The rockefeller university

Background: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in I kappa B alpha that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor kappa light chain enhancer of activated B cells (NF-kappa B) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in I kappa B alpha have impaired noncanonical NF-kappa B activity and defective lymphorganogenesis. Objective: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. Methods: A disease severity scoring system was devised. Stability of I kappa B alpha mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-kappa B signaling in skin-derived fibroblasts. Results: Disease severity was greater in patients with IkBa point mutations than in those with truncation mutations. IkBa point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-kappa B-dependent IL-6 secretion and upregulation of the NF-kappa B subunit 2/p100 and RELB proto-oncogene, NF-kappa B subunit (RelB) components of the noncanonical NF-kappa B pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-kappa B-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus alpha-lymphotoxin beta receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. Conclusions: I kappa B alpha point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-kappa B activity in patients with AD EDA-ID.

The top quark pair production cross section (ad) is measured for the first time in pp collisions at a center-of-mass energy of 5.02 TeV. The data were collected by the CMS experiment at the LHC and correspond to an integrated luminosity of 27.4 pb(-1). The measurement is performed by analyzing events with at least one charged lepton. The measured cross section is sigma(tt) = 69.5 +/- 6.1 (stat) +/- 5.6 (syst) +/- 1.6 (lumi) pb, with a total relative uncertainty of 12%. The result is in agreement with the expectation from the standard model. The impact of the presented measurement on the determination of the gluon distribution function is investigated.

Our body's epithelia are barriers that interface with the terrestrial environment and routinely experience inflammation. Although a vast majority of these inflammatory reactions resolve, they imprint the tissue with a memory. Cells of the immune system are traditionally thought to be the bearers of this memory, allowing them to react faster to subsequent inflammatory pressures (1, 2). Yet, barrier tissues are composites of epithelial, mesenchymal, nervous, vascular, and immunological networks working in unison to sustain optimal function in health and disease. The question of whether tissue-resident cells, distinct from the immune system, are entrained in response to a perturbation remains to be addressed.

Results are presented from a search for the pair production of third-generation squarks in proton-proton collision events with two-body decays to bottom or charm quarks and a neutralino, which produces a significant imbalance in the transverse momentum. The search is performed using a sample of proton-proton collision data at root s = 13 TeV recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 35.9fb(-1). No statistically significant excess of events is observed beyond the expected contribution from standard model processes. Exclusion limits are set in the context of simplified models of bottom or top squark pair production. Models with bottom squark masses up to 1220 GeV are excluded at 95% confidence level for light neutralinos, and models with top squark masses of 510 GeV are excluded assuming that the mass splitting between the top squark and the neutralino is small. (C) 2018 The Author. Published by Elsevier B.V.

Virtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the "silent face" on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center. Somatic hypermutation occurred preferentially at antibody residues that interacted with these glycans, suggesting somatic development of glycan recognition. Resistance to VRC-PG05 in donor #74 involved shifting of glycan-N448 to N446 or mutation of glycan-proximal residue E293. HIV-1 neutralization can thus be achieved at the silent face center by glycan-recognizing antibody; along with other known epitopes, the VRC-PG05 epitope completes coverage by neutralizing antibody of all major exposed regions of the prefusion closed trimer.

Host-symbiont interactions are embedded in ecological communities and range from unspecific to highly specific relationships. Army ants and their arthropod guests represent a fascinating example of species-rich host-symbiont associations where host specificity ranges across the entire generalist -specialist continuum. In the present study, we compared the behavioral and chemical integration mechanisms of two extremes of the generalist -specialist continuum: generalist ant-predators in the genus Tetradonia (Staphylinidae: Aleocharinae: Athetini), and specialist ant-mimics in the genera Ecitomorpha and Ecitophya (Staphylinidae: Aleocharinae: Ecitocharini). Similar to a previous study of Tetradonia beetles, we combined DNA barcoding with morphological studies to define species boundaries in ant-mimicking beetles. This approach found four ant-mimicking species at our study site at La Selva Biological Station in Costa Rica. Community sampling of Eciton army ant parasites revealed that ant-mimicking beetles were perfect host specialists, each beetle species being associated with a single Eciton species. These specialists were seamlessly integrated into the host colony, while generalists avoided physical contact to host ants in behavioral assays. Analysis of the ants' nestmate recognition cues, i.e. cuticular hydrocarbons (CHCs), showed close similarity in CHC composition and CHC concentration between specialists and Eciton burchellii foreli host ants. On the contrary, the chemical profiles of generalists matched host profiles less well, indicating that high accuracy in chemical host resemblance is only accomplished by socially integrated species. Considering the interplay between behavior, morphology, and cuticular chemistry, specialists but not generalists have cracked the ants' social code with respect to various sensory modalities. Our results support the long-standing idea that the evolution of host-specialization in parasites is a trade-off between the range of potential host species and the level of specialization on any particular host.

Search results are presented for physics beyond the standard model in final states with two opposite-charge, same-flavor leptons, jets, and missing transverse momentum. The data sample corresponds to an integrated luminosity of 35.9 fb(-1) of proton-proton collisions at root s = 13TeV collected with the CMS detector at the LHC in 2016. The analysis uses the invariant mass of the lepton pair, searching for a kinematic edge or a resonant-like excess compatible with the Z boson mass. The search for a kinematic edge targets production of particles sensitive to the strong force, while the resonance search targets both strongly and electroweakly produced new physics. The observed yields are consistent with the expectations from the standard model, and the results are interpreted in the context of simplified models of supersymmetry. In a gauge mediated supersymmetry breaking (GMSB) model of gluino pair production with decay chains including Z bosons, gluino masses up to 1500-1770 GeV are excluded at the 95% confidence level depending on the lightest neutralino mass. In a model of electroweak chargino-neutralino production, chargino masses as high as 610 GeV are excluded when the lightest neutralino is massless. In GMSB models of electroweak neutralino-neutralino production, neutralino masses up to 500-650 GeV are excluded depending on the decay mode assumed. Finally, in a model with bottom squark pair production and decay chains resulting in a kinematic edge in the dilepton invariant mass distribution, bottom squark masses up to 980-1200 GeV are excluded depending on the mass of the next-to-lightest neutralino.

The transverse momentum balance of pairs of back-to-back b quark jets in PbPb and pp collisions recorded with the CMS detector at the LHC is reported. The center-of-mass energy in both collision systems is 5.02 TeV per nucleon pair. Compared to the pp collision baseline, b quark jets have a larger imbalance in the most central PbPb collisions, as expected from the jet quenching effect. The data are also compared to the corresponding measurement with inclusive dijets. In the most central collisions, the imbalance of b quark dijets is comparable to that of inclusive dijets.