Quantification of the density of cooperative neighboring synapses required to evoke endocannabinoid signaling

The spatial pattern of synapse activation may impact on synaptic plasticity. This applies to the synaptically-evoked endocannabinoid-mediated short-term depression at the parallel fiber (PF) to Purkinje cell synapse, the occurrence of which requires close proximity between the activated synapses. Here, we determine quantitatively this required proximity, helped by the geometrical organization of the cerebellar molecular layer. Transgenic mice expressing a calcium indicator selectively in granule cells enabled the imaging of action potential-evoked presynaptic calcium rise in isolated, single PFs. This measurement was used to derive the number of PFs activated within a beam of PFs stimulated in the molecular layer, from which the density of activated PFs (input density) was calculated. This density was on average 2.8μm in sagittal slices and twice more in transverse slices. The synaptically-evoked endocannabinoid-mediated suppression of excitation (SSE) evoked by ten stimuli at 200Hz was determined from the monitoring of either postsynaptic responses or presynaptic calcium rise. The SSE was significantly larger when recorded in transverse slices, where the input density is larger. The exponential description of the SSE plotted as a function of the input density suggests that the SSE is half reduced when the input density decreases from 6 to 2μm. We conclude that, although all PFs are truncated in an acute sagittal slice, half of them remain respondent to stimulation, and activated synapses need to be closer than 1.5μm to synergize in endocannabinoid signaling. © 2013 The authors

Renal cell carcinoma: An update for the practicing urologist

AbstractSystemic therapy for metastatic renal cell carcinoma (mRCC) has evolved drastically, with agents targeting vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) now representing a standard of care. The present paper is to review the current status of relevant clinical trials that were either recently completed or ongoing. (1) Though observation remains a standard of care following resection of localized disease, multiple trials are underway to assess VEGF- and mTOR-directed therapies in this setting. (2) While the preponderance of retrospective data favors cytoreductive nephrectomy in the context of targeted agents, prospective data to support this approach is still forthcoming. (3) The first-line management of mRCC may change substantially with multiple studies exploring vaccines, immune checkpoint inhibitors, and novel targeted agents currently underway. In general, prospective studies that will report within the next several years will be critical in defining the role of adjuvant therapy and cytoreductive nephrectomy. Over the same span of time, the current treatment paradigm for first-line therapy may evolve

Persistent Posttetanic Depression at Cerebellar Parallel Fiber to Purkinje Cell Synapses

Plasticity at the cerebellar parallel fiber to Purkinje cell synapse may underlie information processing and motor learning. In vivo, parallel fibers appear to fire in short high frequency bursts likely to activate sparsely distributed synapses over the Purkinje cell dendritic tree. Here, we report that short parallel fiber tetanic stimulation evokes a ∼7-15% depression which develops over 2 min and lasts for at least 20 min. In contrast to the concomitantly evoked short-term endocannabinoid-mediated depression, this persistent posttetanic depression (PTD) does not exhibit a dependency on the spatial pattern of synapse activation and is not caused by any detectable change in presynaptic calcium signaling. This persistent PTD is however associated with increased paired-pulse facilitation and coefficient of variation of synaptic responses, suggesting that its expression is presynaptic. The chelation of postsynaptic calcium prevents its induction, suggesting that post- to presynaptic (retrograde) signaling is required. We rule out endocannabinoid signaling since the inhibition of type 1 cannabinoid receptors, monoacylglycerol lipase or vanilloid receptor 1, or incubation with anandamide had no detectable effect. The persistent PTD is maximal in pre-adolescent mice, abolished by adrenergic and dopaminergic receptors block, but unaffected by adrenergic and dopaminergic agonists. Our data unveils a novel form of plasticity at parallel fiber synapses: a persistent PTD induced by physiologically relevant input patterns, age-dependent, and strongly modulated by the monoaminergic system. We further provide evidence supporting that the plasticity mechanism involves retrograde signaling and presynaptic diacylglycerol

Are Amphipod invaders a threat to the regional biodiversity? Conservation prospects for the Loire River

