The rockefeller university

Purpose: To investigate the reliability of simulations lot planning pancreatic irreversible electroporation (IRE) ablations compared with computed tomography (CT) and pathology outcomes in an animal Model. Materials and Methods: Simulations were performed varying treatment parameters, including field strength (1.5-2.5 kV/cm), pulse number (70-90 pulses), and pulse length (70-100 us). Pancreatic IRE was performed in six pigs under CT guidance. Two animals each were sacrificed for histology after 1 day, 14 days, and 28 days. Follow-up CT scans were performed on day 0, day 1, day 14, and day 28. Biochemical markets were collected before the procedure, 1 day after the procedure, and 14 days after the procedure. Results: All ablation zones could be visualized on CT scan immediately after the procedure and on day 1 follow-up CT scan, and all animals survived until the designated endpoints.,Histopathology revealed necrosis and edema on day 1 and fibrosis and glandular atrophy after 28 days. Blood vessels close to the ablation zone appeared normal. Laboratory analysis indicated mild to moderate amylasemia and lipasemia with normalization after 14 days: The ablation size on CT scan measured a mean (+/- SD) 146% +/- 18 (day 0, P < .126) and 168% +/- 18 (day 1, P < .026) of the simulation and on pathology measured 119% +/- 10 (day 1, not significant) of the simulation. Conclusions: Results from simulations for planning IRE ablations, CT, and pathology may differ from each other. Ablation zones on CT and pathology appear larger than,Simulated, suggesting that clinically used treatment-planning may underestimate the ablation size in the pancreas.

A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA CBI (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.

A search for a Higgs boson decaying into a Z boson and a photon is described. The analysis is performed using proton-proton collision datasets recorded by the CMS detector at the LHC. Events were collected at center-of-mass energies of 7 TeV and 8 TeV, corresponding to integrated luminosities of 5.0 fb(-1) and 19.6 fb(-1), respectively. The selected events are required to have opposite-sign electron or muon pairs. No excess above standard model predictions has been found in the 120-160 GeV mass range and the first limits on the Higgs boson production cross section times the H -> Z gamma branching fraction at the LHC have been derived. The observed at 95% confidence level limits are between about 4 and 25 times the standard model cross section times the branching fraction. For a standard model Higgs boson mass of 125 GeV the expected limit at the 95% confidence level is 10 and the observed limit is 9.5. Models predicting the Higgs boson production cross section times the H -> Z gamma branching fraction to be larger than one order of magnitude of the standard model prediction are excluded for most of the 125-157 GeV mass range. (C) 2013 CERN. Published by Elsevier B.V. All rights reserved.

Approximately 90% of patients with isolated agammaglob ulinemia and failure of B cell development have mutations in genes required for signaling through the pre-B cell and B cell receptors. The nature of the gene defect in the majority of remaining patients is unknown. We recently identified 4 patients with agatnmaglobulinemia and markedly decreased numbers of peripheral B cells. The B cells that could be detected had an unusual phenotype characterized by the increased expression of CD19 but the absence of a B cell receptor. Genetic studies demonstrated that all 4 patients had the exact same de novo mutation in the broadly expressed transcription factor E47. The mutant protein (E555K) was stable in patient-derived EBV-transformed cell lines and cell lines transfected with expression vectors. E555K in the transfected cells localized normally to the nucleus and resulted in a dominant negative effect when bound to DNA as a homodimer with wild-type E47. Mutant E47 did permit DNA binding by a tissue-specific heteroclimeric DNA-binding partner, myogenic differentiation 1 (MYOD). These findings document a mutational hot-spot in E47 and represent an autosomal dominant form of agammaglobulinemia. Further, they indicate that E47 plays a critical role in enforcing the block in development of B cell precursors that lack functional antigen receptors.

Agonistic anti-TNF receptor (TNFR) superfamily member antibodies are a class of promising antitumor therapies in active clinical investigation. An unexpected requirement for inhibitory Fc gamma receptor Fc gamma RIIB coengagement has recently been described for their in vivo antitumor activities. Although these findings have informed the design of more potent antitumor agonistic, anti-TNFR therapies, the underlying mechanism has remained obscure. Through detailed genetic analysis of strains conditionally deleted for Fc gamma RIIB on defined cellular populations or mutated in specific signaling components, we now demonstrate that different agonistic antiTNFR antibodies have specific requirements for Fc gamma RIIB expression on defined cellular populations and function in trans in the absence of Fc gamma RIIB signaling components, thus supporting a general mechanism of FcRIIB cross-linking in vivo for the activities of these antibodies.

Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS(1-4). However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants(5-7). A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals(8). These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9-14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian-human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques(15,16). Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4-7 days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3-5 weeks in some long-term chronically SHIV-infected animals with low CD41 T-cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected individuals experiencing immune dysfunction.

Mycobacterium tilburgii rarely causes disseminated disease. We describe a case of M. tilburgii infection in an otherwise healthy 33-year-old woman, who was found to carry bi-allelic mutations of the gene encoding the beta 1 chain of the IL-12 receptor.

Eukaryotic ribosome assembly involves a plethora of factors, which ensure that a correctly folded ribosome contains all ribosomal protein components. Among these assembly factors, Yar1 has recently emerged as a molecular chaperone for ribosomal protein rpS3 of the small ribosomal subunit (40S) in yeast. In complex with its chaperone, rpS3 is imported into the nucleus and protected from aggregation. How rpS3 and other ribosomal proteins are initially sequestered and subsequently integrated into pre-ribosomal particles is currently poorly understood. Here, we present the crystal structure of yeast rpS3 in complex with its chaperone Yar1 at 2.8 angstrom resolution. The crystal structure rationalizes how Yar1 can protect rpS3 from aggregation while facilitating nuclear import and suggests a mechanism for a stepwise exchange of molecular partners that ribosomal proteins interact with during ribosome assembly. (C) 2013 Elsevier Ltd. All rights reserved.

De novo protein synthesis is necessary for long-lasting modifications in synaptic strength and dendritic spine dynamics that underlie cognition. Fragile X syndrome (FXS), characterized by intellectual disability and autistic behaviors, holds promise for revealing the molecular basis for these long-term changes in neuronal function. Loss of function of the fragile X mental retardation protein (FMRP) results in defects in synaptic plasticity and cognition in many models of the disease. FMRP is a polyribosome-associated RNA-binding protein that regulates the synthesis of a set of plasticity-reated proteins by stalling ribosomal translocation on target mRNAs. The recent identification of mRNA targets of FMRP and its upstream regulators, and the use of small molecules to stall ribosomes in the absence of FMRP, have the potential to be translated into new therapeutic avenues for the treatment of FXS.

Dyskeratosis congenita (DC) is a telomere-mediated syndrome defined by mucocutaneous features. The X-linked mode of inheritance accounts for half the cases, and is thought to predominantly manifest in childhood as bone marrow failure. We identified two male probands who presented in the fifth decade with idiopathic pulmonary fibrosis and cancer. Their pedigrees displayed consecutively affected generations. Five of six females (83%) manifested mucocutaneous features of DC, and two had wound-healing complications. No mutations in autosomal dominant telomere genes were present, but exome sequencing revealed novel variants in the X-chromosome DKC1 gene that predicted missense mutations in conserved residues, p.Thr49Ser and p.Pro409Arg. Variants segregated with the telomere phenotype, and affected females were heterozygotes, showing skewed X-inactivation. Telomerase RNA levels were compromised in cells from DKC1 mutation carriers, consistent with their pathogenic role. These findings indicate that females with heterozygous DKC1 mutations may be at increased risk for developing penetrant telomere phenotypes that, at times, may be associated with clinical morbidity.