The rockefeller university

Searches for resonant and nonresonant pair-produced Higgs bosons (HH) decaying respectively into l nu l nu, through either W or Z bosons, and b (b) over bar are presented. The analyses are based on a sample of proton-proton collisions at root s = 13 TeV, collected by the CMS experiment at the LHC, corresponding to an integrated luminosity of 35.9 fb(-1). Data and predictions from the standard model are in agreement within uncertainties. For the standard model HH hypothesis, the data exclude at 95% confidence level a product of the production cross section and branching fraction larger than 72 fb, corresponding to 79 times the standard model prediction. Constraints are placed on different scenarios considering anomalous couplings, which could affect the rate and kinematics of HH production. Upper limits at 95% confidence level are set on the production cross section of narrow-width spin-0 and spin-2 particles decaying to Higgs boson pairs, the latter produced with minimal gravity-like coupling.

Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions under which the fibrils are grown determine many types of reported fibril polymorphism, including different twist patterns. Twist-based polymorphs display unique mechanical properties in vitro, and the relevance of twist polymorphism in amyloid diseases has been suggested. We present transmission electron microscopy images of A beta 42-derived (amyloid beta) fibrils, which are associated with Alzheimer's disease, demonstrating the presence of twist variability even within a single long fibril. To better understand the molecular underpinnings of twist polymorphism, we present a structural and thermodynamics analysis of molecular dynamics simulations of the twisting of beta-sheet protofilaments of a well-characterized cross-beta model: the GNNQQNY peptide from the yeast prion Sup35. The results show that a protofilament model of GNNQQNY is able to adopt twist angles from -11 degrees on the left-hand side to +8 degrees on the right-hand side in response to various external conditions, keeping an unchanged peptide structure. The potential of mean force (PMF) of this cross-beta structure upon twisting revealed that only similar to 2k(B)T per peptide are needed to stabilize a straight conformation with respect to the left-handed free-energy minimum. The PMF also shows that the canonical structural core of beta-sheets, i.e., the hydrogen-bonded backbone beta-strands, favors the straight conformation. However, the concerted effects of the side chains contribute to twisting, which provides a rationale to correlate polypeptide sequence, environmental growth conditions and number of protofilaments in a fibril with twist polymorphisms.

For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3 overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.

Vertebrate ears employ hair bundles to transduce mechanical movements into electrical signals, but their performance is limited by noise. Hair bundles are substantially more sensitive to periodic stimulation when they are mechanically active, however, than when they are passive. We developed a model of active hair-bundle mechanics that predicts the conditions under which a bundle is most sensitive to periodic stimulation. The model relies only on the existence of mechanotransduction channels and an active adaptation mechanism that recloses the channels. For a frequency-detuned stimulus, a noisy hair bundle's phase-locked response and degree of entrainment as well as its detection bandwidth are maximized when the bundle exhibits low-amplitude spontaneous oscillations. The phase-locked response and entrainment of a bundle are predicted to peak as functions of the noise level. We confirmed several of these predictions experimentally by periodically forcing hair bundles held near the onset of self-oscillation. A hair bundle's active process amplifies the stimulus preferentially over the noise, allowing the bundle to detect periodic forces less than 1 pN in amplitude. