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21.
To cope with temperature fluctuations, molecular thermosensors in animals play a pivotal role in accurately sensing ambient temperature. Transient receptor potential melastatin 8 (TRPM8) is the most established cold sensor. In order to understand how the evolutionary forces bestowed TRPM8 with cold sensitivity, insights into both emergence of cold sensing during evolution and the thermodynamic basis of cold activation are needed. Here, we show that the trpm8 gene evolved by forming and regulating two domains (MHR1-3 and pore domains), thus determining distinct cold-sensitive properties among vertebrate TRPM8 orthologs. The young trpm8 gene without function can be observed in the closest living relatives of tetrapods (lobe-finned fishes), while the mature MHR1-3 domain with independent cold sensitivity has formed in TRPM8s of amphibians and reptiles to enable channel activation by cold. Furthermore, positive selection in the TRPM8 pore domain that tuned the efficacy of cold activation appeared late among more advanced terrestrial tetrapods. Interestingly, the mature MHR1-3 domain is necessary for the regulatory mechanism of the pore domain in TRPM8 cold activation. Our results reveal the domain-based evolution for TRPM8 functions and suggest that the acquisition of cold sensitivity in TRPM8 facilitated terrestrial adaptation during the water-to-land transition.

Given that temperature influences all biological operations, the evolution of thermosensory adaptation is crucial in shaping the specialized temperature-dependent inhabitation of an organism. At the cellular level, thermosensory neurons in the dorsal root ganglia or trigeminal ganglia innervate the skin and transmit temperature information to the spinal cord and the brain. To bestow such neurons with thermal sensitivity, animals have a toolkit of temperature-sensitive ion channels located on the cell membrane at the molecular level. Accordingly, several members of the transient receptor potential (TRP) superfamily with steep thermosensitivity (referred to as thermoTRP) have attracted the general interest in the field of thermal biology, as they sufficiently cause steep changes in depolarizing currents upon either heating or cooling and thus are considered as the primary molecular sensors of temperature (14). Therefore, the evolutionary strategy for directly tuning the thermal activation in thermoTRPs can be employed by animals for their specialized thermosensory adaptation, as seen in vampire bats, pit-bearing snakes, platypus, penguins, squirrels, and camels (59).As heat sensation (warmth and extreme heat) provides the precondition of a fundamental and conserved biological survival process, the genes that encode heat sensors are considered ancient in many metazoan organisms. The annotation of trpv1 is consistently available in the genomes of fishes, insects, amphibians, reptiles, birds, and mammals. Despite the species-specific temperature-sensitive ranges, a growing number of studies have reported the functional convergence of these heat-sensitive thermoTRP orthologs at the protein level (10), suggesting the essential role of these channels in heat perception across species. Compared to heat sensors, the cold-sensitive thermoTRP likely evolved late. As the most established cold sensor responsive to low temperatures and cooling compounds, transient receptor potential melastatin 8 (TRPM8) was found in somatosensory neurons, and genetic ablation of trpm8 either in the neurons or mice led to a largely decreased cold sensitivity (4, 1113). Interestingly, cold activation of amphibian TRPM8 has been tested (14), while sequencing efforts indicated the absence of the trpm8 gene in 12 fish species from 10 different orders (15). Several specific domains that may alter TRPM8 cold activation have been reported, including the pore domain, voltage sensing apparatus, and C terminus (8, 1619). Notably, although the efficacy of cold activation is largely altered by residue substitutions in the pore domain, the channel mutants are still cold sensitive (8). Therefore, these findings based on domain/residue swapping among cold-sensitive TRPM8 orthologs may not draw an overall picture in functionally important domains responsible for cold sensitivity. How did the trpm8 gene originate? How did TRPM8 integrate and modulate cold sensitivity throughout evolution? The answers to such questions probably lead us to understand the evolution of temperature perception and identify the essential structural elements that shape TRPM8 cold activation.In this study, we show the presence of the young trpm8 gene in lobe-finned fishes, believed to be the ancestors that gave rise to all land vertebrates (20). Such a young type of trpm8 derived from the trpm2 exon shuffling was originated and formed during the expansion of lobe-finned fish genomes. By detecting the positive selection-rich domains, we described the formation of the thermosensitive MHR1-3 domain in amphibian and reptile species that enables TRPM8 to undergo conformational changes at low temperatures. Furthermore, we found that the TRPM8 pore domain of terrestrial vertebrates evolved to tune the efficacy of cold activation, in which a cold-sensitive MHR1-3 domain is indispensable to achieve such a modulatory mechanism. Together, our findings suggest that the trpm8 gene origination and formation of the TRPM8 MHR1-3 domain contributed to the transition of vertebrate life from water to land and that the efficacy of cold activation tuned by the TRPM8 pore domain diversified the setting of temperature-adaptive phenotypes in terrestrial vertebrates.  相似文献   
22.