The impact of invasions on local biodiversity is well established, but their impact on regional biodiversity has so far been only sketchily documented. To address this question, we studied the impact at various observation scales (ranging from the microhabitat to the whole catchment) of successive arrivals of non-native amphipods on the amphipod assemblage of the Loire River basin in France. Amphipod assemblages were studied at 225 sites covering the whole Loire catchment. Non-native species were dominant at all sites in the main channel of the Loire River, but native species were still present at most of the sites. We found that the invaders have failed to colonize most of tributaries of the Loire River. At the regional scale, we found that since the invaders first arrived 25 years ago, the global amphipod diversity has increased by 33% (from 8 to 12 species) due to the arrival of non-native species. We discuss the possibility that the lack of any loss of biodiversity may be directly linked to the presence of refuges at the microhabitat scale in the Loire channel and in the tributaries, which invasive species have been unable to colonize. The restoration of river quality could increase the number of refuges for native species, thus reducing the impact of invader

Prioritization of fish communities with a view to conservation and restoration on a large scale European basin, the Loire (France)

The hierarchical organization of important sites for the conservation or the restoration of fish communities is a great challenge for managers, especially because of financial or time constraints. In this perspective, we developed a methodology, which is easy to implement in different locations. Based on the fish assemblage characteristics of the Loire basin (France), we created a synthetic conservation value index including the rarity, the conservation status and the species origin. The relationship between this new synthetic index and the Fish-Based Index allowed us to establish a classification protocol of the sites along the Loire including fish assemblages to be restored or conserved. Sites presenting disturbed fish assemblages, a low rarity index, few threatened species, and a high proportion of non-native species were considered as important for the restoration of fish biodiversity. These sites were found mainly in areas where the assemblages are typical of the bream zone, e.g. with a higher number of eurytopic and limnophilic species. On the contrary, important sites for conservation were defined as having an important conservation potential (high RI, a lot of threatened species, and few nonnatives fish species) and an undisturbed fish assemblage similar to the expected community if habitats are undisturbed. Important sites for conservation were found in the Loire basin’s medium reaches which host assemblages typical for the grayling and the barbell zones, e.g. with a higher number of rheophilic species. The synthetic conservation value index could be adapted and completed with other criteria according to management priorities and capacities

Assessing the conservation value of waterbodies: the example of the Loire floodplain (France)

In recent decades, two of the main management tools used to stem biodiversity erosion have been biodiversity monitoring and the conservation of natural areas. However, socio-economic pressure means that it is not usually possible to preserve the entire landscape, and so the rational prioritisation of sites has become a crucial issue. In this context, and because floodplains are one of the most threatened ecosystems, we propose a statistical strategy for evaluating conservation value, and used it to prioritise 46 waterbodies in the Loire floodplain (France). We began by determining a synthetic conservation index of fish communities (Q) for each waterbody. This synthetic index includes a conservation status index, an origin index, a rarity index and a richness index. We divided the waterbodies into 6 clusters with distinct structures of the basic indices. One of these clusters, with high Q median value, indicated that 4 waterbodies are important for fish biodiversity conservation. Conversely, two clusters with low Q median values included 11 waterbodies where restoration is called for. The results picked out high connectivity levels and low abundance of aquatic vegetation as the two main environmental characteristics of waterbodies with high conservation value. In addition, assessing the biodiversity and conservation value of territories using our multi-index approach plus an a posteriori hierarchical classification methodology reveals two major interests: (i) a possible geographical extension and (ii) a multi-taxa adaptation

A phase 1 trial of SGNâ CD70A in patients with CD70â positive, metastatic renal cell carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148406/1/cncr31912.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148406/2/cncr31912_am.pd

Garden and landscape-scale correlates of moths of differing conservation status: significant effects of urbanization and habitat diversity

Moths are abundant and ubiquitous in vegetated terrestrial environments and are pollinators, important herbivores of wild plants, and food for birds, bats and rodents. In recent years, many once abundant and widespread species have shown sharp declines that have been cited by some as indicative of a widespread insect biodiversity crisis. Likely causes of these declines include agricultural intensification, light pollution, climate change, and urbanization; however, the real underlying cause(s) is still open to conjecture. We used data collected from the citizen science Garden Moth Scheme (GMS) to explore the spatial association between the abundance of 195 widespread British species of moth, and garden habitat and landscape features, to see if spatial habitat and landscape associations varied for species of differing conservation status. We found that associations with habitat and landscape composition were species-specific, but that there were consistent trends in species richness and total moth abundance. Gardens with more diverse and extensive microhabitats were associated with higher species richness and moth abundance; gardens near to the coast were associated with higher richness and moth abundance; and gardens in more urbanized locations were associated with lower species richness and moth abundance. The same trends were also found for species classified as increasing, declining and vulnerable under IUCN (World Conservation Union) criteria

Oral Insulin

Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation