The rockefeller university

The Y(1S), Y(2S), and Y(3S) production cross sections in proton-proton collisions at root s = 7 TeV are measured using a data sample collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 3.1 +/- 0.3 pb(-1). Integrated over the rapidity range vertical bar y vertical bar < 2, we find the product of the Y(1S) production cross section and branching fraction to dimuons to be sigma(pp -> Y(1S)X) center dot B(Y(1S) -> mu(+)mu(-)) = 7.37 +/- 0.13(-0.42)(+0.61) +/- 0.81 nb, where the first uncertainty is statistical, the second is systematic, and the third is associated with the estimation of the integrated luminosity of the data sample. This cross section is obtained assuming unpolarized Y(1S) production. With the assumption of fully transverse or fully longitudinal production polarization, the measured cross section changes by about 20%. We also report the measurement of the Y(1S), Y(2S), and Y(3S) differential cross sections as a function of transverse momentum and rapidity.

Heat shock protein 70 (Hsp70) is a chaperone protein that helps protect against cellular stress, a function that may be co-opted to fight human diseases. In particular, the upregulation of Hsp70 can suppress the neurotoxicity of misfolded proteins, suggesting possible therapeutic strategies in neurodegenerative diseases. Alternatively, in cancer cells where high levels of Hsp70 inhibit both intrinsic and extrinsic apoptotic pathways, a reduction in Hsp70 levels may induce apoptosis. To evaluate and identify, in a single assay format, small molecules that induce or inhibit endogenous Hsp70, we have designed and optimized a microtiter assay that relies on whole-cell immunodetection of Hsp70. The assay utilizes a minimal number of neuronal or cancer cells, yet is sufficiently sensitive and reproducible to permit quantitative determinations. We further validated the assay using a panel of Hsp70 modulators. In conclusion, we have developed an assay that is fast, robust, and cost efficient. As such, it can be implemented in most research laboratories. The assay should greatly improve the speed at which novel Hsp70 inducers and inhibitors of expression can be identified and evaluated.

Aim Genetic research representative of the population is crucial to understanding the underlying causes of many diseases. In a prospective evaluation of informed consent we assessed the willingness of individuals of different ethnicities, gender and drug dependence history to participate in genetic studies in which their genetic sample could be shared with a repository at the National Institutes of Health. Methods Potential subjects were recruited from the general population through the use of flyers and referrals from previous participants and clinicians with knowledge of our study. They could consent to 11 separate choices so that they could specify how and with whom their genetic sample could be shared. Rates of affirmative consent were then analysed by gender, ethnicity and drug dependence history. Results Of 1416 volunteers enrolled, 99.7% gave affirmative informed consent for studies of addiction conducted in our laboratory. No significant difference was found for participation in genetic studies conducted in our laboratory by gender, ethnicity or drug dependence history. Over all 11 questions, individuals with a history of drug use were more likely to agree to consent to participate in our study than were healthy volunteers. Conclusion A high percentage of each category of gender, ethnicity and drug history, gave affirmative consent at all levels. The level of detail in and the amount of time spent reviewing the informed consent, and a relationship of trust with the clinical investigator may contribute to this outcome.

Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro(4), we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.

We report on the first measurement of the angular distributions of final state electrons in p (p) over bar -> gamma*/Z -> e(+)e(-) + X events produced in the Z boson mass region at root s = 1.96 TeV. The data sample collected by the CDF II detector for this result corresponds to 2.1 fb(-1) of integrated luminosity. The angular distributions are studied as a function of the transverse momentum of the electron-positron pair and show good agreement with the Lam-Tung relation, consistent with a spin-1 description of the gluon, and demonstrate that, at high values of the transverse momentum, Z bosons are produced via quark-antiquark annihilation and quark-gluon Compton processes.

Ciliogenesis precedes lineage-determining signaling in skin development. To understand why, we performed shRNA-mediated knockdown of seven intraflagellar transport proteins (IFTs) and conditional ablation of Ift-88 and Kif3a during embryogenesis. In both cultured keratinocytes and embryonic epidermis, all of these eliminated cilia, and many (not Kif3a) caused hyperproliferation. Surprisingly and independent of proliferation, ciliary mutants displayed defects in Notch signaling and commitment of progenitors to differentiate. Notch receptors and Notch-processing enzymes colocalized with cilia in wild-type epidermal cells. Moreover, differentiation defects in ciliary mutants were cell autonomous and rescued by activated Notch (NICD). By contrast, Shh signaling was neither operative nor required for epidermal ciliogenesis, Notch signaling, or differentiation. Rather, Shh signaling defects in ciliary mutants occurred later, arresting hair follicle morphogenesis in the skin. These findings unveil temporally and spatially distinct functions for primary cilia at the nexus of signaling, proliferation, and differentiation.