感冒四季皆发,一般症状轻浅,但少数反复发作,缠绵难愈,患者深受其苦。张伯礼教授注重感冒防-治-康全流程辨治,首以病证合参,明确风邪犯肺,可累及鼻咽;再明辨寒热虚实,关注兼夹之证,把握小儿感冒的疾病特点和治疗策略;注重病程变化,久病不忘气血并调,内外兼治,强调先安未受邪之地;重视防治养生,综合调节,知冷暖,劳逸结合。  相似文献   
23.
目的 探究经络拔罐联合小茴香热敷对胃脘痛患者疼痛程度及复发的影响。方法 选取江西省新余市中医院2017年6月—2019年8月收治的胃脘痛患者88例,按随机数字表法分为研究组(44例)及对照组(44例)。对照组行常规护理,研究组在对照组基础上行经络拔罐联合小茴香热敷。对比2组干预前后中医证候积分、疼痛程度评分及复发率。结果 研究组干预后中医证候积分及VAS评分均低于对照组,差异有统计学意义(P <0.05);研究组胃脘痛复发率低于对照组,差异有统计学意义(P <0.05)。结论 经络拔罐联合小茴香热敷可有效缓解胃脘痛患者胃脘部疼痛感,并可降低疾病复发率,具有推广价值。  相似文献   
24.
Despite the rising evidence in favor of immunotherapy (IT), the treatment of oncological patients affected by so-called “cold tumors” still represents an open issue. Cold tumors are characterized by an immunosuppressive (so-called cold) tumor microenvironment (TME), which favors host immune system suppression, cancer immune-escape, and a worse response to IT. However, the TME is not a static element, but dynamically mutates and can be changed. Radiotherapy (RT) can modulate a cold microenvironment, rendering it better at tumor killing by priming the quiescent host immune system, with a consequent increase in immunotherapy response. The combination of TME radiomodulation and IT could therefore be a strategy for those patients affected by cold tumors, with limited or no response to IT. Thus, this review aims to provide an easy, rapid, and practical overview of how RT could convert the cold TME and why cold tumor radiomodulation could represent an interesting strategy in combination with IT.  相似文献   
25.
目的:探讨薄荷油腹部湿热敷对维持性血液透析患者便秘的疗效。方法将60例维持性血液透析便秘患者随机分为观察组与对照组各30例,观察组患者采用薄荷油腹部湿热敷,对照组给予番泻叶3~6 g泡水顿服,疗程均为2周。观察2组患者的疗效及排便时患者的反应。结果观察组总有效率明显高于对照组,2组比较差异有统计学意义(P〈0.05)。结论薄荷油腹部湿热敷操作简单,无副作用,不仅可以使维持性血液透析患者保持大便通畅,而且可以减少因便秘引起的不适和并发症,进而提高患者的生活质量。  相似文献   
26.
