The rockefeller university

Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD patients, posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporating both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated significantly less activation to the Threat condition and increased activity to the Safe condition in the subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show the temporal pattern of activity decrease found in control subjects. (C) 2010 Elsevier Ltd. All rights reserved.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor and is thought to arise from genetic anomalies in developmental pathways required for the normal maturation of the cerebellar cortex, notably developmental pathways for granule cell progenitor (GCP) neurogenesis. Over the past decade, a wide range of studies have identified genes and their regulators within signaling pathways, as well as noncoding RNAs, that have crucial roles in both normal cerebellar development and pathogenesis. These include the Notch, Wnt/beta-catenin, bone morphogenic proteins (Bmp) and Sonic Hedgehog (Shh) pathways. In this review, we highlight the function of these pathways in the growth of the cerebellum and the formation of MB. A better understanding of the developmental origins of these tumors will have significant implications for enhancing the treatment of this important childhood cancer.

Measurements of the total and differential cross sections d sigma/dp(T)(B) and d sigma/dy(B) for B+ mesons produced in pp collisions at root s = 7 TeV are presented. The data correspond to an integrated luminosity of 5.8 pb(-1) collected by the CMS experiment operating at the LHC. The exclusive decay B+ -> J/psi K+, with J/psi -> mu(+)mu(-), is used to detect B+ mesons and to measure the production cross section as a function of p(T)(B) and y(B). The total cross section for p(T)(B) > 5 GeV and vertical bar y(B)vertical bar < 2.4 is measured to be 28.1 +/- 2.4 +/- 2.0 +/- 3.1 mu b, where the first uncertainty is statistical, the second is systematic, and the last is from the luminosity measurement.

Background: HIV-1 subtype B and subtype F are prevalent in the AIDS epidemic of Brazil. Recombinations between these subtypes have generated at least four BF circulating recombinant forms (CRFs). CRF28_BF and CRF29_BF are among the first two BF recombinants being identified in Brazil and they contributed significantly to the epidemic. However, the evolution and demographic histories of the CRFs are unclear. Methodology/Principal Findings: A collection of gag and pol sequences sampled within Brazil was screened for CRF28_BF-like and CRF29_BF-like recombination patterns. A Bayesian coalescent framework was employed to delineate the phylogenetic, divergence time and population dynamics of the virus having CRF28_BF-like and CRF29_BF-like genotype. These recombinants were phylogenetically related to each other and formed a well-supported monophyletic clade dated to 1988-1989. The effective number of infections by these recombinants grew exponentially over a five-year period after their emergence, but then decreased toward the present following a logistic model of population growth. The demographic pattern of both recombinants closely resembles those previously reported for CRF31_BC. Conclusions: We revealed that HIV-1 recombinants of the CRF28_BF/CRF29_BF clade are still circulating in the Brazilian population. These recombinants did not exhibit a strong founder effect and showed a decreasing prevalence in the AIDS epidemic of Brazil. Our data suggested that multiple URFs may also play a role in shaping the epidemic of recombinant BF HIV-1 in the region.

Viral vaccine vectors have emerged as an attractive strategy for the development of a human immunodeficiency virus (HIV) vaccine. Recombinant Newcastle disease virus (rNDV) stands out as a vaccine vector since it has a proven safety profile in humans, it is a potent inducer of both alpha interferon (IFN-alpha) and IFN-beta) production, and it is a potent inducer of dendritic cell (DC) maturation. Our group has previously generated an rNDV vector expressing a codon-optimized HIV Gag protein and demonstrated its ability to induce a Gag-specific CD8(+) T cell response in mice. In this report we demonstrate that the Gag-specific immune response can be further enhanced by the targeting of the rNDV-encoded HIV Gag antigen to DCs. Targeting of the HIV Gag antigen was achieved by the addition of a single-chain Fv (scFv) antibody specific for the DC-restricted antigen uptake receptor DEC205 such that the DEC205 scFv-Gag molecule was encoded for expression as a fusion protein. The vaccination of mice with rNDV coding for the DC-targeted Gag antigen induced an enhanced Gag-specific CD8(+) T cell response and enhanced numbers of CD4(+) T cells and CD8(+) T cells in the spleen relative to vaccination with rNDV coding for a nontargeted Gag antigen. Importantly, mice vaccinated with the DEC205-targeted vaccine were better protected from challenge with a recombinant vaccinia virus expressing the HIV Gag protein. Here we demonstrate that the targeting of the HIV Gag antigen to DCs via the DEC205 receptor enhances the ability of an rNDV vector to induce a potent antigen-specific immune response.

