The rockefeller university

Results on factorization breaking in soft and hard hadron-hadron collisions, photo-production and deep inelastic scattering exhibit a universal behavior in a renormalization model where diffraction is mediated by a saturated colorless exchange with vacuum quantum numbers. Using this model, diffractive and total cross sections are predicted for LHC energies.

The mechanosensory hair cells of many auditory receptor organs are tuned by an electrical resonance that increases their responses to stimulation over a narrow band of frequencies. The small oscillations of membrane potential characteristic of this phenomenon have previously been detectable only through intracellular electrode measurements, which are laborious and preclude analysis at the level of an entire sensory organ. We used a voltage-sensitive dye to image hair-cell electrical resonance in an intact preparation of the bullfrog's sacculus, a receptor organ sensitive to low-frequency seismic and auditory stimuli. Imaging revealed distinct populations of hair cells whose resonant response varied with the frequency of transepithelial electrical stimulation. Most of the hair cells in the saccular epithelium in vitro were electrically tuned to stimulation at 25-50 Hz. The frequency dependence of the fluorescence signal was sensitive to pharmacological blockade of large-conductance Ca2+-sensitive K+ channels and to enzymatic digestion. At an elevated concentration of Ca2+, we observed transient fluorescence signals that probably represented action potentials. The stroboscopic imaging and analysis techniques described here present a general approach for studying subthreshold oscillations in electrically excitable cells.

Objectives: Genome-wide association (GWA) studies still rely on the common-disease common-variant hypothesis since the assumption is associated with increased power. In GWA studies, polymorphisms are genotyped and their association with disease is investigated. Most of the identified associations are indirect and reflect a shared inheritance of the genotyped markers and genetically linked causal variants. We have compared six statistics of genetic association regarding their ability to discriminate between markers and causal susceptibility variants, including a probability value (Pval) and a Bayes Factor (BF) based on logistic regression, and the attributable familial relative risk (FRR). Methods: We carried out a simulation-based sensitivity analysis to explore several conceivable scenarios. Theoretical results were illustrated by established causal associations with age-related macular degeneration and by using imputed data based on HapMap for a case-control study of breast cancer. Results: Our data indicate that a representation of genetic association by FRRs and BFs generally facilitates the distinction of causal variants. The FRR showed the best discriminative power under most investigated scenarios, but no single statistic outperformed the others in all situations. For example, rare moderate-to low-penetrance variants (allele frequency: 1%, dominant odds ratio: <= 2.0) seem to be best discriminated by BFs. Conclusions: Present results may help to fully utilize the data generated in association studies that take advantage of next generation sequencing and/or multiple imputation based on the 1000 Genomes Project. Copyright (C) 2011 S. Karger AG, Basel

Epstein Barr virus (EBV) is a lymphotrophic gamma-herpesvirus that infects more than 90% of the adult human population. It transforms B cells in vitro and is associated with lymphomas in vivo. In most EBV carriers the emergence of these malignancies, however, is prevented by T cell mediated immune control. Part of this control is mediated by CD8+ T cells, which mainly target a subset of viral nuclear antigens, EBNA3A, B and C, in healthy EBV carriers. In HLA-B8 positive individuals, the dominant CTL response is biased towards recognition of EBNA3A. However, spontaneously arising EBV-associated malignancies, such as Hodgkin's lymphoma and nasopharyngeal carcinoma do not express EBNA3s and instead express latent membrane protein 2 (LMP2) as well as LMP1 and EBNA1. Here we describe the new HLA-B8 restricted, LMP2 derived CD8+ T cell epitope, LMP2345-352. Although the frequency of LMP2345-352 specific CD8+ T cells is usually lower than immunodominant EBNA3A specific CD8+ T cells in fresh blood, the former can be expanded in the majority of HLA-B8+ EBV carriers after 1 week co-culture with peptide pulsed dendritic cells. We demonstrate that LMP2345-352 specific CD8+ T cells secrete IFN-gamma and kill both peptide pulsed targets as well as HLA-B8 matched LCL and LMP2 expressing Hodgkin's lymphoma cells. We suggest that cytotoxic CD8+ T cell responses against LMP2 coexist with the immunodominant EBNA3 specific responses in healthy EBV carriers and help to resist EBV associated malignancies.

