The rockefeller university

The transcriptional output at a genomic locus in eukaryotes is determined, in part, by the pattern of histone modifications that are read and interpreted by key effector proteins. The histone deacetylase activity of the evolutionarily conserved Rpd3S/Sirt3S complex is crucial for suppressing aberrant transcription from cryptic start sites within intragenic regions of actively transcribed genes. Precise targeting of the complex relies on the chromatin binding activities of the MRG15 (MRG stands for mortality factor on chromosome 4 related gene) and Pf1 subunits. Whereas the molecular target of the MRG15 chromodomain (CD) has been suggested to be H3K36me(2/3), the precise molecular target of the Pf1 plant homeodomain 1 (PHD1) has remained elusive. Here, we show that Pf1 PHD1 binds preferentially to the unmodified extreme N-terminus of histone H3 (H3K4me(0)) but not to H3K4me(2/3), which are enriched in the promoter and 5' regions of genes. Unlike previously characterized CD and PHD domains that bind to their targets with micromolar affinity, both MRG15 CD and Pf1 PHD1 bind to their targets with >100 mu M affinity, offering an explanation for why both MRG15 CD and Pf1 PHD1 domains are required to target the Rpd3S/Sin3S complex to chromatin. Our results also suggest that bivalency, rather than cooperativity, is the operative mechanism by which Pf1 and MRG15 combine to engage H3 in a biologically significant manner. Finally, the studies reveal an unanticipated role of Pf1 PHD1 in engaging the MRG15 MRG domain, albeit in a Pf1 MRG-binding-domain-dependent manner, implying a key role for the MRG15 MRG-Pf1 MBD interaction in chromatin targeting of the Rpd3S/Sin3S complex. (C) 2012 Elsevier Ltd. All rights reserved.

Background: Most anxiety and depressive disorders are twice as common in women compared with men, and the sex difference in prevalence typically emerges during adolescence. Hormonal changes across the menstrual cycle and during the postpartum and perimenopausal periods are associated with increased risk for anxiety and depression symptoms. In humans and animals, reduced brain-derived neurotrophic factor (BDNF) has been associated with increased expression of affective pathology. Recently, a single nucleotide polymorphism (SNP) in the BDNF gene (BDNF Valine66Methionine [Val66Met]), which reduces BDNF bioavailability, has been identified in humans and associated with a variety of neuropsychiatric disorders. Although BDNF expression can be directly influenced by estrogen and progesterone, the potential impact of the BDNF Val66Met SNP on sensitivity to reproductive hormone changes remains an open question. Methods: As a predictive model, we used female mice in which the human SNP (BDNF Val66Met) was inserted into the mouse BDNF gene. Using standard behavioral paradigms, we tested the impact of this SNP on age and estrous-cycle-specific expression of anxiety-like behaviors. Results: Mice homozygous for the BDNF Val66Met SNP begin to exhibit increased anxiety-like behaviors over prepubertal and early adult development, show significant fluctuations in anxiety-like behaviors over the estrous cycle, and, as adults, differ from wild-type mice by showing significant fluctuations in anxiety-like behaviors over the estrous cycle-specifically, more anxiety-like behaviors during the estrus phase. Conclusions: These findings have implications regarding the potential role of this SNP in contributing to developmental and reproductive hormone-dependent changes in affective disorders in humans.

The paraneoplastic neurologic disorders target several families of neuron-specific RNA binding proteins (RNABPs), revealing that there are unique aspects of gene expression regulation in the mammalian brain. Here, we used HITS-CLIP to determine robust binding sites targeted by the neuronal Elav-like (nElavl) RNABPs. Surprisingly, nElav protein binds preferentially to GU-rich sequences in vivo and in vitro, with secondary binding to AU-rich sequences. nElavl null mice were used to validate the consequence of these binding events in the brain, demonstrating that they bind intronic sequences in a position dependent manner to regulate alternative splicing and to 3'UTR sequences to regulate mRNA levels. These controls converge on the glutamate synthesis pathway in neurons; nElavl proteins are required to maintain neurotransmitter glutamate levels, and the lack of nElavl leads to spontaneous epileptic seizure activity. The genome-wide analysis of nElavl targets reveals that one function of neuron-specific RNABPs is to control excitation-inhibition balance in the brain.