During development, a polarized epidermal sheet undergoes stratification and differentiation to produce the skin barrier. Through mechanisms that are poorly understood, the process involves actin dynamics, spindle reorientation and Notch signalling. To elucidate how epidermal embryogenesis is governed, we conditionally targeted serum response factor (Sri), a transcription factor that is essential for epidermal differentiation. Unexpectedly, previously ascribed causative defects are not responsible for profoundly perturbed embryonic epidermis. Seeking the mechanism for this, we identified actins and their regulators that were downregulated after ablation. Without Sri, cells exhibit a diminished cortical network and in mitosis, they fail to round up, features we recapitulate with low-dose actin inhibitors in vivo and shRNA-knockdown in vitro. Altered concomitantly are phosphorylated ERM and cortical myosin-IIA, shown in vitro to establish a rigid cortical actomyosin network and elicit critical shape changes. We provide a link between these features and Sri loss, and we show that the process is physiologically relevant in skin, as reflected by defects in spindle orientation, asymmetric cell divisions, stratification and differentiation.

Background: Recent studies show that mutations in Leucine Rich Repeat Kinase 2 (LRRK2) are the cause of the most common inherited and some sporadic forms of Parkinson's disease (PD). The molecular mechanism underlying the pathogenic role of LRRK2 mutations in PD remains unknown. Methodology/Principal Findings: Using affinity purification and mass spectrometric analysis, we investigated phosphorylation sites and binding proteins of LRRK2 purified from mouse brain. We identified multiple phosphorylation sites at N-terminus of LRRK2 including S910, S912, S935 and S973. Focusing on the high stoichiometry S935 phosphorylation site, we developed an anti-pS935 specific antibody and showed that LRRK2 is constitutively phosphorylated at S935 in various tissues (including brain) and at different ages in mice. We find that 14-3-3 proteins (especially isoforms gamma and eta) bind LRRK2 and this binding depends on phosphorylation of S935. The binding of 14-3-3, with little effect on dimer formation of LRRK2, confers protection of the phosphorylation status of S935. Furthermore, we show that protein kinase A (PKA), but not LRRK2 kinase itself, can cause the phosphorylation of LRRK2 at S935 in vitro and in cell culture, suggesting that PKA is a potential upstream kinase that regulates LRRK2 function. Finally, our study indicates that the common PD-related mutations of LRRK2, R1441G, Y1699C and G2019S, decrease homeostatic phosphorylation levels of S935 and impair 14-3-3 binding of LRRK2. Conclusions/Significance: LRRK2 is extensively phosphorylated in vivo, and the phosphorylation of specific sites (e.g. S935) determines 14-3-3 binding of LRRK2. We propose that 14-3-3 is an important regulator of LRRK2-mediated cellular functions. Our study suggests that PKA, a cAMP-dependent kinase involved in regulating dopamine physiology, is a potential upstream kinase that phosphorylates LRRK2 at S935. Furthermore, the reduction of phosphorylation/14-3-3 binding of LRRK2 due to the common familial PD-related mutations provides novel insight into the pathogenic mechanism of LRRK2-linked PD.

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF(+/-)) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF(+/-) mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF(+/-) mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. (C) 2010 Wiley-Liss, Inc.

The ovarian hormone estrogen increases the axospinous synapse density in the hippocampal CA1 region of young female rats but fails to do so in aged rats. This estrogen-mediated alteration of spine synapse structures suggests the coincident requirement for the structural reorganization of the underlying actin cytoskeleton network. Actin reorganization is known to require the deactivation of Cofilin, an actin depolymerization factor. Cofilin is deactivated by LIM kinase (LIMK), and LIMK activity is modulated by the phosphorylation of specific residues. We have previously demonstrated that estrogen is able to increase phosphorylated LIMK (pLIMK) immunoreactivity (IR) in the hippocampus in vivo and that this estrogen-stimulated pLIMK-IR is decreased in the aged brain. Because Cofilin phosphorylation allows for actin filament elongation and spine synapse growth, we sought to determine if estrogen acts through Cofilin and if such estrogen action requires the observed LIMK activity. Using both hippocampal neurons and the NG108-15 neuroblastoma cell line, we demonstrate here that estrogen stimulates the phosphotylation of Cofilin in vitro. Furthermore, this estrogen action on Cofilin requires LIMK. Lastly, while initiating the phosphorylation of LIMK and Cofilin, estrogen can also stimulate the formation of filopodial extensions, an early step in the formation of nascent spines, demonstrating that estrogen can alter the actin-dependent neuronal morphology. This linkage of estrogen communication to Cofilin via LIMK provides the functionality to the age-sensitive pLIMK-IR that we have observed in vivo. (C) 2010 Elsevier B.V. All rights reserved.