Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia

The vanilloid receptor-1 (VR1) is a ligand-gated, non-selective cation channel expressed predominantly by sensory neurons. VR1 responds to noxious stimuli including capsaicin, the pungent component of chilli peppers, heat and extracellular acidification, and it is able to integrate simultaneous exposure to these stimuli. These findings and research linking capsaicin with nociceptive behaviours (that is, responses to painful stimuli in animals have led to VR1 being considered as important for pain sensation. Here we have disrupted the mouse VR1 gene using standard gene targeting techniques. Small diameter dorsal root ganglion neurons isolated from VR1-null mice lacked many of the capsaicin-, acid- and heat-gated responses that have been previously well characterized in small diameter dorsal root ganglion neurons from various species. Furthermore, although the VR1-null mice appeared normal in a wide range of behavioural tests, including responses to acute noxious thermal stimuli, their ability to develop carrageenan-induced thermal hyperalgesia was completely absent. We conclude that VR1 is required for inflammatory sensitization to noxious thermal stimuli but also that alternative mechanisms are sufficient for normal sensation of noxious heat.     

Transmission distortion of t-haplotypes is due to interactions between meiotic partners

The T/t-complex of the mouse includes a series of recessive lethal and semi-lethal mutations but, despite such lethalities, mutant t-haplotypes are found in high frequency in wild mouse populations. This polymorphism is apparently maintained because heterozygous males preferentially transmit the t-bearing chromosome to their offspring. Despite many attempts to define the basis of the transmission ratio distortion, it has been unclear whether this is because t-bearing sperm have better than average fertilizing ability or whether +-bearing sperm in heterozygous males are rendered defective. To examine this point, we constructed male (XY in equilibrium XY) chimaeras containing +/+ and +/tw73 genotypes, marked respectively by albino and pigmented coat colours, and two isozyme variants. Such males produce a mixture of three different sperm types: +-bearing sperm from the +/+ genotype, +-bearing sperm from the +/t genotype, and t-bearing sperm from the +/t genotype. Appropriate matings can distinguish between these three types, and our data, reported here, show that t-bearing sperm in chimaeric mice maintain their advantage over their 'meiotic partners' but do not have any advantage over sperm from the +/+ genotype.     

Sympathetic regulation of cardiac calcium current is due exclusively to cAMP-dependent phosphorylation.

The positive inotropic effect of the sympathetic nervous system on the heart is partly mediated by an increase in the voltage-gated Ca2+ current (ICa). This increase is generally attributed to beta-adrenergic receptor-stimulated cyclic AMP-dependent phosphorylation of the Ca2+ channel. It has been suggested that cAMP-dependent phosphorylation cannot explain all the effects of beta-adrenergic agonists on ICa and that a parallel membrane-delimited pathway involving the 'direct' action of the G protein Gs also stimulates ICa. A precedent exists for such a membrane-delimited pathway in the activation of a K+ channel by acetylcholine in heart. A membrane-delimited pathway for stimulation of ICa might be important in rapid beat-to-beat regulation of contraction by the sympathetic nervous system, because isoproterenol may produce a biphasic increase in ICa with the rapid phase (tau = 150 ms) putatively mediated by the direct pathway and the slow phase (tau = 35 s) by cAMP-dependent phosphorylation. Here we report that in frog, rat, and guinea pig ventricular myocytes ICa increases slowly and monophasically in response to isoproterenol. The increase is completely blocked by inhibitors of cAMP-dependent phosphorylation. Furthermore, the time course of the increase in ICa closely parallels the increase in contractile force produced by sympathetic nerve stimulation. These data refute earlier suggestions that regulation of Ca2+ channels by the sympathetic nervous system involves or requires a direct G-protein pathway.     

Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction.

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.     

Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.

Growing axons are guided by both diffusible and substrate-bound factors. Growth cones of retinal neurons exhibit chemoattractive turning towards the diffusible factor netrin-1 in vitro and are guided into the optic nerve head (ONH) by localized netrin-1. Here we report that, in Xenopus, laminin-1 from the extracellular matrix (ECM), converts netrin-mediated attraction into repulsion. A soluble peptide fragment of laminin-1 (YIGSR) mimics this laminin-induced conversion. Low levels of cyclic AMP in growth cones also lead to the conversion of netrin-induced attraction into repulsion, and we show that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect. At the netrin-1-rich ONH, where axons turn sharply to leave the eye, laminin-1 is confined to the retinal surface. Repulsion from the region in which laminin and netrin are coexpressed may help to drive axons into the region where only netrin is present, providing a mechanism for their escape from the retinal surface. Consistent with this idea, YIGSR peptides applied to the developing retina cause axons to be misdirected at the ONH. These findings indicate that ECM molecules not only promote axon outgrowth, but also modify the behaviour of growth cones in response to diffusible guidance cues.     

The knee at cosmic ray spectra is explained due to interactions at the sources

In the paper the authors from the Key Laboratory of Particle Astrophysics, Institute of High Energy Physics, Chinese Academy of Sciences in Beijing proposed a new model trying to explain the knee at cosmic ray spectra. The knee kept as a puzzle in cosmic ray physics for nearly half a century. The work was inspired by the recent observation of anomalous excess of electrons and positrons in cosmic rays. The work tries to explain the knee and the electron/positron excess in a single model.......     

