Spider toxins activate the capsaicin receptor to produce inflammatory pain

Bites and stings from venomous creatures can produce pain and inflammation as part of their defensive strategy to ward off predators or competitors. Molecules accounting for lethal effects of venoms have been extensively characterized, but less is known about the mechanisms by which they produce pain. Venoms from spiders, snakes, cone snails or scorpions contain a pharmacopoeia of peptide toxins that block receptor or channel activation as a means of producing shock, paralysis or death. We examined whether these venoms also contain toxins that activate (rather than inhibit) excitatory channels on somatosensory neurons to produce a noxious sensation in mammals. Here we show that venom from a tarantula that is native to the West Indies contains three inhibitor cysteine knot (ICK) peptides that target the capsaicin receptor (TRPV1), an excitatory channel expressed by sensory neurons of the pain pathway. In contrast with the predominant role of ICK toxins as channel inhibitors, these previously unknown 'vanillotoxins' function as TRPV1 agonists, providing new tools for understanding mechanisms of TRP channel gating. Some vanillotoxins also inhibit voltage-gated potassium channels, supporting potential similarities between TRP and voltage-gated channel structures. TRP channels can now be included among the targets of peptide toxins, showing that animals, like plants (for example, chilli peppers), avert predators by activating TRP channels on sensory nerve fibres to elicit pain and inflammation.     

Chemotropic effect of specific target epithelium in the developing mammalian nervous system

Developing nerve fibres are guided to their targets by specific directional cues which are thought to be expressed in the tissues along the route and may involve the extracellular matrix. Another possibility, that directional cues emanate from the target itself, is consistent with the recent demonstration of homing behaviour by ectopic retinal ganglion axons and our previous demonstration that early trigeminal neurites grow directly to their virgin peripheral target in vitro. Here we show that this chemotropic effect is precisely limited to the trigeminal system; trigeminal ganglion neurites grow directly to their own target field but not to the adjoining field, normally innervated by the geniculate ganglion; furthermore, the trigeminal field does not influence the growth of geniculate neurites. Also, when trigeminal ganglia are co-cultured with isolated tissue layers of their target, neurites grow only towards the epithelial and not the mesenchymal component. These findings suggest that trigeminal epithelium is specified to attract correct innervation and that pathway mesenchyme, in which preformed guidance cues have been postulated, may provide favourable conditions for nerve fibre growth but not govern its direction.     

Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers

Most local anaesthetics used clinically are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. These anaesthetics block sodium channels and thereby the excitability of all neurons, not just sensory neurons. We tested the possibility of selectively blocking the excitability of primary sensory nociceptor (pain-sensing) neurons by introducing the charged, membrane-impermeant lidocaine derivative QX-314 through the pore of the noxious-heat-sensitive TRPV1 channel. Here we show that charged sodium-channel blockers can be targeted into nociceptors by the application of TRPV1 agonists to produce a pain-specific local anaesthesia. QX-314 applied externally had no effect on the activity of sodium channels in small sensory neurons when applied alone, but when applied in the presence of the TRPV1 agonist capsaicin, QX-314 blocked sodium channels and inhibited excitability. Inhibition by co-applied QX-314 and capsaicin was restricted to neurons expressing TRPV1. Injection of QX-314 together with capsaicin into rat hindpaws produced a long-lasting (more than 2 h) increase in mechanical and thermal nociceptive thresholds. Long-lasting decreases in pain sensitivity were also seen with regional injection of QX-314 and capsaicin near the sciatic nerve; however, in contrast to the effect of lidocaine, the application of QX-314 and capsaicin together was not accompanied by motor or tactile deficits.     

TRPV3 is a calcium-permeable temperature-sensitive cation channel

Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43 degrees C; TRPV1 (ref. 1)), noxious heat (>52 degrees C; TRPV2 (ref. 2)), and cooling (< 22 degrees C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the molecular determinants of temperature sensing in the range between approximately 22 degrees C and 40 degrees C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temperature from 22 degrees C to 40 degrees C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temperature, sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1.     

