Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing.

Ageing is associated with increased vulnerability to environmental cold exposure. Previously, we identified the role of the cold-sensitive transient receptor potential (TRP) A1, M8 receptors as vascular cold sensors in mouse skin. We hypothesised that this dynamic cold-sensor system may become dysfunctional in ageing. We show that behavioural and vascular responses to skin local environmental cooling are impaired with even moderate ageing, with reduced TRPM8 gene/protein expression especially. Pharmacological blockade of the residual TRPA1/TRPM8 component substantially diminished the response in aged, compared with young mice. This implies the reliance of the already reduced cold-induced vascular response in ageing mice on remaining TRP receptor activity. Moreover, sympathetic-induced vasoconstriction was reduced with downregulation of the α2c adrenoceptor expression in ageing. The cold-induced vascular response is important for sensing cold and retaining body heat and health. These findings reveal that cold sensors, essential for this neurovascular pathway, decline as ageing onsets

Noninvasive genetic population survey of snow leopards (Panthera uncia) in Kangchenjunga conservation area, Shey Phoksundo National Park and surrounding buffer zones of Nepal

<p>Abstract</p> <p>Background</p> <p>The endangered snow leopard is found throughout major mountain ranges of Central Asia, including the remote Himalayas. However, because of their elusive behavior, sparse distribution, and poor access to their habitat, there is a lack of reliable information on their population status and demography, particularly in Nepal. Therefore, we utilized noninvasive genetic techniques to conduct a preliminary snow leopard survey in two protected areas of Nepal.</p> <p>Results</p> <p>A total of 71 putative snow leopard scats were collected and analyzed from two different areas; Shey Phoksundo National Park (SPNP) in the west and Kangchanjunga Conservation Area (KCA) in the east. Nineteen (27%) scats were genetically identified as snow leopards, and 10 (53%) of these were successfully genotyped at 6 microsatellite loci. Two samples showed identical genotype profiles indicating a total of 9 individual snow leopards. Four individual snow leopards were identified in SPNP (1 male and 3 females) and five (2 males and 3 females) in KCA.</p> <p>Conclusions</p> <p>We were able to confirm the occurrence of snow leopards in both study areas and determine the minimum number present. This information can be used to design more in-depth population surveys that will enable estimation of snow leopard population abundance at these sites.</p

Influence of Cold-TRP Receptors on Cold-Influenced Behaviour

The transient receptor potential (TRP) channels, TRPA1 and TRPM8, are thermo-receptors that detect cold and cool temperatures and play pivotal roles in mediating the cold-induced vascular response. In this study, we investigated the role of TRPA1 and TRPM8 in the thermoregulatory behavioural responses to environmental cold exposure by measuring core body temperature and locomotor activity using a telemetry device that was surgically implanted in mice. The core body temperature of mice that were cooled at 4 °C over 3 h was increased and this was accompanied by an increase in UCP-1 and TRPM8 level as detected by Western blot. We then established an effective route, by which the TRP antagonists could be administered orally with palatable food. This avoids the physical restraint of mice, which is crucial as that could influence the behavioural results. Using selective pharmacological antagonists A967079 and AMTB for TRPA1 and TRPM8 receptors, respectively, we show that TRPM8, but not TRPA1, plays a direct role in thermoregulation response to whole body cold exposure in the mouse. Additionally, we provide evidence of increased TRPM8 levels after cold exposure which could be a protective response to increase core body temperature to counter cold

TAB1-Induced Autoactivation of p38α Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185

ABSTRACT p38α mitogen-activated protein kinase is essential to cellular homeostasis. Two principal mechanisms to activate p38α exist. The first relies on dedicated dual-specificity kinases such as mitogen-activated protein kinase kinase (MAP2K) 3 (MKK3) or 6 (MKK6), which activate p38α by phosphorylating Thr180 and Tyr182 within the activation segment. The second is by autophosphorylation of Thr180 and Tyr182 in cis, mediated by p38α binding the scaffold protein TAB1. The second mechanism occurs during myocardial ischemia, where it aggravates myocardial infarction. Based on the crystal structure of the p38α-TAB1 complex we replaced threonine 185 of p38α with glycine (T185G) to prevent an intramolecular hydrogen bond with Asp150 from being formed. This mutation did not interfere with TAB1 binding to p38α. However, it disrupted the consequent long-range effect of this binding event on the distal activation segment, releasing the constraint on Thr180 that oriented its hydroxyl for phosphotransfer. Based on assays performed in vitro and in vivo, the autoactivation of p38α(T185G) was disabled, while its ability to be activated by upstream MAP2Ks and to phosphorylate downstream substrates remained intact. Furthermore, myocardial cells expressing p38α(T185G) were resistant to injury. These findings reveal a mechanism to selectively disable p38α autoactivation and its consequences, which may ultimately circumvent the toxicity associated with strategies that inhibit p38α kinase activity under all circumstances, such as with ATP-competitive inhibitors.</p

An insight into the diet and prey preference of tigers in Bardia National Park, Nepal

Conservation Biolog