Insights into channel function via channel dysfunction

The nicotinic synapse has been a touchstone for advances in neuroscience ever since Jean Nicot, the French ambassador to Portugal, sent some tobacco seeds home to Paris in 1550 with a note that the New World plant had interesting effects when smoked. Now the muscle nicotinic acetylcholine receptor (nAChR) is a well-studied example of ligand-gated ion channels. After a motor neuron is stimulated, the nerve impulse reaches the presynaptic terminal, where it evokes release of acetylcholine (ACh) into the synapse. The nAChR depolarizes the postsynaptic muscle and triggers muscle action potentials; muscle contraction follows. To date, several nAChR subtypes have been successfully isolated, purified, imaged, and expressed, and unitary currents have been recorded from these channels (1). Researchers continue to unravel the molecular mechanisms of these macromolecules that are embedded in membranes at vertebrate nerve-muscle synapses, at invertebrate nicotinic synapses (which explains why nicotine-producing tobacco plants have a select advantage against invertebrate pests), and in the vertebrate central system (which explains Jean Nicot’s fascination with those leaves). However, the precise structural events that trigger channel opening or "gating" remain mostly unknown

Mutations Linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Affect Allosteric Ca²⁺ Activation of the α4β2 Nicotinic Acetylcholine Receptor

Extracellular Ca²⁺ robustly potentiates the acetylcholine response of α4β2 nicotinic receptors. Rat orthologs of five mutations linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)—α4(S252F), α4(S256L), α4(+L264), β2(V262L), and β2(V262M)—reduced 2 mM Ca²⁺ potentiation of the α4β2 1 mM acetylcholine response by 55 to 74%. To determine whether altered allosteric Ca²⁺ activation or enhanced Ca²⁺ block caused this reduction, we coexpressed the rat ADNFLE mutations with an α4 N-terminal mutation, α4(E180Q), that abolished α4β2 allosteric Ca²⁺ activation. In each case, Ca²⁺ inhibition of the double mutants was less than that expected from a Ca²⁺ blocking mechanism. In fact, the effects of Ca²⁺ on the ADNFLE mutations near the intracellular end of the M2 region—α4(S252F) and α4(S256L)—were consistent with a straightforward allosteric mechanism. In contrast, the effects of Ca²⁺ on the ADNFLE mutations near the extracellular end of the M2 region—α4(+L264)β2, β2(V262L), and β2(V262M)—were consistent with a mixed mechanism involving both altered allosteric activation and enhanced block. However, the effects of 2 mM Ca²⁺ on the α4β2, α4(+L264)β2, and α4β2(V262L) single-channel conductances, the effects of membrane potential on the β2(V262L)-mediated reduction in Ca²⁺ potentiation, and the effects of eliminating the negative charges in the extracellular ring on this reduction failed to provide any direct evidence of mutant-enhanced Ca²⁺ block. Moreover, analyses of the α4β2, α4(S256L), and α4(+L264) Ca²⁺ concentration-potentiation relations suggested that the ADNFLE mutations reduce Ca²⁺ potentiation of the α4β2 acetylcholine response by altering allosteric activation rather than by enhancing block

Importance, but not intensity of plant interactions relates to species diversity under the interplay of stress and disturbance

