Regulation of NMDA Receptor Signaling at Single Synapses by Human Anti-NMDA Receptor Antibodies

The NMDA receptor (NMDAR) subunit GluN1 is critical for receptor function and plays a pivotal role in synaptic plasticity. Mounting evidence has shown that pathogenic autoantibody targeting of the GluN1 subunit of NMDARs, as in anti-NMDAR encephalitis, leads to altered NMDAR trafficking and synaptic localization. However, the underlying signaling pathways affected by antibodies targeting the NMDAR remain to be fully delineated. It remains unclear whether patient antibodies influence synaptic transmission via direct effects on NMDAR channel function. Here, we show using short-term incubation that GluN1 antibodies derived from patients with anti-NMDAR encephalitis label synapses in mature hippocampal primary neuron culture. Miniature spontaneous calcium transients (mSCaTs) mediated via NMDARs at synaptic spines are not altered in pathogenic GluN1 antibody exposed conditions. Unexpectedly, spine-based and cell-based analyses yielded distinct results. In addition, we show that calcium does not accumulate in neuronal spines following brief exposure to pathogenic GluN1 antibodies. Together, these findings show that pathogenic antibodies targeting NMDARs, under these specific conditions, do not alter synaptic calcium influx following neurotransmitter release. This represents a novel investigation of the molecular effects of anti-NMDAR antibodies associated with autoimmune encephalitis

The type VI secretion system of Xanthomonas phaseoli pv. manihotis is involved in virulence and in vitro motility.

BACKGROUND: The type VI protein secretion system (T6SS) is important in diverse cellular processes in Gram-negative bacteria, including interactions with other bacteria and with eukaryotic hosts. In this study we analyze the evolution of the T6SS in the genus Xanthomonas and evaluate its importance of the T6SS for virulence and in vitro motility in Xanthomonas phaseoli pv. manihotis (Xpm), the causal agent of bacterial blight in cassava (Manihot esculenta). We delineate the organization of the T6SS gene clusters in Xanthomonas and then characterize proteins of this secretion system in Xpm strain CIO151. RESULTS: We describe the presence of three different clusters in the genus Xanthomonas that vary in their organization and degree of synteny between species. Using a gene knockout strategy, we also found that vgrG and hcp are required for maximal aggressiveness of Xpm on cassava plants while clpV is important for both motility and maximal aggressiveness. CONCLUSION: We characterized the T6SS in 15 different strains in Xanthomonas and our phylogenetic analyses suggest that the T6SS might have been acquired by a very ancient event of horizontal gene transfer and maintained through evolution, hinting at their importance for the adaptation of Xanthomonas to their hosts. Finally, we demonstrated that the T6SS of Xpm is functional, and significantly contributes to virulence and motility. This is the first experimental study that demonstrates the role of the T6SS in the Xpm-cassava interaction and the T6SS organization in the genus Xanthomonas

New insights into the classification and nomenclature of cortical GABAergic interneurons.

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus

Soil: the great connector of our lives now and beyond COVID-19

Humanity depends on the existence of healthy soils, both for the production of food and for ensuring a healthy, biodiverse environment, among other functions. COVID-19 is threatening food availability in many places of the world due to the disruption of food chains, lack of workforce, closed borders and national lockdowns. As a consequence, more emphasis is being placed on local food production, which may lead to more intensive cultivation of vulnerable areas and to soil degradation. In order to increase the resilience of populations facing this pandemic and future global crises, transitioning to a paradigm that relies more heavily on local food production on soils that are carefully tended and protected through sustainable management is necessary. To reach this goal, the Intergovernmental Technical Panel on Soils (ITPS) of the Food and Agriculture Organization of the United Nations (FAO) recommends five active strategies: improved access to land, sound land use planning, sustainable soil management, enhanced research, and investments in education and extension

PSD95 nanoclusters are postsynaptic building blocks in hippocampus circuits

The molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity.Support from the Wellcome Trust, Medical Research Council, European Commission.This is the final version of the article. It first appeared from Nature Publishing Group via https://doi.org/10.1038/srep2462

PSD95 nanoclusters are postsynaptic building blocks in hippocampus circuits.

The molecular features of synapses in the hippocampus underpin current models of learning and cognition. Although synapse ultra-structural diversity has been described in the canonical hippocampal circuitry, our knowledge of sub-synaptic organisation of synaptic molecules remains largely unknown. To address this, mice were engineered to express Post Synaptic Density 95 protein (PSD95) fused to either eGFP or mEos2 and imaged with two orthogonal super-resolution methods: gated stimulated emission depletion (g-STED) microscopy and photoactivated localisation microscopy (PALM). Large-scale analysis of ~100,000 synapses in 7 hippocampal sub-regions revealed they comprised discrete PSD95 nanoclusters that were spatially organised into single and multi-nanocluster PSDs. Synapses in different sub-regions, cell-types and locations along the dendritic tree of CA1 pyramidal neurons, showed diversity characterised by the number of nanoclusters per synapse. Multi-nanocluster synapses were frequently found in the CA3 and dentate gyrus sub-regions, corresponding to large thorny excrescence synapses. Although the structure of individual nanoclusters remained relatively conserved across all sub-regions, PSD95 packing into nanoclusters also varied between sub-regions determined from nanocluster fluorescence intensity. These data identify PSD95 nanoclusters as a basic structural unit, or building block, of excitatory synapses and their number characterizes synapse size and structural diversity.Support from the Wellcome Trust, Medical Research Council, European Commission.This is the final version of the article. It first appeared from Nature Publishing Group via https://doi.org/10.1038/srep2462

Green Criminology Before ‘Green Criminology’: Amnesia and Absences

Although the first published use of the term ‘green criminology’ seems to have been made by Lynch (Green criminology. Aldershot, Hampshire, 1990/2006), elements of the analysis and critique represented by the term were established well before this date. There is much criminological engagement with, and analysis of, environmental crime and harm that occurred prior to 1990 that deserves acknowledgement. In this article, we try to illuminate some of the antecedents of green criminology. Proceeding in this way allows us to learn from ‘absences’, i.e. knowledge that existed but has been forgotten. We conclude by referring to green criminology not as an exclusionary label or barrier but as a symbol that guides and inspires the direction of research

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

Altres ajuts: Bayer HealthCare Pharmaceuticals Inc.Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C. Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifier: NCT02835924