An auditory neuron can preserve the temporal fine structure of a low-frequency tone by phase-locking its response to the stimulus. Apart from sound localization, however, much about the role of this temporal information for signal processing in the brain remains unknown. Through psychoacoustic studies we provide direct evidence that humans employ temporal fine structure to discriminate between frequencies. To this end we construct tones that are based on a single frequency but in which, through the concatenation of wavelets, the phase changes randomly every few cycles. We then test the frequency discrimination of these phase-changing tones, of control tones without phase changes, and of short tones that consist of a single wavelet. For carrier frequencies below a few kilohertz we find that phase changes systematically worsen frequency discrimination. No such effect appears for higher carrier frequencies at which temporal information is not available in the central auditory system.

We report on a search for the standard model Higgs boson produced in association with a vector boson in the full data set of proton-antiproton collisions at root s = 1.96 TeV recorded by the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.45 fb(-1). We consider events having no identified charged lepton, a transverse energy imbalance, and two or three jets, of which at least one is consistent with originating from the decay of a b quark. We place 95% credibility level upper limits on the production cross section times standard model branching fraction for several mass hypotheses between 90 and 150 GeV/c(2). For a Higgs boson mass of 125 GeV/c(2), the observed (expected) limit is 6.7 (3.6) times the standard model prediction.

The dimuon invariant mass spectrum is searched in the range between 5.5 and 14 GeV for a light pseudoscalar Higgs boson a, predicted in a number of new physics models, including the next-to-minimal supersymmetric standard model. The data sample used in the search corresponds to an integrated luminosity of 1: 3 fb(-1) collected in pp collisions at root s = 7 TeV with the CMS detector at the LHC. No excess is observed above the background predictions and upper limits are set on the cross section times branching fraction sigma x B(pp -> a -> mu(+) mu(-)) in the range of 1.5-7.5 pb. These results improve on existing bounds on the ab (b) over bar coupling for m(a) < m(gamma(1s)) and are the first significant limits for m(a) > m(gamma(3S)). Constraints on the supersymmetric parameter space are presented in the context of the next-to-minimal model.

Background: Tumor treatment is the mainstay of therapy for paraneoplastic neurologic disorders (PNDs), but it is only effective in some cases and other treatment options are limited. Objective: To evaluate the short-term use of a combination of prednisone and tacrolimus for acute neurologic worsening in PND in which intracellular antigens are targeted. Design: Retrospective single-center case series of patients with PND treated with tacrolimus. Setting: The Rockefeller University Hospital, a research hospital in New York, New York. Patients: Twenty-six patients with PND with high titer (>= 1:1000) anti-HuD, anti-Yo, or anti-CRMP5 autoantibodies were enrolled. Patients were referred from Memorial Sloan Kettering Cancer Center or self-referred. Two patients discontinued intervention owing to adverse events. Interventions: Patients were treated with tacrolimus, 0.15-0.30 mg/kg per day, in 2 divided oral doses with 60 mg per day of oral prednisone, tapered off during 1 to 4 weeks. Main Outcome Measures: The primary outcome measure was median survival. Neurologic examinations before and after treatment as well as adverse events are described. Results: Median survival time was 52 months from time of diagnosis. Some patients experienced neurologic improvement that was functionally meaningful. The incidence of adverse events was similar to that generally reported with tacrolimus. Conclusions: A short course of prednisone and tacrolimus to target central nervous system T cells in patients with PND with acute neurologic decline in which intracellular antigens are targeted was well tolerated and warrants further study. Trial Registration: clinicaltrials.gov Identifier: NCT00378326 Arch Neurol. 2012; 69(9): 1132-1140. Published online May 7, 2012. doi:10.1001/archneurol.2012.595

Platelet-derived growth factor receptor alpha-positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression profiles in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies. Cancer Res; 72(18); 4856-68. (C)2012 AACR.

Although Kaposi's sarcoma (KS) gene expression profile is closer to lymphatic (LEC) rather than blood vascular endothelial cells (BEC), uncertainty still surrounds the cellular origin of KS. To follow KS progression from early to late (nodular) stage, and characterize the molecular fingerprinting associated with each stage, gene arrays were used to compare gene expression profile of 9 skin samples of classic KS (4 Early, 2 Mixed, and 3 Nodular CKS samples) to 4 normal samples. Results for selected genes were validated by Real-time (RT) PCR and immunohistochemistry. Genes regulating immune and defense responses, angiogenesis, apoptosis and proliferation were differentially expressed in different KS stages compared to normal skin. Hierarchical clustering separated normal skin from KS with a clear gradient from early to nodular KS lesions. The gene expression level of endothelium markers, metalloproteinases, angiogenic factors and chemokines, gradually increased from normal !