The lack of clarity on how the intensity and importance of plant interactions change under the co-occurrence of stress and disturbance strongly impedes assessing the relative importance of plant interactions for species diversity. We addressed this issue in subalpine grasslands of the French Pyrenees. A natural soil moisture gradient further experimentally stretched at both ends was used and a mowing disturbance treatment was applied at each position along the soil moisture gradient. Changes in intensity and importance of plant interactions were assessed by a neighbour removal experiment using four target ecotypes. A structural equation modelling approach was used to assess the relative impact of stress, disturbance, the intensity and importance of plant interactions on diversity at both the neighbourhood and community scales. Without mowing, changes in intensity and importance of plant interactions only diverged in the dry part of the soil moisture gradient. The intensity of plant interactions linearly shifted from competition to facilitation with increasing stress, while the importance followed a hump-shaped relationship. Species diversity components were tightly related to the importance of plant interactions only, both the neighbourhood and community scales. Mowing disturbance strongly reduced the importance of facilitation along the soil moisture gradient, and suppressed the relationship between the importance of plant interactions and diversity components. Together, our results highlight that 1) the importance is the best predictor of variations in species diversity in this subalpine herbaceous system, and 2) that fine-scale processes such as plant interactions can affect the entire plant communities. Finally, our results suggest that high level of constraints due to co-occurring stress and disturbance can inhibit the effects of plant interactions on species diversity, highlighting their potential role in regulating diversity and the maintenance/extinction of plant communities. The co-occurrence of stress (i.e. factors such as drought limiting plant growth, sensu Grime 1973) and disturbance (drastic events such as mowing removing plant biomass) can lead to a rapid loss of diversity. Co-occurring negative effects of stress and disturbance on diversity and ecosystem functioning are specific to severe environments such as alpine grasslands or dry steppes OIKOS How plant interactions change along environmental gradients is an unsolved debate, particularly when both stress and disturbance interact. This lack of clarity explains why the relative impact of plant interactions (intensity and importance) on species diversity has been rarely assessed. Using an experimental approach, we found that the importance of plant interactions highly contributed to variation in species diversity, confirming that neighbourhood scale processes such as plant interactions can affect the entire plant communities. The co-occurrence of stress and disturbance inhibited the effects of plant interactions, highlighting that plant interactions may regulate drops of diversity and the maintenance/ extinction of plant communities. Synthesi

Un cas de peste dans une sépulture du XIVe siècle creusée dans la roche : le diagnostic de la chapelle de Barain à Avosnes (Côte-d’Or)

Lors d’un diagnostic réalisé par l’Inrap en 2014 à la chapelle de Barain (Avosnes), des sépultures creusées dans la roche ont pu être mises en évidence, alors que celles-ci sont relativement rares en Bourgogne. L’une d’elles présentait une monnaie datée 1347/1348, période de la Grande Peste. Des tests biomoléculaires ont été effectués sur les ossements pour déterminer l’éventuelle présence du pathogène : ces derniers se sont révélés positifs.During an excavation by Inrap in 2014 at the chapel of Barain (Avosnes), graves excavated in stone were discovered, a relatively rare occurrence in Burgundy. One grave was found to contain a coin dated 1347/1348, the period of the Black Death. Biomolecular tests were undertaken and have revealed the presence of plague pathogens.Anlässlich einer Prospektion des Inrap wurden 2014 in der Kapelle von Barain (Avosnes) in den Felsen gehauene Gräber freigelegt. Diese Art Bestattung ist in der Bourgogne relativ selten. In einer der Grabstätten wurde eine Münze aus den Jahren 1347/1348, der Zeit der Großen Pest, gefunden. An den Knochen wurden biomolekulare Tests vorgenommen, um eine mögliche Präsenz des Pesterregers festzustellen: Die Test erwiesen sich als positiv