红外单光子探测器定标方法研究

紫外激光器输出的355 nm激光泵浦BBO晶体,采用晶体的I类相位匹配,利用晶体的角度调谐特性得到的红外波段光源应用于单光子探测器定标,提出了利用参量下转换产生的纠缠光子对定标SPCM单光子探测器量子效率的方法,介绍了实验原理和定标装置。     

Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels

TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat) and the synthetic ligand 4alphaPDD. An endogenous ligand for this channel has not yet been identified. Here we show that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids. Application of 5',6'-epoxyeicosatrienoic acid at submicromolar concentrations activates TRPV4 in a membrane-delimited manner and causes Ca2+ influx through TRPV4-like channels in vascular endothelial cells. Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone.     

Varicella-zoster virus DNA in human sensory ganglia

Varicella-zoster virus (VZV) causes chickenpox and shingles. Clinical and epidemiological evidence indicates that following an episode of childhood chickenpox (varicella), VZV becomes latent, presumably in dorsal root ganglia, and is reactivated many years later to produce shingles (zoster) in adults. VZV has been demonstrated in ganglia by electron microscopy and by indirect immunofluorescence, and infectious viral particles have been isolated from acutely infected ganglia of patients who died of disseminated VZV infection. However, VZV has not been detected in the ganglia of humans without recent exposure to VZV. Tissue culture explant methods that have been successful in the isolation of herpes simplex virus from ganglia have so far failed in the isolation or reactivation of VZV from trigeminal and other dorsal root ganglia. We describe here the detection of VZV DNA sequences in an acutely infected human sacral ganglion and in normal trigeminal ganglia. These findings support the hypothesis that VZV is latent in normal human ganglia.     

天空背景红外图像仿真

为了使天空背景辐射强度光谱分布最终生成红外探测器焦平面上背景辐射功率分布图像,需要对天空背景辐射各影响因素进行分析,建立准确的背景辐射到探测器光学系统焦平面的辐射能量传输模型.本文利用MODTRAN软件计算不同天候条件下的天空背景辐射强度光谱分布,建立了背景辐射到探测器光学系统焦平面的辐射能量传输模型,给出了天空背景在焦平面上的辐射功率计算方法,利用天空背景辐射功率分布生成其红外图像.最后编写了仿真软件,生成不同天候天空背景图像,并与红外热像仪拍摄的天空背景图像进行了比对,其变化趋势有较高的一致性.     

敲击模式扫描近场光学显微镜

为了实现敲击模式的扫描近场光学显微镜 ,采用以石英音叉为灵敏探测器件 ,将光纤探针垂直音叉侧臂粘接 ,使探针在垂直样品的方向上振动 ,以“敲击”方式探测样品表面的信息 ,实现近场范围的高度控制。仪器结构紧凑 ,操作方便 ,灵敏度高 ,可用于液体环境下的样品探测 ,在对样品形貌进行探测的同时可实现对光信号的调制。将这种探测模式应用于实验 ,获得 2 40 0线 /mm光栅、光盘母盘和生物细胞的形貌图像。实验证明 :这种探测方式分辨率优于 2 0 0 nm,适用于不同硬度的样品 ,可以作为材料学、生物学等领域的有力工具。     

The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels

The mammalian sensory system is capable of discriminating thermal stimuli ranging from noxious cold to noxious heat. Principal temperature sensors belong to the TRP cation channel family, but the mechanisms underlying the marked temperature sensitivity of opening and closing ('gating') of these channels are unknown. Here we show that temperature sensing is tightly linked to voltage-dependent gating in the cold-sensitive channel TRPM8 and the heat-sensitive channel TRPV1. Both channels are activated upon depolarization, and changes in temperature result in graded shifts of their voltage-dependent activation curves. The chemical agonists menthol (TRPM8) and capsaicin (TRPV1) function as gating modifiers, shifting activation curves towards physiological membrane potentials. Kinetic analysis of gating at different temperatures indicates that temperature sensitivity in TRPM8 and TRPV1 arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. Our results suggest a simple unifying principle that explains both cold and heat sensitivity in TRP channels.     

