Dynamic publication model for neurophysiology databases.

We have implemented a pair of database projects, one serving cortical electrophysiology and the other invertebrate neurones and recordings. The design for each combines aspects of two proven schemes for information interchange. The journal article metaphor determined the type, scope, organization and quantity of data to comprise each submission. Sequence databases encouraged intuitive tools for data viewing, capture, and direct submission by authors. Neurophysiology required transcending these models with new datatypes. Time-series, histogram and bivariate datatypes, including illustration-like wrappers, were selected by their utility to the community of investigators. As interpretation of neurophysiological recordings depends on context supplied by metadata attributes, searches are via visual interfaces to sets of controlled-vocabulary metadata trees. Neurones, for example, can be specified by metadata describing functional and anatomical characteristics. Permanence is advanced by data model and data formats largely independent of contemporary technology or implementation, including Java and the XML standard. All user tools, including dynamic data viewers that serve as a virtual oscilloscope, are Java-based, free, multiplatform, and distributed by our application servers to any contemporary networked computer. Copyright is retained by submitters; viewer displays are dynamic and do not violate copyright of related journal figures. Panels of neurophysiologists view and test schemas and tools, enhancing community support

Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice

Objective: Elevated homocysteine concentrations are a risk factor for stroke. A common genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR 677 C→T) results in elevated levels of homocysteine. MTHFR plays a critical role in the synthesis of S-adenosylmethionine (SAM), a global methyl donor. Our previous work has demonstrated that Mthfr+/- mice, which model the MTHFR polymorphism in humans, are more vulnerable to ischemic damage. The aim of this study was to investigate the cellular mechanisms by which the MTHFR-deficiency changes the brain in the context of ischemic stroke injury. Methods: In the present study, three-month-old male Mthfr+/- and wild-type littermate mice were subjected to photothrombosis (PT) damage. Four weeks after PT damage, animals were tested on behavioral tasks, in vivo imaging was performed using T2-weighted MRI, and brain tissue was collected for histological analysis. Results:Mthfr+/- animals used their non-impaired forepaw more to explore the cylinder and had a larger damage volume compared to wild-type littermates. In brain tissue of Mthfr+/- mice methionine adenosyltransferase II alpha (MAT2A) protein levels were decreased within the damage hemisphere and increased levels in hypoxia-induced factor 1 alpha (HIF-1α) in non-damage hemisphere. There was an increased antioxidant response in the damage site as indicated by higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2) in neurons and astrocytes

Tetracyclines That Promote SMN2 Exon 7 Splicing as Therapeutics for Spinal Muscular Atrophy

There is at present no cure or effective therapy for spinal muscular atrophy (SMA), a neurodegenerative disease that is the leading genetic cause of infant mortality. SMA usually results from loss of the SMN1 (survival of motor neuron 1) gene, which leads to selective motor neuron degeneration. SMN2 is nearly identical to SMN1 but has a nucleotide replacement that causes exon 7 skipping, resulting in a truncated, unstable version of the SMA protein. SMN2 is present in all SMA patients, and correcting SMN2 splicing is a promising approach for SMA therapy. We identified a tetracycline-like compound, PTK-SMA1, which stimulates exon 7 splicing and increases SMN protein levels in vitro and in vivo in mice. Unlike previously identified molecules that stimulate SMN production via SMN2 promoter activation or undefined mechanisms, PTK-SMA1 is a unique therapeutic candidate in that it acts by directly stimulating splicing of exon 7. Synthetic small-molecule compounds such as PTK-SMA1 offer an alternative to antisense oligonucleotide therapies that are being developed as therapeutics for a number of disease-associated splicing defects