TGF-β1在不同原因致心肌纤维化中的作用

 心肌纤维化(myocardial fibrosis,MF)是一个复杂的病理过程,涉及多系统和多种不同机制,涉及多种细胞因子参与,其中转化生长因子β1(transforming growth factor-β1,TGF-β1)是重要的促纤维化因子,在病理情况下可通过经典的TGF-β1/smads 通路诱导心肌纤维化的发生发展,并最终导致心力衰竭。本文综述了高血压、糖尿病、射线损伤、病毒性心肌炎导致MF的相关机制,阐述了TGF-β1 信号通路在MF 中的作用。     

HIV infection is blocked in vitro by recombinant soluble CD4

The T-cell surface glycoprotein, CD4 (T4), acts as the cellular receptor for human immunodeficiency virus, type 1 (HIV-1), the first member of the family of viruses that cause acquired immunodeficiency syndrome. HIV recognition of CD4 is probably mediated through the virus envelope glycoprotein (gp120) as shown by co-immunoprecipitation of CD4 and gp120 (ref.5) and by experiments using recombinant gp120 as a binding probe. Here we demonstrate that recombinant soluble CD4(rsT4) purified from the conditioned medium of a stably transfected Chinese hamster ovary cell line is a potent inhibitor of both virus replication and virus-induced cell fusion (syncytium formation). These results suggest that rsT4 is sufficient to bind HIV, and that it represents a potential anti-viral therapy for HIV infection.     

SUMO-1在ApoE-/-小鼠PM2.5暴露中调控血管HIF-1α/VEGF信号通路的研究

本文研究了ApoE-/-小鼠经PM2.5暴露后,其主动脉弓中SUMO-1、HIF-1及其靶基因血管内皮生长因子（VEGF）表达变化规律及HIF-1的SUMO化修饰情况。利用气管滴注方法将颗粒物滴入ApoE-/-小鼠,利用Western blot、QPCR检测小鼠主动脉中SUMO-1、HIF-1、VEGF的表达情况和CO-IP法检测SUMO-1及HIF-1共修饰情况。 结果显示： PM2.5暴露后,小鼠主动脉SUMO-1、HIF-1、VEGF的表达上调。CO-IP 显示：对照组SUMO-1没有对HIF-1α发生SUMO化修饰,PM2.5暴露后SUMO-1对HIF-1α产生了明显的SUMO化修饰。SUMO化的HIF-1与HIF-1α、HIF-1、VEGF蛋白均呈正相关。 PM2.5暴露可能通过上调细胞中SUMO-1的表达,稳定HIF-1α或者上调HIF-1的表达,进而影响VEGF的表达。     

GIBBERELLIN INSENSITIVE DWARF1 encodes a soluble receptor for gibberellin

Gibberellins (GAs) are phytohormones that are essential for many developmental processes in plants. It has been postulated that plants have both membrane-bound and soluble GA receptors; however, no GA receptors have yet been identified. Here we report the isolation and characterization of a new GA-insensitive dwarf mutant of rice, gid1. The GID1 gene encodes an unknown protein with similarity to the hormone-sensitive lipases, and we observed preferential localization of a GID1-green fluorescent protein (GFP) signal in nuclei. Recombinant glutathione S-transferase (GST)-GID1 had a high affinity only for biologically active GAs, whereas mutated GST-GID1 corresponding to three gid1 alleles had no GA-binding affinity. The dissociation constant for GA4 was estimated to be around 10(-7) M, enough to account for the GA dependency of shoot elongation. Moreover, GID1 bound to SLR1, a rice DELLA protein, in a GA-dependent manner in yeast cells. GID1 overexpression resulted in a GA-hypersensitive phenotype. Together, our results indicate that GID1 is a soluble receptor mediating GA signalling in rice.     

自体角膜缘干细胞移植术在治疗眼表疾病中的应用

目的:探讨用自体角膜缘干细胞移植术治疗眼表疾病新方法。方法:应用自体角膜缘干细胞移植术治疗42例(48眼)眼表疾病患者,随访0.6～2a,回顾性评价疗效。结果:术眼移植片成活好,无新生血管长入,48眼均无复发,视力增进,无并发症发生。结论:自体角膜缘干细胞移植术,疗效可靠,无排斥反应,是目前治疗和预防眼表疾病复发的最佳方法之一。     

1-methyl-4-phenylpyridine is neurotoxic to the nigrostriatal dopamine pathway

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is neurotoxic to cerebral dopaminergic neurones in several animal species, and can cause parkinsonism in man. The mechanism of this action may be indirect. MPTP is oxidized in the brain to a pyridinium species, 1-methyl-4-phenylpyridine (MPP+)6. This oxidation is greatly decreased by inhibition of monoamine oxidase B6, as are the biochemical effects of MPTP in the mouse and its neurotoxicity in the monkey. We now show that MPP+ exerts a powerful neurotoxic action on the nigrostriatal dopamine system of the rodent.     

A soluble form of intercellular adhesion molecule-1 inhibits rhinovirus infection

Rhinoviruses belong to the picornavirus family and cause about 50% of common colds. Most rhinoviruses and some coxsackie viruses share a common receptor on human cells. The glycoprotein intercellular adhesion molecule-1 (ICAM-1) has recently been identified as the cellular receptor for the subgroup of rhinoviruses known as the major groups. ICAM-1 is a member of the immunoglobulin supergene family and is a ligand for lymphocyte function-associated antigen-1 (LFA-1); these ICAM-1/LFA-1 interactions are critical to many cell adhesion processes involved in the immunological response. Because anti-ICAM-1 antibodies can block binding of major-group rhinoviruses to cells, we considered that antagonism of virus-receptor interaction might be a way of preventing rhinovirus infection. We have constructed and purified a soluble form of the ICAM-1 molecule, which is normally membrane-bound, and demonstrated that it is a potent and specific inhibitor of rhinovirus infection.