Many viruses trigger the type I interferon (IFN) system, leading to the transcription of hundreds of interferon-stimulated genes (ISGs). The products of these ISGs exert numerous antiviral effector functions, many of which are still not fully described. Recent efforts have been aimed at identifying which ISGs are antiviral and further characterizing their mechanisms of action. IFN effectors vary widely in their magnitude of inhibitory activity and display combinatorial antiviral properties. Collectively, ISGs can target almost any step in a virus life cycle. Some of the most potent antiviral effectors reinforce the system by further inducing IFN or ISGs. Other genes enhance or facilitate viral replication, suggesting that some viruses may have evolved to co-opt IFN effectors for a survival advantage.

Immune responses to hepatitis C virus (HCV) fail to clear the virus in most individuals Why patients who are less likely to clear HCV infection have high plasma levels of CXCL10 (also known as IP-10), a chemokine that directs T cells to sites of infection, has long been unclear In this issue of the JCI, Casrouge and colleagues shed light on this paradox by showing that CXCL10 in the plasma of many HCV patients is enzymatically processed to produce a CXCL10 receptor antagonist These findings introduce a role for chemokine antagonism during HCV infection and unveil new avenues for improved HCV diagnosis and therapy

Filamentous bacteriophage, long and thin filaments that are secreted from the host cells without killing them, have been an antithesis to the standard view of head-and-tail bacterial killing machines. Episomally replicating filamentous phage Ff of Escherichia coli provide the majority of information about the principles and mechanisms of filamentous phage infection, episomal replication and assembly. Chromosomally-integrated "temperate" filamentous phage have complex replication and integration, which are currently under active investigation. The latter are directly or indirectly implicated in diseases caused by bacterial pathogens Vibrio cholerae, Pseudomonas aeruginosa and Neisseria meningitidis. In the first half of the review, both the Ff and temperate phage are described and compared. A large section of the review is devoted to an overview of phage display technology and its applications in nanotechnology.

Viruses in the Flavivirus genus of the Flaviviridae family are arthropod-transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. To identify cellular factors with antiviral activity against flaviviruses, we screened a cDNA library using an iterative approach. We identified a mammalian Hsp40 chaperone protein (DNAJC14) that when overexpressed was able to mediate protection from yellow fever virus (YFV)-induced cell death. Further studies revealed that DNAJC14 inhibits YFV at the step of viral RNA replication. Since replication of bovine viral diarrhea virus (BVDV), a member of the related Pestivirus genus, is also known to be modulated by DNAJC14, we tested the effect of this host factor on diverse Flaviviridae family members. Flaviviruses, including the pathogenic Asibi strain of YFV, Kunjin, and tick-borne Langat virus, as well as a Hepacivirus, hepatitis C virus (HCV), all were inhibited by overexpression of DNAJC14. Mutagenesis showed that both the J-domain and the C-terminal domain, which mediates self-interaction, are required for anti-YFV activity. We found that DNAJC14 does not block YFV nor HCV NS2-3 cleavage, and using non-inhibitory mutants demonstrate that DNAJC14 is recruited to YFV replication complexes. Immunofluorescence analysis demonstrated that endogenous DNAJC14 rearranges during infection and is found in replication complexes identified by dsRNA staining. Interestingly, silencing of endogenous DNAJC14 results in impaired YFV replication suggesting a requirement for DNAJC14 in YFV replication complex assembly. Finally, the antiviral activity of overexpressed DNAJC14 occurs in a time-and dose-dependent manner. DNAJC14 overexpression may disrupt the proper stoichiometry resulting in inhibition, which can be overcome upon restoration of the optimal ratios due to the accumulation of viral nonstructural proteins. Our findings, together with previously published work, suggest that the members of the Flaviviridae family have evolved in unique and important ways to interact with this host Hsp40 chaperone molecule.

Studies m hum ins and rodents indicate that a minimum amount of stored energy is required for normal pubertal development The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons m mice had no effect on puberty or fertility, indicating that direct leptin signaling m Kiss1 neurons is not required for these processes However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation Moreover, unilateral reexpression of endogenous LepR m PMV neurons was sufficient to induce puberty and improve fertility m female LepR-null mice This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency These data suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction at e anatomically dissociated