe coefficient of variation for eight seed traits ranged from 2.87% to 7.94%, with diversity indices (H) from 1.639 to 1.767, indicating rich phenotypic variation. Clustering based on phenotypic traits and SNP data both divided populations into two main groups. Genetic diversity was relatively low (He = 0.22; Ho = 0.17; Pi = 0.19), and AMOVA showed that variation was mainly among individuals (132.83%), with low population differentiation (FST = 0.00-0.04). Redundancy analysis revealed that phenotypic traits were largely influenced by mean temperature of the driest quarter and annual wind speed, while genetic diversity was shaped by precipitation and thermal variables.ConclusionsOur results provide a foundation for understanding the genetic variation of S. alopecuroides, offering valuable insights for its conservation and breeding programs