The acquisition of cold sensitivity during TRPM8 ion channel evolution

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 (1–4). 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 (5–9).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, 11–13). 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, 16–19). 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.     

A stable and reliable animal model for hepatocellular carcinoma with portal vein tumor thrombus

<正>To the Editor:Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [1,2].Portal vein tumor thrombus (PVTT) has been demonstrated to be a poor prognostic indicator for HCC [3-5].However,effective treatment for the condition is still limited.Understanding the insight into the molecular mechanisms behind PVTT development may help to establish a new therapeutic strategy.Animal models which mimic the development of PVTT in humans are necessary to figure out the molecula...     

活血化瘀法在慢性肝病治疗中的应用体会

慢性肝病顽固难愈,包括慢性乙型肝炎、肝纤维化及肝硬化等疾病,往往出现"久病必瘀"的病理机转,所以治疗慢性肝病常在辨证论治的基础上配合活血化瘀法。活血化瘀同时与清热解毒、疏肝理气、健脾益气、补肾益气、软坚散结等法相配伍应用,在慢性肝病的治疗中取得一定疗效。     

Association of body mass index with risk of prediabetes in Chinese adults: A population‐based cohort study

Aims/IntroductionOverweight and obesity in adults are strongly associated with an increased risk of prediabetes, and this study set out to gain a better understanding of the optimal body mass index (BMI) range for assessing the risk of prediabetes in the Chinese population.Materials and MethodsThe cohort study included 100,309 Chinese adults who underwent health screening. Participants were divided into six groups based on the cut‐off point for BMI recommended by the World Health Organization (underweight: <18.5 kg/m², normal‐weight: 18.5–24.9 kg/m², pre‐obese: 25.0–29.9 kg/m², obese class I: 30.0–34.9 kg/m², obese class II: 35.0–39.9 kg/m², and obese class III ≥40 kg/m²). The association of BMI with prediabetes and the shape of the correlation were modeled using multivariate Cox regression and restricted cubic spline regression, respectively.ResultsIn the multivariate Cox regression model, with normal weight as the control group, underweight people had a lower risk of developing prediabetes, whereas obese and pre‐obese people had a higher risk of prediabetes. Additionally, in the restricted cubic spline model, we found that the association of BMI with prediabetes follows a positive dose–response relationship, but does not conform to the pattern of obesity paradox. Among the general population in China, a BMI of 23.03 kg/m² might be a potential intervention threshold for prediabetes.ConclusionsThe national cohort study found that the association of BMI with prediabetes follows a positive dose–response relationship, rather than a pattern of obesity paradox. For Chinese people with normal weight, more attention should be paid to glucose metabolism when BMI exceeds 23.03 kg/m².     

Cluster phenotypes in a non-idiopathic pulmonary fibrosis fibrotic interstitial lung diseases cohort in Singapore

BackgroundNon-idiopathic pulmonary fibrosis fibrosing interstitial lung diseases (F-ILDs) may demonstrate a progressive disease trajectory similar to idiopathic pulmonary fibrosis (IPF). We aimed to identify novel F-ILD phenotypes in a multi-ethnic South-East Asian population.MethodsF-ILD subjects (n=201) were analysed using unsupervised hierarchical cluster analysis and their outcomes compared against IPF (n=86).ResultsFour clusters were identified. Cluster 1 (n=53, 26.4%) comprised older Chinese males with high body mass index (BMI) and comorbidity burden, higher baseline forced vital capacity (FVC) percentage predicted and lower diffusing capacity of the lung for carbon monoxide (DLCO) percentage predicted. They had similar mortality to IPF. Cluster 2 (n=67, 33.3%) had younger female non-smokers with low comorbidity burden, groundglass changes on high-resolution chest computed tomography (HRCT) and a positive anti-nuclear antibody (ANA) titre ≥1:160. They had lower baseline FVC and higher DLCO, low mortality and slower lung function decline. Cluster 3 (n=42, 20.9%) consisted male smokers with low comorbidity burden, emphysema on HRCT and high baseline lung function. They had low mortality and slow lung function decline. Cluster 4 (n=39, 19.4%) was the highest risk and comprised of mainly Indians with high BMI. They had the highest proportion of ischemic heart disease (IHD) and previous pulmonary tuberculosis. Subjects had the lowest baseline lung function, highest mortality, and fastest lung function decline. Survival differences across clusters remained significant following adjustment for treatment.ConclusionsWe identified four distinct F-ILD clinical phenotypes with varying disease trajectories. This demonstrates heterogeneity in F-ILD and the need for complementary approaches for classification and prognostication beyond ATS/ERS guideline diagnosis.     

