Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

system. mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging.Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma

Polemics between sages and priests towards the end of the days of the Second Temple.

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Whole-Genome Discovery of Transcription Factor Binding Sites by Network-Level Conservation

Comprehensive identification of DNA cis-regulatory elements is crucial for a predictive understanding of transcriptional network dynamics. Strong evidence suggests that these DNA sequence motifs are highly conserved between related species, reflecting strong selection on the network of regulatory interactions that underlie common cellular behavior. Here, we exploit a systems-level aspect of this conservation—the network-level topology of these interactions—to map transcription factor (TF) binding sites on a genomic scale. Using network-level conservation as a constraint, our algorithm finds 71% of known TF binding sites in the yeast Saccharomyces cerevisiae, using only 12% of the sequence of a phylogenetic neighbor. Most of the novel predicted motifs show strong features of known TF binding sites, such as functional category and/or expression profile coherence of their corresponding genes. Network-level conservation should provide a powerful constraint for the systematic mapping of TF binding sites in the larger genomes of higher eukaryotes

Discovery of Novel Proteasome Inhibitors Using a High- Content Cell-Based Screening System

The regulated degradation of damaged or misfolded proteins, as well as down-regulation of key signaling proteins, within eukaryotic and bacterial cells is catalyzed primarily by large, ATP-dependent multimeric proteolytic complexes, termed proteasomes. Inhibition of proteasomal activity affects a wide variety of physiological and pathological processes, and was found to be particularly effective for cancer therapy. We report here on the development of a novel high throughput assay for proteasome inhibition using a unique, highly sensitive live-cell screening, based on the cytoplasm-to-nucleus translocation of a fluorescent proteasome inhibition reporter (PIR) protein, consisting of nuclear localization signal-deficient p53 derivative. We further show here that mdm2, a key negative regulator of p53 plays a key role in the accumulation of PIR in the nucleus upon proteasome inhibition. Using this assay, we have screened the NCI Diversity Set library, containing 1,992 low molecular weight synthetic compounds, and identified four proteasome inhibitors. The special features of th