Alésia : un nouvel atelier de bronzier dans le quartier des Champs de l’Église

L’oppidum d’Alésia en Côte-d’Or, sur le territoire de la commune d’Alise-Sainte-Reine, a été occupé par une agglomération gallo-romaine du Ier jusqu’au IVe siècle ap. J.-C. De 1997 à 2003, des fouilles ont été réalisées au lieu-dit Les Champs de l’Église, situé à proximité du cimetière actuel. Trois bâtiments ont été mis au jour ainsi que des inhumations d’époque mérovingiennes. Seuls les vestiges d’un des bâtiments restent bien conservés, permettant d’identifier plusieurs phases : un atelier lié à la métallurgie du bronze et un bâtiment à vocation domestique.The oppidum of Alésia is located in the Côte-d’Or department in the village of Alise-Sainte-Reine. This site was occupied by a Gallo-roman agglomeration from the Ist century A.D. to the IVth century A.D. From 1997 to 2003, excavations were carried out at “Champs de l’Eglise”, a site near the village cemetery. Three Gallo-roman buildings and several Merovingian graves were found. Only one of the buildings was well enough preserved to observe different chronological phases, one linked to bronze working, another to a dwelling.An der Stelle des Oppidums von Alésia (Departement Côte-d’Or) auf dem Gebiet der Gemeinde Alise-Sainte-Reine bestand vom 1. bis 4. Jh. n. Chr. eine gallo-römische Siedlung. Von 1997 bis 2003 wurden am Ort mit der Flurbezeichnung „Les Champs de l’Eglise“, in der Nähe des heutigen Friedhofs, Grabungen durchgeführt. Drei Gebäude sind zutage gekommen sowie Bestattungen aus merowingischer Zeit. Nur die Überreste eines dieser drei Gebäude erlauben es, verschiedene Phasen zu erkennen: eine Werkstatt, die in Zusammenhang mit der Bronzemetallurgie steht und ein Wohngebäude

New imidazo[1,2-a]quinoxaline derivatives: Synthesis and in vitro activity against human melanoma

International audienceNew imidazo[1,2-a]quinoxaline analogues have been synthesized in good yields via a bimolecular condensation of 2-imidazole carboxylic acid, followed by a coupling with ortho-fluoroaniline and subsequent substitution on the imidazole ring by Suzuki Cross-coupling reaction using microwave assistance. Antitumor activities of these derivatives were evaluated by growth inhibition of A375 cells in vitro. All compounds exhibited high activities compared to imiquimod and fotemustine used as references

Tumour biology, metastatic sites and taxanes sensitivity as determinants of eribulin mesylate efficacy in breast cancer: results from the ERIBEX retrospective, international, multicenter study.

BACKGROUND: Our retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting. METHODS: Patients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data. RESULTS: Two hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [1-9]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [1-19]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20-31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25-4.3) and 11.2 (95 %CI: 9.3-12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3-4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia. CONCLUSION: EM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors

The BIODESERT survey: assessing the impacts of grazing on the structure and functioning of global drylands

Grazing by domestic livestock is both the main land use across drylands worldwide and a major desertification and global change driver. The ecological consequences of this key human activity have been studied for decades, and there is a wealth of information on its impacts on biodiversity and ecosystem processes. However, most field assessments of the ecological impacts of grazing on drylands conducted to date have been carried out at local or regional scales and have focused on single ecosystem attributes (e.g., plant productivity) or particular taxa (mainly aboveground, e.g., plants). Here we introduce the BIODESERT survey, the first systematic field survey devoted to evaluating the joint impacts of grazing by domestic livestock and climate on the structure and functioning of dryland ecosystems worldwide. This collaborative global survey was carried out between 2016 and 2019 and has involved the collection of field data and plant, biocrust, and soil samples from a total of 326 45 m × 45 m plots from 98 sites located in 25 countries from 6 continents. Here we describe the major characteristics and the field protocols used in this survey. We also introduce the organizational aspects followed, as these can be helpful to everyone wishing to establish a global collaborative network of researchers. The BIODESERT survey provides baseline data to assess the current status of dryland rangelands worldwide and the impacts of grazing on these key ecosystems, and it constitutes a good example of the power of collaborative research networks to study the ecology of our planet using much-needed field data.This research has been supported by the European Research Council (ERC grant agreement no. 647038 – BIODESERT) and the Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana (grant no. CIDEGENT/2018/041). Nicolas Gross was supported by CAP 20-25 (16-IDEX-0001) and the AgreenSkills+ fellowship program which has received funding from the EU's Seventh Framework Programme under grant agreement no. 996 FP7-609398 (AgreenSkills+ contract). Hugo Saiz is supported by a María Zambrano fellowship funded by the Ministry of Universities and European Union Next Generation plan