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Patel S.J.,Sloan Kettering Cancer Center | Trivedi G.L.,Cold Spring Harbor Laboratory Cold Spring Harbor | Darie C.C.,Clarkson University | Clarkson B.D.,Sloan Kettering Cancer Center
Journal of Cellular and Molecular Medicine | Year: 2016

B-cell novel protein-1 (BCNP1) or Family member of 129C (FAM129C) was identified as a B-cell-specific plasma-membrane protein. Bioinformatics analysis predicted that BCNP1 might be heavily phosphorylated. The BCNP1 protein contains a pleckstrin homology (PH) domain, two proline-rich (PR) regions and a Leucine Zipper (LZ) domain suggesting that it may be involved in protein-protein interactions. Using The Cancer Genome Atlas (TCGA) data sets, we investigated the correlation of alteration of the BCNP1 copy-number changes and mutations in several cancer types. We also investigated the function of BCNP1 in cellular signalling pathways. We found that BCNP1 is highly altered in some types of cancers and that BCNP1 copy-number changes and mutations co-occur with other molecular alteration events for TP53 (tumour protein P53), PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase, Catalytic Subunit Alpha), MAPK1 (mitogen-activated protein kinase-1; ERK: extracellular signal regulated kinase), KRAS (Kirsten rat sarcoma viral oncogene homolog) and AKT2 (V-Akt Murine Thymoma Viral Oncogene Homolog 2). We also found that PI3K (Phoshoinositide 3-kinase) inhibition and p38 MAPK (p38 mitogen-activated protein kinase) activation leads to reduction in phosphorylation of BCNP1 at serine residues, suggesting that BCNP1 phosphorylation is PI3K and p38MAPK dependent and that it might be involved in cancer. Its degradation depends on a proteasome-mediated pathway. © 2016 Journal of Cellular and Molecular Medicine and Foundation for Cellular and Molecular Medicine.

PubMed | University of Oregon and Cold Spring Harbor Laboratory Cold Spring Harbor
Type: | Journal: Frontiers in systems neuroscience | Year: 2014

Two opposing constraints exist when choosing a model organism for studying the neural basis of adaptive decision-making: (1) experimental access and (2) behavioral complexity. Available molecular and genetic approaches for studying neural circuits in the mouse fulfill the first requirement. In contrast, it is still under debate if mice can perform cognitive tasks of sufficient complexity. Here we compare learning and performance of mice and rats, the preferred behavioral rodent model, during an acoustic flexible categorization two-alternative choice task. The task required animals to switch between two categorization definitions several times within a behavioral session. We found that both species achieved similarly high performance levels. On average, rats learned the task faster than mice, although some mice were as fast as the average rat. No major differences in subjective categorization boundaries or the speed of adaptation between the two species were found. Our results demonstrate that mice are an appropriate model for the study of the neural mechanisms underlying adaptive decision-making, and suggest they might be suitable for other cognitive tasks as well.

PubMed | Brandeis University, Cold Spring Harbor Laboratory Cold Spring Harbor, New York University and Haifa University
Type: | Journal: Frontiers in computational neuroscience | Year: 2014

A classic problem in neuroscience is how temporal sequences (TSs) can be recognized. This problem is exemplified in the olfactory system, where an odor is defined by the TS of olfactory bulb (OB) output that occurs during a sniff. This sequence is discrete because the output is subdivided by gamma frequency oscillations. Here we propose a new class of brute-force solutions to recognition of discrete sequences. We demonstrate a network architecture in which there are a small number of modules, each of which provides a persistent snapshot of what occurs in a different gamma cycle. The collection of these snapshots forms a spatial pattern (SP) that can be recognized by standard attractor-based network mechanisms. We will discuss the implications of this strategy for recognizing odor-specific sequences generated by the OB.

PubMed | Mount Sinai School of Medicine, Penn State College of Medicine, Cold Spring Harbor LaboratoryCold Spring Harbor and Cold Spring Harbor Laboratory Cold Spring Harbor
Type: | Journal: Frontiers in neural circuits | Year: 2016

Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial two-photon tomography to detect expression of c-FosGFP - a marker of neuronal activation - in c-fosGFP transgenic mice subjected to the learned helplessness (LH) procedure, a widely used model of stress-induced depression-like phenotype in laboratory animals. We found that mice showing helpless behavior had an overall brain-wide reduction in the level of neuronal activation compared with mice showing resilient behavior, with the exception of a few brain areas, including the locus coeruleus, that were more activated in the helpless mice. In addition, the helpless mice showed a strong trend of having higher similarity in whole-brain activity profile among individuals, suggesting that helplessness is represented by a more stereotypic brain-wide activation pattern. This latter effect was confirmed in rats subjected to the LH procedure, using 2-deoxy-2[18F]fluoro-D-glucose positron emission tomography to assess neural activity. Our findings reveal distinct brain activity markings that correlate with adaptive and maladaptive behavioral responses to stress, and provide a framework for further studies investigating the contribution of specific brain regions to maladaptive stress responses.