Peptidergic transmitters in synaptic boutons of sympathetic ganglia

In sympathetic ganglia of the bullfrog, a slow synaptic potential lasting for minutes--the late slow excitatory postsynaptic potential (e.p.s.p.)--was discovered. This slow response, unlike other previously known synaptic potentials in the autonomic nervous system, is not mediated by acetylcholine or monoamines. Similar non-cholinergic, non-adrenergic slow synaptic potentials have since been found in several other vertebrate autonomic ganglia. We found that the late slow e.p.s.p. is probably mediated by a peptide that is identical to, or closely resembles, mammalian luteinizing hormone releasing hormone (LHRH), because (1) when applied directly to sympathetic neurones, LHRH and its agonists elicit a slow depolarization, associated with similar changes in membrane conductance and excitability as those occurring during the late slow e.p.s.p. Furthermore, both peptide-induced and nerve-evoked responses are blocked by antagonists of LHRH; and (2) radioimmunoassays indicate that a chain of sympathetic ganglia contains 100-800 pg of a LHRH-like peptide. Its distribution among spinal nerves, the great reduction of this substance following denervation, and its release from ganglia following isotonic KCl treatment or nerve stimulation suggest that the LHRH-like material is contained in preganglionic nerve fibres. Here we report that immunohistochemical staining of sympathetic ganglia shows that LHRH-like immunoreactivity is indeed present in synaptic boutons. We also show that the two types of ganglion cells (B cells and C cells) receive strikingly different patterns of peptidergic innervation.     

Long-term regenerated nerve fibres retain sensitivity to potassium channel blocking agents

Mammalian myelinated peripheral nerve fibres display a remarkable degree of regeneration following a discrete nerve crush. Nerve crush disrupts the axon cylinder, but leaves the basement membrane of the Schwann cell intact. These intact endoneurial tubes provide pathways to guide the regenerating axon sprouts. After contact with the periphery is established, the regenerating fibres enlarge and myelinate. Conduction velocity recovers to nearly normal and functional recovery is, in many cases, nearly complete. A distinct feature of normal mature myelinated axons is the insensitivity of these fibres to potassium channel blocking agents. In contrast, immature myelinated axons are exquisitely sensitive to the K channel blocking agent 4-aminopyridine (4-AP). Application of 4-AP to immature myelinated fibres leads to a delayed membrane depolarization with action potential burst activity in response to a single stimulus. This sensitivity to 4-AP is attenuated as the fibres mature. Previous studies have demonstrated a sensitivity to 4-AP in regenerating nerve fibres; this sensitivity differentiates the regenerating axon segments from their normal parent axon segments. Such studies have not, however, examined the question of whether regenerated fibres, which have re-established peripheral connections and are functionally active, fully recapitulate the functional organization of normal mature myelinated fibres. We demonstrate here that while sensitivity to the potassium channel blocking agents 4-AP and 3, 4-diaminopyridine (3, 4-DAP) is lost in the normal course of myelinated axon maturation, this property is present in long-term regenerated axons. This suggests that long-term regenerated mammalian axons are characterized by a functional organization that bears a closer resemblance to that of immature myelinated fibres than to that of adult myelinated fibres.     

飞机目标的红外建模与探测器成像

基于红外物理学、热传递学,分析了飞机飞行过程中的主要辐射源.运用商业软件FLUENT,计算得到了飞机温度场和辐射场分布.综合大气透过率、探测器响应等因素影响,推导导引头探测器的基本教学模型.最后在搭建OpenGL软件平台的基础上,通过实验得到了导引头探测器接收到的飞机红外辐射图像.     

A transitional snake from the Late Cretaceous period of North America

Snakes are the most diverse group of lizards, but their origins and early evolution remain poorly understood owing to a lack of transitional forms. Several major issues remain outstanding, such as whether snakes originated in a marine or terrestrial environment and how their unique feeding mechanism evolved. The Cretaceous Coniophis precedens was among the first Mesozoic snakes discovered, but until now only an isolated vertebra has been described and it has therefore been overlooked in discussions of snake evolution. Here we report on previously undescribed material from this ancient snake, including the maxilla, dentary and additional vertebrae. Coniophis is not an anilioid as previously thought a revised phylogenetic analysis of Ophidia shows that it instead represents the most primitive known snake. Accordingly, its morphology and ecology are critical to understanding snake evolution. Coniophis occurs in a continental floodplain environment, consistent with a terrestrial rather than a marine origin; furthermore, its small size and reduced neural spines indicate fossorial habits, suggesting that snakes evolved from burrowing lizards. The skull is intermediate between that of lizards and snakes. Hooked teeth and an intramandibular joint indicate that Coniophis fed on relatively large, soft-bodied prey. However, the maxilla is firmly united with the skull, indicating an akinetic rostrum. Coniophis therefore represents a transitional snake, combining a snake-like body and a lizard-like head. Subsequent to the evolution of a serpentine body and carnivory, snakes evolved a highly specialized, kinetic skull, which was followed by a major adaptive radiation in the Early Cretaceous period. This pattern suggests that the kinetic skull was a key innovation that permitted the diversification of snakes.     

