Amplified Cold Transduction in Native Nociceptors by M-Channel Inhibition

Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8(transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-based screening assay and heterologously expressed potassium channels, we found that the effects of camphor are mediated by inhibition of K(v)7.2/3 channels subtypes that generate the M-current in neurons. In line with this finding, the specific M-current blocker XE991 reproduced the cold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol-like camphor-potently inhibits K(v)7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia

Landscape-use optimisation with regards to the groundwater resources protection in mountain hardrock areas, LOWRGREP

Synthesis of work performed during the European Project LOWRGREPThis report assesses the degree of interference of human activities with the hydrosphere in mountain-zones, all located in hard-rock areas of different countries in the European Union. Each of the test-regions has a specific degree of protection: from regions with very few inhabitants and very low human impact, to regions submitted to a strong anthropogenic impact. The investigations focused on the changes in water quality and on the simulation of various alternatives leading to optimum landscape-use from the point of view of water-management. The project's own Geographic Information System was used to fulfil the following objective: present all the obtained knowledge and analyse all the data in user-friendly form (maps of water vulnerability) and make this knowledge available for potential users with, for instance, the creation and use of a web site. A simulation tool has been developed which facilitates the assessment of the impact of landscape-use on the water budget of the catchment. In all the areas investigated chloride is present, only in winter and very close to roads. Another result of this work is the decreasing impact on water of sulphur and sulphuric compounds in Germany and in the Czech Republic, while the nitrogen impact is increasing. Recommendations concerning the landscape-use presented for all the regions in particular for good practices in agricultur

Groundwater dependent ecosystems. Part I: Hydroecological status and trends

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Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment. Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the tumor microenvironment and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that tumor microenvironment is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including anti-tumor agents with those targeting stromal cell metabolism, anti-angiogenic drugs and/or immunotherapy are being developed as promising therapeutics.Mª Carmen Ocaña is recipient of a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sport. Supported by grants BIO2014-56092-R (MINECO and FEDER), P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

The core domain as the force sensor of the yeast mechanosensitive TRP channel

Stretch-activated conductances are commonly encountered in careful electric recordings. Those of known proteins (TRP, MscL, MscS, K2p, Kv, etc.) all share a core, which houses the ion pathway and the gate, but no recognizable force-sensing domain. Like animal TRPs, the yeast TRPY1 is polymodal, activated by stretch force, Ca2+, etc. To test whether its S5–S6 core senses the stretch force, we tried to uncouple it from the peripheral domains by strategic peptide insertions to block the covalent core–periphery interactions. Insertion of long unstructured peptides should distort, if not disrupt, protein structures that transmit force. Such insertions between S6 and the C-terminal tail largely removed Ca2+ activation, showing their effectiveness. However, such insertions as well as those between S5 and the N-terminal region, which includes S1–S4, did not significantly alter mechanosensitivity. Even insertions at both locations flanking the S5–S6 core did not much alter mechanosensitivity. Tryptophan scanning mutations in S5 were also constructed to perturb possible noncovalent core–periphery contacts. The testable tryptophan mutations also have little or no effects on mechanosensitivity. Boltzmann fits of the wild-type force–response curves agree with a structural homology model for a stretch-induced core expansion of ∼2 nm2 upon opening. We hypothesize that membrane tension pulls on S5–S6, expanding the core and opening the TRPY1 gate. The core being the major force sensor offers the simplest, though not the only, explanation of why so many channels of disparate designs are mechanically sensitive. Compared with the bacterial MscL, TRPY1 is much less sensitive to force, befitting a polymodal channel that relies on multiple stimuli

Geophysical Monitoring System (GMS)

More than 500,000 km of embankment are used in Europe for transport and flood defence, representing a \u80 1bn infrastructure asset base, which supports and protects the economy of Europe (e.g. property worth some \u80 2,000 bn is protected from flooding.) Presently the state and performance of these embankments can only be investigated visually or by slow intrusive methods (boreholes etc.) Potential now exists to apply a geophysical investigation tool, originally developed for military applications, for rapid non-intrusive identification of \u91hot spots\u92 of deterioration in embankments. Better targeting of maintenance interventions using this approach will achieve substantial whole-life cost savings and avoid failures costly for the economy and society. Geophysical investigation involves generating electro-magnetic fields and mapping their propagation through soils and structures. The method finds perturbations in the electro-magnetic fields arising from concealed boundaries or changed materials.Floodsit

New transitional pathways in direct marketing of food: Case study on farmers' markets in the Czech Republic

The paper focuses on the phenomenon farmers‘ markets in the Czech Republic. Boom of the farmers’ markets is used as an illustration for ongoing transition process within agrofood regime. The paper provides information about the incumbent regime (based on sale of food via large retail chain store) and the alternative initiative and its logic. The farmer’s markets have developed from previous marginal activities framed by the alternative food networks. Using the secondary sources and empirical material (16 interviews) there is in details described the mechanisms of anchorage that enables the initiative to gain new position in the regime. The analysis shows that the success of the initiative has been conditioned by several factors that have aligned and created a stable structure in the regime