PubMed | Cold Spring Harbor Laboratory Cold Spring Harbor
Type: Journal Article | Journal: Epigenomics | Year: 2014

Chromatin is vital to normal cells, and its deregulation contributes to a spectrum of human ailments. An emerging concept is that aberrant chromatin regulation culminates in gene expression programs that set the stage for the seemingly diverse pathologies of cancer, developmental disorders and neurological syndromes. However, the mechanisms responsible for such common etiology have been elusive. Recent evidence has implicated lesions affecting chromatin-remodeling proteins in cancer, developmental disorders and neurological syndromes, suggesting a common source for these different pathologies. Here, we focus on the chromodomain helicase DNA binding chromatin-remodeling family and the recent evidence for its deregulation in diverse pathological conditions, providing a new perspective on the underlying mechanisms and their implications for these prevalent human diseases.

PubMed | Cold Spring Harbor LaboratoryCold Spring Harbor, Champalimaud Center for the UnknownLisbon and Cold Spring Harbor Laboratory Cold Spring Harbor
Type: | Journal: Frontiers in neuroanatomy | Year: 2016

Recombinant Sindbis viruses are important tools in neuroscience because they combine rapid and high transgene expression with a capacity to carry large transgenes. Currently, two packaging systems based on the defective helper (DH) RNAs DH(26S)5SIN and DH-BB(tRNA;TE12) are available for generating recombinant Sindbis virus that is neurotropic (able to infect neurons and potentially other cells). Both systems produce a fraction of viral particles that can propagate beyond the primary infected neuron. When injected into mouse brain, viruses produced using these DH RNAs produce transgene expression at the injection site, but also elsewhere in the brain. Such ectopic labeling caused recombinant Sindbis viruses to be classified as anterograde viruses with limited retrograde spread, and can complicate the interpretation of neuroanatomical and other experiments. Here we describe a new DH RNA, DH-BB(5SIN;TE12ORF), that can be used to produce virus that is both neurotropic and propagation-incompetent. We show in mice that DH-BB(5SIN;TE12ORF)-packaged virus eliminates infection of cells outside the injection site. We also provide evidence that ectopically labeled cells observed in previous experiments with recombinant Sindbis virus resulted from secondary infection by propagation-competent virus, rather than from inefficient retrograde spread. Virus produced with our new packaging system retains all the advantages of previous recombinant Sindbis viruses, but minimizes the risks of confounding results with unwanted ectopic labeling. It should therefore be considered in future studies in which a neurotropic, recombinant Sindbis virus is needed.

PubMed | Cold Spring Harbor Laboratory Cold Spring Harbor
Type: | Journal: Frontiers in systems neuroscience | Year: 2011

We present a behavioral paradigm for the study of duration perception in the rat, and report the result of neurotoxic lesions that have the goal of identifying sites that mediate duration perception. Using a two-alternative forced-choice paradigm, rats were either trained to discriminate durations of pure tones (range=[200,500]ms; boundary=316ms; Weber fraction after training=0.240.04), or were trained to discriminate frequencies of pure tones (range=[8,16]kHz; boundary=11.3kHz; Weber=0.160.11); the latter task is a control for non-timing-specific aspects of the former. Both groups discriminate the same class of sensory stimuli, use the same motions to indicate decisions, have identical trial structures, and are trained to psychophysical threshold; the tasks are thus matched in a number of sensorimotor and cognitive demands. We made neurotoxic lesions of candidate timing-perception areas in the cerebral cortex of both groups. Following extensive bilateral lesions of the auditory cortex, the performance of the frequency discrimination group was significantly more impaired than that of the duration discrimination group. We also found that extensive bilateral lesions of the medial prefrontal cortex resulted in little to no impairment of both groups. The behavioral framework presented here provides an audition-based approach to study the neural mechanisms of time estimation and memory for durations.

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