红外探测器光谱响应测量研究

设计了一个红外探测器的光谱响应测试系统,并对系统原理进行了分析.对不同温度和频率情况下的热释电探测器进行光谱响应实验.实验结果表明,热释电探测器对红外辐射信号的响应不同,但电压变化曲线的趋势基本一致,从而验证了红外探测器光谱响应理论.该设计能有效抑制系统的干扰信号,提高信噪比,具有测量精度高、稳定性好的优点.     

Biomechanics: independent evolution of running in vampire bats

Most tetrapods have retained terrestrial locomotion since it evolved in the Palaeozoic era, but bats have become so specialized for flight that they have almost lost the ability to manoeuvre on land at all. Vampire bats, which sneak up on their prey along the ground, are an important exception. Here we show that common vampire bats can also run by using a unique bounding gait, in which the forelimbs instead of the hindlimbs are recruited for force production as the wings are much more powerful than the legs. This ability to run seems to have evolved independently within the bat lineage.     

矿井地质构造红外探测的理论与实践

红外探测实践表明 ,地质构造引起的岩石密度变化是影响岩石表面红外辐射分布的主导因素 .提出地质构造区密度变化状态模型 ,根据红外辐射原理 ,从岩石有效辐射面变化的角度 ,定性分析了地质构造、岩石密度和辐射功率等因素之间的相关性 ,建立了相关方程 ,介绍了红外探测地质构造的基本方法和适用条件 ,并结合实例说明了应用过程 .为研究红外探测技术在矿井水文地质、瓦斯地质、煤炭自燃等方面的应用提供了理论基础与分析方法 .图 4 ,参 5     

辐射光弹毁伤机理实验研究

该文通过实验研究了辐射光弹药的毁伤机理 ,给出了实验结果 ,并对实验结果进行了分析和讨论。实验表明 ,药剂配方基本成份选用正确 ,比例合理 ,实验方案经济、有效 ,干扰光源的红外辐射特性能覆盖目标的红外特性 ,对红外探测器进行干扰和破坏在技术上是可行的 ,但药剂最佳配方问题和辐射光有效辐射强度提高问题有待于进一步解决     

红外辐射对比度概念的探讨

为了更方便理解红外辐射对比度的含义,针对目前红外辐射对比度计算使用的物理量和公式比较混乱的情况,从红外探测的实现方法出发,分析指出对比度衡量的标准物理量应该为在探测器处的红外辐射照度。当目标与背景不在同一位置且与探测器相距较远时,用辐射亮度、辐射出射度计算对比度分析探测效果是不恰当的。相对对比度应该使用目标与背景在探测器处的红外辐射照度差值的绝对值除以目标与背景的红外辐射照度平均值作计算。     

光幕幕厚与大气对弹丸红外热辐射探测性能影响研究

为改善光电探测靶的探测性能,研究了光电探测器对光幕区中弹丸红外热辐射能的获取,分析了幕厚、弹丸长度、弹丸辐射面积、大气衰减与光幕区弹丸红外热辐射特性的关系。采用将弹体划分为多个小面元的方法,建立了弹丸红外热辐射计算方程。研究了光电探测器的弹体红外热辐射通量计算方法。根据红外热辐射大气衰减理论,分析了不同波长光电探测器获得的弹丸红外热辐射能与大气透过率的关系,并计算了光电探测器在不同幕厚和作用距离下获得的弹丸红外热辐射能。结果表明:当探测距离一定时,弹丸作用于光幕的表面红外热辐射能与光电探测器接收辐射能成正比;当弹体长度与幕厚相等时,光电探测器获得的信号最强;距离越远大气的红外透过率越小,探测灵敏度越低;3~5μm波长光电探测器可获得最佳弹丸红外热辐射能。