Integrating Patient Concerns into Parkinson’s Disease Management

Parkinson’s disease (PD) is a complex motor and non-motor disorder and management is often challenging. In this review, we explore emerging approaches to improve the care of patients, drawing from the literature regarding patient-centred care, patient and caregiver perspectives and priorities, gaps in knowledge among patients and caregivers and the need for accurate information, individual variability in disease manifestations, prognostication of disease course, new developments in health technologies and personalized medicine, specialty care, pharmacological and non-pharmacological management, financial burden, lifestyle and work-related issues, support groups and palliative care.     

正常踝关节内、外侧韧带的解剖及其影像学表现

目的:探讨正常踝关节内、外侧韧带的解剖形态及其MRI和CT表现。方法:6例正常人踝关节新鲜标本MRI扫描,解剖显示内、外侧韧带后,CT断层扫描与MRI对照观察踝关节内、外侧韧带的影像学表现;在30例正常志愿者踝关节的MRI上测量内、外韧带的宽度及厚度。结果:MRI横断面及冠状面可充分显示踝关节内、外侧韧带及其周围组织的解剖结构;踝关节内、外侧韧带在冠状面及横断面上所测的宽、厚度,男女间存在一定的差异。结论:MRI能清晰地显示踝关节的解剖结构,所测量的正常踝关节内、外侧韧带的宽、厚度数据,为临床诊断踝关节内、外侧韧带的病变提供了形态学依据。     

成批危重烧伤患者合并吸入性损伤的成功救治经验

目的 探讨吸入性损伤的早期急救、确诊方法 和综合治疗措施,以进一步提高其救治水平.方法 35例危重烧伤患者中,14例因发生吸入性损伤于当地行紧急气管切开术,并随后转入解放军总医院第一附属医院烧伤科.采用以下措施进行救治:应用气管镜诊断吸入性损伤程度,探取痰痂及坏死脱落黏膜,止血,根据黏膜修复程度指导拔除气管套管(拔管)的时机;人工鼻湿化气道和防治感染;使用化痰药,并定时翻身叩背、振动排痰;雾化表皮细胞生长因子促进黏膜修复.结果 气管镜检查见14例患者吸入性损伤程度分别为中度3例,重度8例,特重度3例.7例于伤后1周内拔管,6例于伤后第2周拔管,1例肺部感染严重者于伤后42天拔管.痰培养11例为无细菌生长,3例发现细菌,其中2例发生肺部感染.治疗过程中用气管镜探取痰痂3次,避免了窒息的发生.所有患者均救治成功.结论 重度吸入性损伤行气管切开越早越好;气管镜有助于准确诊断损伤程度,取出痰痂和坏死黏膜,防止气道阻塞,动态观察气管黏膜的修复,指导拔管时机;人工鼻、黏膜修复药物以及各种促排痰措施的综合应用对治疗吸入性损伤有积极意义.     

螺旋CT胆系成像的临床应用

目的：探讨螺旋ＣＴ胆系成像（ＳＣＴＣ）技术,并对其临床应用价值做一评估。方法：采用５０％ 胆影葡胺２０～４０ ｍ ｌ静脉缓注。３３ 例延时３０～６０ ｍ ｉｎ,１６例延时９０ ｍｉｎ 后行螺旋ＣＴ容积扫描,将图像数据传至工作站作三维、四维及ＭＰＲ成像。结果：我们用此法检查了４９ 例病人,其中２５例为胆囊结石,９例胆总管结石,胆囊术后胆总管狭窄２例,５例为胆管癌,正常者８ 例。结论：螺旋ＣＴ胆系成像是有效的无创伤性胆系成像技术,弥补了常规ＣＴ及螺旋ＣＴ平扫在胆系疾病诊断中的不足。