Interleukin-6 Secretion by Astrocytes Is Dynamically Regulated by PI3K-mTOR-Calcium Signaling

After contusion spinal cord injury (SCI), astrocytes become reactive and form a glial scar. While this reduces spreading of the damage by containing the area of injury, it inhibits regeneration. One strategy to improve the recovery after SCI is therefore to reduce the inhibitory effect of the scar, once the acute phase of the injury has passed. The pleiotropic cytokine interleukin-6 (IL-6) is secreted immediately after injury and regulates scar formation; however, little is known about the role of IL-6 in the sub-acute phases of SCI. Interestingly, IL-6 also promotes axon regeneration, and therefore its induction in reactive astrocytes may improve regeneration after SCI. We found that IL-6 is expressed by astrocytes and neurons one week post-injury and then declines. Using primary cultures of rat astrocytes we delineated the molecular mechanisms that regulate IL-6 expression and secretion. IL-6 expression requires activation of p38 and depends on NF-κB transcriptional activity. Activation of these pathways in astrocytes occurs when the PI3K-mTOR-AKT pathway is inhibited. Furthermore, we found that an increase in cytosolic calcium concentration was necessary for IL-6 secretion. To induce IL-6 secretion in astrocytes, we used torin2 and rapamycin to block the PI3K-mTOR pathway and increase cytosolic calcium, respectively. Treating injured animals with torin2 and rapamycin for two weeks, starting two weeks after injury when the scar has been formed, lead to a modest effect on mechanical hypersensitivity, limited to the period of treatment. These data, taken together, suggest that treatment with torin2 and rapamycin induces IL-6 secretion by astrocytes and may contribute to the reduction of mechanical hypersensitivity after SCI

Imatinib Enhances Functional Outcome after Spinal Cord Injury

We investigated whether imatinib (Gleevec®, Novartis), a tyrosine kinase inhibitor, could improve functional outcome in experimental spinal cord injury. Rats subjected to contusion spinal cord injury were treated orally with imatinib for 5 days beginning 30 minutes after injury. We found that imatinib significantly enhanced blood-spinal cord-barrier integrity, hindlimb locomotor function, sensorimotor integration, and bladder function, as well as attenuated astrogliosis and deposition of chondroitin sulfate proteoglycans, and increased tissue preservation. These improvements were associated with enhanced vascular integrity and reduced inflammation. Our results show that imatinib improves recovery in spinal cord injury by preserving axons and other spinal cord tissue components. The rapid time course of these beneficial effects suggests that the effects of imatinib are neuroprotective rather than neurorestorative. The positive effects on experimental spinal cord injury, obtained by oral delivery of a clinically used drug, makes imatinib an interesting candidate drug for clinical trials in spinal cord injury

Teaching Computation in Neuroscience: Notes on the 2019 Society for Neuroscience Professional Development Workshop on Teaching

The 2019 Society for Neuroscience Professional 1Development Workshop on Teaching reviewed current tools, approaches, and examples for teaching computation in neuroscience. Robert Kass described the statistical foundations that students need to properly analyze data. Pascal Wallisch compared MATLAB and Python as programming languages for teaching students. Adrienne Fairhall discussed computational methods, training opportunities, and curricular considerations. Walt Babiec provided a view from the trenches on practical aspects of teaching computational neuroscience. Mathew Abrams concluded the session with an overview of resources for teaching and learning computational modeling in neuroscience

Recommendations for repositories and scientific gateways from a neuroscience perspective

Digital services such as repositories and science gateways have become key resources for the neuroscience community, but users often have a hard time orienting themselves in the service landscape to find the best fit for their particular needs. INCF (International Neuroinformatics Coordinating Facility) has developed a set of recommendations and associated criteria for choosing or setting up and running a repository or scientific gateway, intended for the neuroscience community, with a FAIR neuroscience perspective. These recommendations have neurosciences as their primary use case but are often general. Considering the perspectives of researchers and providers of repositories as well as scientific gateways, the recommendations harmonize and complement existing work on criteria for repositories and best practices. The recommendations cover a range of important areas including accessibility, licensing, community responsibility and technical and financial sustainability of a service.Comment: 10 pages, submitted to Scientific Dat

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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A Standards Organization for Open and FAIR Neuroscience: the International Neuroinformatics Coordinating Facility

There is great need for coordination around standards and best practices in neuroscience to support efforts to make neuroscience a data-centric discipline. Major brain initiatives launched around the world are poised to generate huge stores of neuroscience data. At the same time, neuroscience, like many domains in biomedicine, is confronting the issues of transparency, rigor, and reproducibility. Widely used, validated standards and best practices are key to addressing the challenges in both big and small data science, as they are essential for integrating diverse data and for developing a robust, effective, and sustainable infrastructure to support open and reproducible neuroscience. However, developing community standards and gaining their adoption is difficult. The current landscape is characterized both by a lack of robust, validated standards and a plethora of overlapping, underdeveloped, untested and underutilized standards and best practices. The International Neuroinformatics Coordinating Facility (INCF), an independent organization dedicated to promoting data sharing through the coordination of infrastructure and standards, has recently implemented a formal procedure for evaluating and endorsing community standards and best practices in support of the FAIR principles. By formally serving as a standards organization dedicated to open and FAIR neuroscience, INCF helps evaluate, promulgate, and coordinate standards and best practices across neuroscience. Here, we provide an overview of the process and discuss how neuroscience can benefit from having a dedicated standards body

Logistic support provided to Australian disaster medical assistance teams: results of a national survey of team members

Background: It is likely that calls for disaster medical assistance teams (DMATs) continue in response to international disasters. As part of a national survey, the present study was designed to evaluate the Australian DMAT experience and the need for logistic support.\ud \ud Methods: Data were collected via an anonymous mailed survey distributed via State and Territory representatives on the Australian Health Protection Committee, who identified team members associated with Australian DMAT deployments from the 2004 Asian Tsunami disaster.\ud \ud Results: The response rate for this survey was 50% (59/118). Most of the personnel had deployed to the South East Asian Tsunami affected areas. The DMAT members had significant clinical and international experience. There was unanimous support for dedicated logistic support with 80% (47/59) strongly agreeing. Only one respondent (2%) disagreed with teams being self sufficient for a minimum of 72 hours. Most felt that transport around the site was not a problem (59%; 35/59), however, 34% (20/59) felt that transport to the site itself was problematic. Only 37% (22/59) felt that pre-deployment information was accurate. Communication with local health providers and other agencies was felt to be adequate by 53% (31/59) and 47% (28/59) respectively, while only 28% (17/59) felt that documentation methods were easy to use and reliable. Less than half (47%; 28/59) felt that equipment could be moved easily between areas by team members and 37% (22/59) that packaging enabled materials to be found easily. The maximum safe container weight was felt to be between 20 and 40 kg by 58% (34/59).\ud \ud Conclusions: This study emphasises the importance of dedicated logistic support for DMAT and the need for teams to be self sufficient for a minimum period of 72 hours. There is a need for accurate pre deployment information to guide resource prioritisation with clearly labelled pre packaging to assist access on site. Container weights should be restricted to between 20 and 40 kg, which would assist transport around the site, while transport to the site was seen as problematic. There was also support for training of all team members in use of basic equipment such as communications equipment, tents and shelters and water purification systems