The rockefeller university

Over the past two decades, disability activists, ethicists, and genetic counselors have examined the moral complexities inherent in prenatal genetic counseling and considered whether and in what ways genetic counseling may negatively affect individuals in the disability community. Many have expressed concerns about defining disability in the context of prenatal decision-making, as the definition presented may influence prenatal choices. In the past few years, publications have begun to explore the responsibility of counselors in presenting a balanced view of disability and have questioned the preparedness of counselors for this duty. Currently, the Accreditation Council for Genetic Counseling (ACGC) only minimally includes disability training in their competencies for genetic counselors, and in their accreditation requirements for training programs. In an attempt to describe current practice, this article details two studies that assess disability training in ABGC-accredited genetic counseling programs. Results from these studies demonstrate that experience with disability is not required by the majority of programs prior to matriculation. Though most program directors agree on the importance of including disability training in the curriculum, there is wide variability in the amount and types of training students receive. Hours dedicated to disability exposure among programs ranged from 10 to 600 hours. Eighty-five percent of program directors surveyed agree that skills for addressing disability should be added to the core competencies. Establishing a set of disability competencies would help to ensure that all graduates have the skills necessary to provide patients with an accurate understanding of disability that facilitates informed decision-making. (C) 2014 Wiley Periodicals, Inc.

Embryos allocate cells to the three germ layers in a spatially ordered sequence. Human embryonic stem cells (hESCs) can generate the three germ layers in culture; however, differentiation is typically heterogeneous and spatially disordered. We show that geometric confinement is sufficient to trigger self-organized patterning in hESCs. In response to BMP4, colonies reproducibly differentiated to an outer trophectoderm-like ring, an inner ectodermal circle and a ring of mesendoderm expressing primitive-streak markers in between. Fates were defined relative to the boundary with a fixed length scale: small colonies corresponded to the outer Layers of larger ones. Inhibitory signals limited the range of BMP4 signaling to the colony edge and induced a gradient of Activin-Nodal signaling that patterned mesendodermal fates. These results demonstrate that the intrinsic tendency of stem cells to make patterns can be harnessed by controlling colony geometries and provide a quantitative assay for studying paracrine signaling in early development.

Measurements of the muon charge asymmetry in inclusive pp -> W + X production at root s = 7 TeV are presented. The data sample corresponds to an integrated luminosity of 4.7 fb(-1) recorded with the CMS detector at the LHC. With a sample of more than 20 million W -> mu nu events, the statistical precision is greatly improved in comparison to previous measurements. These new results provide additional constraints on the parton distribution functions of the proton in the range of the Bjorken scaling variable x from 10(-3) to 10(-1). These measurements and the recent CMS measurement of associated W + charm production are used together with the cross sections for inclusive deep inelastic e(+/-) p scattering at HERA in a next-to-leading-order QCD analysis. The determination of the valence quark distributions is improved, and the strange-quark distribution is probed directly through the leading-order process g + s -> W + c in proton-proton collisions at the LHC.

The intestinal epithelium harbors large populations of activated and memory lymphocytes, yet these cells do not cause tissue damage in the steady state. We investigated how intestinal T cell effector differentiation is regulated upon migration to the intestinal epithelium. Using gene loss-and gain-of-function strategies, as well as reporter approaches, we showed that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4(+) T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8 alpha alpha homodimers. Interferon-gamma sensing and T-bet expression by CD4(+) T cells were both required for this program, which was distinct from conventional T helper differentiation but shared by other IEL populations, including TCR alpha beta(+)CD8 alpha alpha(+) IELs. We conclude that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes.

Purpose To respond to increased public and programmatic demand to address underenrollment of clinical translational research studies, the authors examined participant recruitment practices at Clinical and Translational Science Award (CTSA) sites and make recommendations for performance metrics and accountability. Method The CTSA Recruitment and Retention taskforce in 2010 invited representatives at 46 CTSAs to complete an online 48-question survey querying accrual and recruitment outcomes, practices, evaluation methods, policies, and perceived gaps in related knowledge/practice. Descriptive statistical and thematic analyses were conducted. Results Forty-six respondents representing 44 CTSAs completed the survey. Recruitment conducted by study teams was the most common practice reported (78%-91%, by study type); 39% reported their institution offered recruitment services to investigators. Respondents valued study feasibility assessment as a successful practice (39%); desired additional resources included feasibility assessments (49%) and participant registries (44%). None reported their institution systematically required justification of feasibility; some indicated relevant information was considered prior to institutional review board (IRB) review (30%) or contract approval (22%). All respondents' IRBs tracked study progress, but only 10% of respondents could report outcome data for timely accrual. Few reported written policies addressing poor accrual or provided data to support recruitment practice effectiveness. Conclusions Many CTSAs lack the necessary framework to support study accrual. Recom-men-dations to enhance accrual include arti-culating institutional expectations and policy for routine recruitment planning; providing recruitment expertise to inform feasibility assessment and recruit-ment planning; and developing interdepartmental coordination and integrated informatics infrastructure to drive the conduct, evaluation, and improvement of recruitment practices.

STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels.

The normalised differential top quark-antiquark production cross section is measured as a function of the jet multiplicity in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC with the CMS detector. The measurement is performed in both the dilepton and lepton+jets decay channels using data corresponding to an integrated luminosity of 5.0 fb(-1). Using a procedure to associate jets to decay products of the top quarks, the differential cross section of the t (t) over bar production is determined as a function of the additional jet multiplicity in the lepton+jets channel. Furthermore, the fraction of events with no additional jets is measured in the dilepton channel, as a function of the threshold on the jet transverse momentum. The measurements are compared with predictions from perturbative quantum chromodynamics and no significant deviations are observed.

A search is reported for massive resonances decaying into a quark and a vector boson (W or Z), or two vector bosons (WW, WZ, or ZZ). The analysis is performed on an inclusive sample of multijet events corresponding to an integrated luminosity of 19.7 fb(-1), collected in proton-proton collisions at a centre-of-mass energy of 8 TeV with the CMS detector at the LHC. The search uses novel jet-substructure identification techniques that provide sensitivity to the presence of highly boosted vector bosons decaying into a pair of quarks. Exclusion limits are set at a confidence level of 95% on the production of: (i) excited quark resonances q* decaying to qW and qZ for masses less than 3.2 TeV and 2.9 TeV, respectively, (ii) a Randall-Sundrum graviton G(RS) decaying into WW for masses below 1.2 TeV, and (iii) a heavy partner of the W boson W' decaying into WZ for masses less than 1.7 TeV. For the first time mass limits are set on W' -> WZ and G(RS) -> WW in the all-jets final state. The mass limits on q* -> qW, q* -> qZ, W' -> WZ, G(RS) -> WW are the most stringent to date. A model with a "bulk" graviton G(bulk) that decays into WW or ZZ bosons is also studied.

Background: Although broadly neutralizing monoclonal antibodies (bNAbs) have always been considered to be a potential therapeutic option for the prophylaxis and treatment of HIV infection, their lack of breadth against all HIV variants has been one of the limiting factors. To provide sufficient neutralization breadth and potency against diverse viruses, including neutralization escape mutants, strategies to combine different bNAbs have been explored recently. Methods: We rationally designed and engineered a novel bispecific HIV-1-neutralizing antibody (bibNAb), iMabm36. The potency and breadth of iMabm36 against HIV were extensively characterized in vitro. Results: iMabm36 comprises the anti-CD4 Ab ibalizumab (iMab) linked to 2 copies of the single-domain Ab m36, which targets a highly conserved CD4-induced epitope. iMabm36 neutralizes a majority of a large, multiclade panel of pseudoviruses (96%, n = 118) at an IC50 concentration of less than 10 mu g/mL, with 83% neutralized at an IC50 concentration of less than 0.1 mu g/mL. In addition, iMabm36 neutralizes a small panel of replication-competent transmitted-founder viruses to 100% inhibition at a concentration of less than 0.1 mu g/mL in a peripheral blood mononuclear cell-based neutralizing assay. Mechanistically, the improved antiviral activity of iMabm36 is dependent on both the CD4-binding activity of the iMab component and the CD4i-binding activity of the m36 component. After characterizing that viral resistance to iMabm36 neutralization was due to mutations residing in the bridging sheet of gp120, an optimized m36 variant was engineered that, when fused to iMab, improved antiviral activity significantly. Conclusions: The interdependency of this dual mechanism of action enables iMabm36 to potently inhibit HIV-1 entry. These results demonstrate that mechanistic-based design of bibNAbs can generate potential preventive and therapeutic candidates for HIV/AIDS.

Background: The complex societies of ants and other social insects rely on sophisticated chemical communication. Two families of small soluble proteins, the odorant binding and chemosensory proteins (OBPs and CSPs), are believed to be important in insect chemosensation. To better understand the role of these proteins in ant olfaction, we examined their evolution and expression across the ants using phylogenetics and sex-and tissue-specific RNA-seq. Results: We find that subsets of both OBPs and CSPs are expressed in the antennae, contradicting the previous hypothesis that CSPs have replaced OBPs in ant olfaction. Both protein families have several highly conserved clades with a single ortholog in all eusocial hymenopterans, as well as clades with more dynamic evolution and many taxon-specific radiations. The dynamically evolving OBPs and CSPs have been hypothesized to function in chemical communication. Intriguingly, we find that seven members of the conserved clades are expressed specifically in the antennae of the clonal raider ant Cerapachys biroi, whereas only one dynamically evolving CSP is antenna specific. The orthologs of the conserved, antenna-specific C. biroi genes are also expressed in antennae of the ants Camponotus floridanus and Harpegnathos saltator, indicating that antenna-specific expression of these OBPs and CSPs is conserved across ants. Most members of the dynamically evolving clades in both protein families are expressed primarily in non-chemosensory tissues and thus likely do not fulfill chemosensory functions. Conclusions: Our results identify candidate OBPs and CSPs that are likely involved in conserved aspects of ant olfaction, and suggest that OBPs and CSPs may not rapidly evolve to recognize species-specific signals.