The Super-Cooling Agent Icilin Reveals a Mechanism of Coincidence Detection by a Temperature-Sensitive TRP Channel

AbstractTRPM8, a member of the transient receptor potential family of ion channels, depolarizes somatosensory neurons in response to cold. TRPM8 is also activated by the cooling agents menthol and icilin. When exposed to menthol or cold, TRPM8 behaves like many ligand-gated channels, exhibiting rapid activation followed by moderate Ca2+-dependent adaptation. In contrast, icilin activates TRPM8 with extremely variable latency followed by extensive desensitization, provided that calcium is present. Here, we show that, to achieve full efficacy, icilin requires simultaneous elevation of cytosolic Ca2+, either via permeation through TRPM8 channels or by release from intracellular stores. Thus, two stimuli must be paired to elicit full channel activation, illustrating the potential for coincidence detection by TRP channels. Determinants of icilin sensitivity map to a region of TRPM8 that corresponds to the capsaicin binding site on the noxious heat receptor TRPV1, suggesting a conserved molecular logic for gating of these thermosensitive channels by chemical agonists

A single TRPV1 amino acid controls species sensitivity to capsaicin.

Chili peppers produce capsaicin (a vanilloid) that activates the transient receptor potential cation channel subfamily V member 1 (TRPV1) on sensory neurons to alter their membrane potential and induce pain. To identify residues responsible for differential TRPV1 capsaicin sensitivity among species, we used intracellular Ca2+ imaging to characterize chimeras composed of capsaicin-sensitive rat TRPV1 (rTRPV1) and capsaicin-insensitive chicken TRPV1 (cTRPV1) exposed to a series of capsaicinoids. We found that chimeras containing rat E570-V686 swapped into chicken receptors displayed capsaicin sensitivity, and that simply changing the alanine at position 578 in the S4-S5 helix of the chicken receptor to a glutamic acid was sufficient to endow it with capsaicin sensitivity in the micromolar range. Moreover, introduction of lysine, glutamine or proline at residue A578 also elicited capsaicin sensitivity in cTRPV1. Similarly, replacing corresponding rTRPV1 residue E570 with lysine or glutamine retained capsaicin sensitivity. The hydrophilic capsaicin analog Cap-EA activated a cTRPV1-A578E mutant, suggesting that A578 may participate in vanilloid binding. The hydrophilic vanilloid agonist zingerone did not activate any A578 mutants with capsaicin sensitivity, suggesting that the vanilloid group alone is not sufficient for receptor activation. Our study demonstrates that a subtle modification of TRPV1 in different species globally alters capsaicin responses

Regulation of IRK3 Inward RectifierK+ Channel by m1 Acetylcholine Receptorand Intracellular Magnesium

AbstractInward rectifier K+ channels control the cell's membrane potential and neuronal excitability. We report that the IRK3 but not the IRK1 inward rectifier K+ channel activity is inhibited by m1 muscarinic acetylcholine receptor. This m1 modulation cannot be accounted for by protein kinase C, Ca2+, or channel phosphorylation, but can be mimicked by Mg2+. Based on quantitative analyses of IRK3 and two different IRK1 mutant channels bestowed with sensitivity to m1 modulation, we suggest that the resting Mg2+ level causes chronic inhibition of IRK3 channels, and m1 receptor stimulation may lead to an increase of cytoplasmic Mg2+ concentration and further channel inhibition, due to the ability of Mg2+ to lead these channels into a prolonged inactivated state

A Geometrically Constrained Point Matching based on View-invariant Cross-ratios, and Homography

In computer vision, finding point correspondence among images plays an important role in many applications, such as image stitching, image retrieval, visual localization, etc. Most of the research worksfocus on the matching of local feature before a sampling method is employed, such as RANSAC, to verify initial matching results via repeated fitting of certain global transformation among the images. However, incorrect matches may still exist, while careful examination of such problems is often skipped. Accordingly, a geometrically constrained algorithm is proposed in this work to verify the correctness of initially matched SIFT keypoints based on view-invariant cross-ratios (CRs). By randomly forming pentagons from these keypoints and matching their shape and location among images with CRs, robust planar region estimation can be achieved efficiently for the above verification, while correct and incorrect matches of keypoints can be examined easily with respect to those shape and location matched pentagons. Experimental results show that satisfactory results can be obtained for various scenes with single as well as multiple planar regions

Polymicrobial bloodstream infection involving Aeromonas species: Analysis of 62 cases