目的:观察不同的针刺刺激量施于关元穴对寒凝类痛经模型大鼠子宫组织中收缩素受体( OTR)及肌球蛋白轻链激酶( MLCK)含量的影响。方法将处于动情间期3月龄的SD雌性大鼠32只,随机分为盐水组、寒凝类痛经模型组24只,造模成功后将寒凝类痛经模型组又分为模型组、刺激量A组和刺激量B组,每组8只。除盐水组外,模型组、刺激量A组和刺激量B组均采用全身冷冻法结合苯甲酸雌二醇注射法造模。盐水组和模型组不予针刺,刺激量A组予以粗针、深刺、行手法;刺激量B组予以细针、浅刺、不施手法。采用荧光定量PCR方法检测大鼠子宫组织中缩宫素受体( OTR)的含量。采用ELISA(酶联免疫法)测量大鼠子宫组织中MLCK的含量。结果与盐水组比较,模型组的子宫收缩波个数、波峰峰值、活动度及MLCK水平均升高( P﹤0.01);与模型组比较,刺激量A组的子宫收缩波个数明显减少( P﹤0.05)、MLCK含量明显降低( P﹤0.01),刺激量B组的OTR mRNA相对表达量降低( P﹤0.05);与刺激量A组比较,刺激量B组收缩波个数增多( P﹤0.05)、OTR mRNA相对表达量降低( P﹤0.01)。结论不同刺激量针刺关元穴对寒凝类痛经模型大鼠的效应有所不同,粗针、深刺、行手法的效应较强于细针、浅刺、不行手法的针刺效应,提示针刺的刺激量也是决定针刺疗效的因素之一。  相似文献   
27.
银屑病分型论治浅解   总被引:2,自引:0,他引:2  
银屑病又名牛皮癣,中医称之为白疕,是一种常见易复发的慢性炎症性皮肤病,以云母状鳞屑、红膜症、点状出血为临床特征.近年来,银屑病发病呈上升趋势,其初期有明显的季节性,呈冬重夏轻,无论男女老幼皆可发病,目前病因未明,尚缺乏有效的治疗方法.自2000年以来,我们根据银屑病的临床表现,将其辨证分型为:血热毒盛,寒湿侵袭、脉络瘀阻、血虚风燥、肝肾亏虚等五型,对证治疗取得了比较明显的疗效,现予介绍,以求同道斧正.  相似文献   
28.
中药溻渍法以中医整体观念和辨证论治理论为指导,通过辨证组方,有药味少、药量大,功洪力专的特点,且药液直接作用于患处,使腠理开疏,药力直达病所,达到治疗目的,具有操作简便、不良反应小、安全可靠的优点。药液既能荡涤创面又不影响内服药的功效,既防止了药物注射或口服给药对肝、肾的损害,又避免了肝脏的"首过效应",生物利用度高。  相似文献   
29.
This paper investigated the influence of deep cryogenic treatments (DCT) on the tensile strength, elongation to fracture and conductivity of a deformation-processed Cu-Ni-Co-Si alloy. The tensile properties were measured using a mechanical testing machine. The conductivity was evaluated using a low-resistance tester. The microstructure and precipitated phases were analyzed using scanning electron microscopy (SEM), transmission electron microscopy (TEM), an energy dispersive spectrometer (EDS) and an X-ray diffractometer (XRD). The tensile strength, elongation to fracture and conductivity of the Cu-1.34Ni-1.02Co-0.61Si alloy before and after cold rolling at 47% reduction increased with increasing DCT time and tended to be stable at about 36 h. The microstructure became more uniform after the DCT. The grain size was refined and was smallest after DCT for 48 h. The DCT promoted the precipitation of the solid solution elements Ni, Co and Si from the Cu matrix to form many fine and evenly distributed 20–70 nm spherical second-phase particles in the grains and grain boundaries.  相似文献   
30.
Fifteen subjects undertook repeated periods of hyperventilation of cold dry air and hyperventilation of warm humidified air followed by cold dry air. Hyperventilation of cold dry air induced a biphasic response with initial bronchodilatation followed by bronchoconstriction. However, exercise produced a greater rise in forced expiratory volume in 1 second (FEV1) than hyperventilation alone. Hyperventilation of cold dry air resulted in a period of refractoriness to a second stress of the same type. Refractoriness induced by exercise or hyperventilation of cold dry air may be the result of refractoriness of the trigger site in the large airways.  相似文献   
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