Insomnia is a common problem for people with chronic pain. Cortical GABAergic neurons are part of the neurobiological substrate that underlies homeostatic sleep regulation. In the present study, we confirmed that sciatic nerve ligation caused thermal hyperalgesia and tactile allodynia in mice. In this experimental model for neuropathic pain, we found an increase in wakefulness and a decrease in non-rapid eye movement sleep under a neuropathic pain-like state. Under these conditions, membrane-bound GABA (c-aminobutyric acid) transporters (GATs) on activated glial fibrillary acidic protein-positive astrocytes were significantly increased in the cingulate cortex, and extracellular GABA levels in this area after depolarization were rapidly decreased by nerve injury. Furthermore, sleep disturbance induced by sciatic nerve ligation was improved by the intracingulate cortex injection of a GAT-3 inhibitor. These findings provide novel evidence that sciatic nerve ligation decreases extracellular-released GABA in the cingulate cortex of mice. These phenomena may, at least in part, explain the insomnia in patients with neuropathic pain. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Estrogen and progestins have been used by millions of women as effective combined contraceptives. The safety of hormonal contraceptives has been documented by years of follow-up and serious adverse events that may be related to their use are rare in the young population exposed to these agents. The balance between the benefits and the risks of contraceptive steroids is generally positive in particular when comparing to the risks of pregnancy and especially in women with risk factors. The metabolic changes induced by the synthetic steroids used in contraception, such as lipoprotein changes, insulin response to glucose, and coagulation factors have been considered as potential markers of cardiovascular and venous risk. Observations of these effects have led to modifications of the composition of hormonal contraceptive in order to minimize these changes and hence potentially decrease the risks. The synthetic estrogen Ethinyl-Estradiol (EE) exerts a stronger effect that natural estradiol (E2) on hepatic metabolism including estrogen-dependent markers such as liver proteins. This stronger hepatic impact of EE has been related to its 17 alpha-ethinyl group which prevents the inactivation of the molecule and results in a more pronounced hepatic effect of EE as compared to estradiol. Due to its strong activity, administering EE via a non-oral route does not prevent its impact on liver proteins. In order to circumvent the metabolic changes induced by EE, newer products using more natural compounds such as estradiol (E2) and estradiol valerate (E2V) have been introduced. The synthetic progestins used for contraception are structurally related either to testosterone (T) (estranes and gonanes) or to progesterone (pregnanes and 19-norpregnanes). Several new progestins have been designed to bind more specifically to the progesterone receptor and to minimize side-effects related to androgenic, estrogenic or glucocorticoid receptor interactions. Dienogest (DNG), and drospirenone (DRSP) and the 19-norpregnanes including NestoroneA (R) (NES), nomegestrol acetate (NOMAc) and trimegestone (TMG) have been combined with estrogen either EE or E2 or estradiol valerate (E2V). Risks and benefits of the newer progestins used in contraception depend upon the type of molecular structure, the type and dose of estrogen associated in a combination and the route of administration. The lower metabolic impact of estradiol-based combinations may result in an improved safety profile, but large surveillance studies are warranted to confirm this plausible hypothesis. So far, the contraindications and warnings for use of current COCs also apply to the estradiol-based COCs.

The existence of neuron-specific endocytic protein isoforms raises questions about their importance for specialized neuronal functions. Dynamin, a GTPase implicated in the fission reaction of endocytosis, is encoded by three genes, two of which, dynamin 1 and 3, are highly expressed in neurons. We show that dynamin 3, thought to play a predominantly postsynaptic role, has a major presynaptic function. Although lack of dynamin 3 does not produce an overt phenotype in mice, it worsens the dynamin 1 KO phenotype, leading to perinatal lethality and a more severe defect in activity-dependent synaptic vesicle endocytosis. Thus, dynamin 1 and 3, which together account for the overwhelming majority of brain dynamin, cooperate in supporting optimal rates of synaptic vesicle endocytosis. Persistence of synaptic transmission in their absence indicates that if dynamin plays essential functions in neurons, such functions can be achieved by the very low levels of dynamin 2.

The accurate perception of sound frequency by vertebrates relies upon the tuning of hair cells, which are arranged along auditory organs according to frequency. This arrangement, which is termed a tonotopic gradient, results from the coordination of many cellular and extracellular features. Seeking the mechanisms that orchestrate those features and govern the tonotopic gradient, we used expression microarrays to identify genes differentially expressed between the high- and low-frequency cochlear regions of the chick (Gallus gallus). Of the three signaling systems that were represented extensively in the results, we focused on the notch pathway and particularly on DNER, a putative notch ligand, and PTK, a receptor phosphatase that controls DNER trafficking. Immunohistochemistry confirmed that both proteins are expressed more strongly in hair cells at the cochlear apex than in those at the base. At the apical surface of each hair cell, the proteins display polarized, mutually exclusive localization patterns. Using morpholinos to decrease the expression of DNER or PTK as well as a retroviral vector to overexpress DNER, we observed disturbances of hair-bundle morphology and orientation. Our results suggest a role for DNER and PTK in hair-cell development and possibly in the specification of tonotopy. (C) 2011 Elsevier Inc. All rights reserved.