33 research outputs found
Neuronal networks provide rapid neuroprotection against spreading toxicity
Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients. Here, using hippocampal neurons (DIV 15-20) cultured in microfluidic devices in order to deliver a localized excitotoxic insult, we replicate secondary spreading toxicity and demonstrate that this process is driven by GluN2B receptors. In addition to the modeling of spreading toxicity, this approach has uncovered a previously unknown, fast acting, GluN2A-dependent neuroprotective signaling mechanism. This mechanism utilizes the innate capacity of surrounding neuronal networks to provide protection against both forms of spreading neuronal toxicity, synaptic hyperactivity and direct glutamate excitotoxicity. Importantly, network neuroprotection against spreading toxicity can be effectively stimulated after an excitotoxic insult has been delivered, and may identify a new therapeutic window to limit brain damage
Generation and characterization of a defective HIV-1 Virus as an immunogen for a therapeutic vaccine
BACKGROUND: The generation of new immunogens able to elicit strong specific immune responses remains a major challenge in the attempts to obtain a prophylactic or therapeutic vaccine against HIV/AIDS. We designed and constructed a defective recombinant virus based on the HIV-1 genome generating infective but non-replicative virions able to elicit broad and strong cellular immune responses in HIV-1 seropositive individuals. RESULTS: Viral particles were generated through transient transfection in producer cells (293-T) of a full length HIV-1 DNA carrying a deletion of 892 base pairs (bp) in the pol gene encompassing the sequence that codes for the reverse transcriptase (NL4-3/ΔRT clone). The viral particles generated were able to enter target cells, but due to the absence of reverse transcriptase no replication was detected. The immunogenic capacity of these particles was assessed by ELISPOT to determine γ-interferon production in a cohort of 69 chronic asymptomatic HIV-1 seropositive individuals. Surprisingly, defective particles produced from NL4-3/ΔRT triggered stronger cellular responses than wild-type HIV-1 viruses inactivated with Aldrithiol-2 (AT-2) and in a larger proportion of individuals (55% versus 23% seropositive individuals tested). Electron microscopy showed that NL4-3/ΔRT virions display immature morphology. Interestingly, wild-type viruses treated with Amprenavir (APV) to induce defective core maturation also induced stronger responses than the same viral particles generated in the absence of protease inhibitors. CONCLUSIONS: We propose that immature HIV-1 virions generated from NL4-3/ΔRT viral clones may represent new prototypes of immunogens with a safer profile and stronger capacity to induce cellular immune responses than wild-type inactivated viral particles.This study was supported by grants FIS PI050265, FIS PI040503, FIS PI070291, FIS Intrasalud 080752, FIS PS09/01297, FIS PI10/02984, SAF2006-26667-E, FIT 09-010-205-9, FIPSE 36780/08, Fundación Mútua Madrileña, TRA-094, EC10-153, ISCIII-RETIC RD06/0006, HIVACAT–HIV Development Program in Catalonia, FIPSE 36630/07, UE Program Health 2009 CHAARM. Spanish Health Institute Carlos III (ISCIII) and the Health Department of the Catalan Government (Generalitat de Catalunya). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S
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National Institutes of Health StrokeNet Training Core
Background and Purpose- The National Institutes of Health (NIH) StrokeNet provides a nationwide infrastructure to advance stroke research. Capitalizing on this unique opportunity, the NIH StrokeNet Training Core (NSTC) was established with the overarching goal of enhancing the professional development of a diverse spectrum of professionals who are embedded in the stroke clinical trials network of the NIH StrokeNet. Methods- This special report provides a descriptive account of the rationale, organization, and activities of the NSTC since its inception in 2013. Current processes and their evolution over time for facilitating training of NIH StrokeNet trainees have been highlighted. Data collected for monitoring training are summarized. Outcomes data (publications and grants) collected by NSTC was supplemented by publicly available resources. Results- The NSTC comprises of cross-network faculty, trainees, and education coordinators. It helps in the development and monitoring of training programs and organizes educational and career development activities. Trainees are provided directed guidance towards their mandated research projects, including opportunities to present at the International Stroke Conference. The committee has focused on developing sustainable models of peer-to-peer interaction and cross-institutional mentorships. A total of 124 professionals (43.7% female, 10.5% underrepresented minorities) have completed training between 2013 and 2018, of whom 55% were clinical vascular neurologists. Of the total, 85% transitioned to a formal academic position and 95% were involved in stroke research post-training. Altogether, 1659 indexed publications have been authored or co-authored by NIH StrokeNet Trainees, of which 58% were published during or after their training years. Based on data from 109 trainees, 33% had submitted 72 grant proposals as principal or co-principal investigators of which 22.2% proposals have been funded. Conclusions- NSTC has provided a foundation to foster nationwide training in stroke research. Our data demonstrate strong contribution of trainees towards academic scholarship. Continued innovation in educational methodologies is required to adapt to unique training opportunities such as the NIH StrokeNet