AbstractObjectiveTo better understand Aeromonas-involved polymicrobial bacteremia (AIPMB).Materials and MethodsWe conducted a retrospective analysis of patients with AIPMB admitted to three large referral hospitals in Taiwan between 2001 and 2008.ResultsOf a total of 62 patients with AIPMB, 22 had healthcare-associated infection and 40 had community-acquired infection. Enterobacteriaceae was the most common concurrent pathogen (82%). The leading underlying diseases/conditions in the affected patients were solid cancers (45%), recent gastric acid suppressant therapy (39%) and liver cirrhosis (26%). More than 95% of the Aeromonas isolates were susceptible to an aminoglycoside, a third- or fourth-generation cephalosporin, imipenem or ciprofloxacin. Antibiotic susceptibilities did not significantly differ between Aeromonas isolates in patients with healthcare-associated AIPMBs and those in patients with community-acquired AIPMBs. Coinfection with Enterobacteriaceae occurred more commonly in community-acquired AIPMB (93% vs. 64%; p=0.012).ConclusionsAIPMB occurred commonly in patients with liver cirrhosis, solid cancers or recent gastric acid suppressant therapy. Enterobacteriaceae were the most common concurrent pathogens. Similar antibiotic profiles were found in Aeromonas isolates of healthcare-associated and community-acquired AIPMBs

Glycogen synthase kinase 3α and 3β have distinct functions during cardiogenesis of zebrafish embryo

<p>Abstract</p> <p>Background</p> <p>Glycogen synthase kinase 3 (GSK3) encodes a serine/threonine protein kinase, is known to play roles in many biological processes. Two closely related GSK3 isoforms encoded by distinct genes: GSK3α (51 kDa) and GSK3β (47 kDa). In previously studies, most GSK3 inhibitors are not only inhibiting GSK3, but are also affecting many other kinases. In addition, because of highly similarity in amino acid sequence between GSK3α and GSK3β, making it difficult to identify an inhibitor that can be selective against GSK3α or GSK3β. Thus, it is relatively difficult to address the functions of GSK3 isoforms during embryogenesis. At this study, we attempt to specifically inhibit either GSK3α or GSK3β and uncover the isoform-specific roles that GSK3 plays during cardiogenesis.</p> <p>Results</p> <p>We blocked <it>gsk3α </it>and <it>gsk3β </it>translations by injection of morpholino antisense oligonucleotides (MO). Both <it>gsk3α</it>- and <it>gsk3β</it>-MO-injected embryos displayed similar morphological defects, with a thin, string-like shaped heart and pericardial edema at 72 hours post-fertilization. However, when detailed analysis of the <it>gsk3α</it>- and <it>gsk3β</it>-MO-induced heart defects, we found that the reduced number of cardiomyocytes in <it>gsk3α </it>morphants during the heart-ring stage was due to apoptosis. On the contrary, <it>gsk3β </it>morphants did not exhibit significant apoptosis in the cardiomyocytes, and the heart developed normally during the heart-ring stage. Later, however, the heart positioning was severely disrupted in <it>gsk3β </it>morphants. <it>bmp4 </it>expression in <it>gsk3β </it>morphants was up-regulated and disrupted the asymmetry pattern in the heart. The cardiac valve defects in <it>gsk3β </it>morphants were similar to those observed in <it>axin1 </it>and <it>apc</it>^{<it>mcr </it>}mutants, suggesting that GSK3β might play a role in cardiac valve development through the Wnt/β-catenin pathway. Finally, the phenotypes of <it>gsk3α </it>mutant embryos cannot be rescued by <it>gsk3β </it>mRNA, and vice versa, demonstrating that GSK3α and GSK3β are not functionally redundant.</p> <p>Conclusion</p> <p>We conclude that (1) GSK3α, but not GSK3β, is necessary in cardiomyocyte survival; (2) the GSK3β plays important roles in modulating the left-right asymmetry and affecting heart positioning; and (3) GSK3α and GSK3β play distinct roles during zebrafish cardiogenesis.</p

SICA-mediated cytoadhesion of Plasmodium knowlesi-infected red blood cells to human umbilical vein endothelial cells

Zoonotic malaria due to Plasmodium knowlesi infection in Southeast Asia is sometimes life-threatening. Post-mortem examination of human knowlesi malaria cases showed sequestration of P. knowlesi-infected red blood cells (iRBCs) in blood vessels, which has been proposed to be linked to disease severity. This sequestration is likely mediated by the cytoadhesion of parasite-iRBCs to vascular endothelial cells; however, the responsible parasite ligands remain undetermined. This study selected P. knowlesi lines with increased iRBC cytoadhesion activity by repeated panning against human umbilical vein endothelial cells (HUVECs). Transcriptome analysis revealed that the transcript level of one gene, encoding a Schizont Infected Cell Agglutination (SICA) protein, herein termed SICA-HUVEC, was more than 100-fold increased after the panning. Transcripts of other P. knowlesi proteins were also significantly increased, such as PIR proteins exported to the iRBC cytosol, suggesting their potential role in increasing cytoadhesion activity. Transgenic P. knowlesi parasites expressing Myc-fused SICA-HUVEC increased cytoadhesion activity following infection of monkey as well as human RBCs, confirming that SICA-HUVEC conveys activity to bind to HUVECs