Molecular Control of the Amount, Subcellular Location and Activity State of Translation Elongation Factor 2 (eEF-2) in Neurons Experiencing Stress

Eukaryotic elongation factor 2 (eEF-2) is an important regulator of the protein translation machinery wherein it controls the movement of the ribosome along the mRNA. The activity of eEF-2 is regulated by changes in cellular energy status and nutrient availability, and posttranslational modifications such as phosphorylation and mono-ADP-ribosylation. However, the mechanisms regulating protein translation under conditions of cellular stress in neurons are unknown. Here we show that when rat hippocampal neurons experience oxidative stress (lipid peroxidation induced by exposure to cumene hydroperoxide; CH), eEF-2 is hyperphosphorylated and ribosylated resulting in reduced translational activity. The degradation of eEF-2 requires calpain proteolytic activity and is accompanied by accumulation of eEF-2 in the nuclear compartment. The subcellular localization of both native and phosphorylated forms of eEF-2 is influenced by CRM1 and 14.3.3, respectively. In hippocampal neurons p53 interacts with non-phosphorylated (active) eEF-2, but not with its phosphorylated form. The p53 – eEF-2 complexes are present in cytoplasm and nucleus, and their abundance increases when neurons experience oxidative stress. The nuclear localization of active eEF-2 depends upon its interaction with p53, as cells lacking p53 contain less active eEF-2 in the nuclear compartment. Overexpression of eEF-2 in hippocampal neurons results in increased nuclear levels of eEF-2, and decreased cell death following exposure to CH. Our results reveal novel molecular mechanisms controlling the differential subcellular localization and activity state of eEF-2 that may influence the survival status of neurons during periods of elevated oxidative stress.España, Ministerio de Ciencia e Innovación BFU2010-20882.España, Ministerio de Educación, Cultura y Deporte postdoctoral fellowship (EX2009-0918

Infrastructure for Open Access: Mechanics, Economics, Politics

Using the Pennsylvania State University Libraries as a case study, this essay explores the development of a library-based open access publishing program, and illustrates how open access library publishing can facilitate open access models by providing additional infrastructure for the dissemination of scholarly content

Cytochalasins Useful in Providing Protection Against Nerve Cell Injury Associated with Neurodegenerative Disorders

The present invention relates to novel therapeutic uses of certain compounds to protect nerve cells from injury and death. The compounds include cytochalasin D and related analogs, and cytochalasin E and related analogs

MLPerf Inference Benchmark

Machine-learning (ML) hardware and software system demand is burgeoning. Driven by ML applications, the number of different ML inference systems has exploded. Over 100 organizations are building ML inference chips, and the systems that incorporate existing models span at least three orders of magnitude in power consumption and five orders of magnitude in performance; they range from embedded devices to data-center solutions. Fueling the hardware are a dozen or more software frameworks and libraries. The myriad combinations of ML hardware and ML software make assessing ML-system performance in an architecture-neutral, representative, and reproducible manner challenging. There is a clear need for industry-wide standard ML benchmarking and evaluation criteria. MLPerf Inference answers that call. In this paper, we present our benchmarking method for evaluating ML inference systems. Driven by more than 30 organizations as well as more than 200 ML engineers and practitioners, MLPerf prescribes a set of rules and best practices to ensure comparability across systems with wildly differing architectures. The first call for submissions garnered more than 600 reproducible inference-performance measurements from 14 organizations, representing over 30 systems that showcase a wide range of capabilities. The submissions attest to the benchmark's flexibility and adaptability.Comment: ISCA 202

VIEWPOINT: MECHANISMS OF ACTION AND THERAPEUTIC POTENTIAL OF NEUROHORMETIC PHYTOCHEMICALS

The nervous system is of fundamental importance in the adaptive (hormesis) responses of organisms to all types of stress, including environmental “toxins”. Phytochemicals present in vegetables and fruits are believed to reduce the risk of several major diseases including cardiovascular disease, cancers and neurodegenerative disorders. Although antioxidant properties have been suggested as the basis of health benefits of phytochemicals, emerging findings suggest a quite different mechanism of action. Many phytochemicals normally function as toxins that protect the plants against insects and other damaging organisms. However, at the relatively low doses consumed by humans and other mammals these same “toxic” phytochemicals activate adaptive cellular stress response pathways that can protect the cells against a variety of adverse conditions. Recent findings have elucidated hormetic mechanisms of action of phytochemicals (e.g., resveratrol, curcumin, sulforaphanes and catechins) using cell culture and animal models of neurological disorders. Examples of hormesis pathways activated by phytochemicals include the transcription factor Nrf-2 which activates genes controlled by the antioxidant response element, and histone deacetylases of the sirtuin family and FOXO transcription factors. Such hormetic pathways stimulate the production of antioxidant enzymes, protein chaperones and neurotrophic factors. In several cases neurohormetic phytochemicals have been shown to suppress the disease process in animal models relevant to neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, and can also improve outcome following a stroke. We are currently screening a panel of biopesticides in order to establish hormetic doses, neuroprotective efficacy, mechanisms of action and therapeutic potential as dietary supplements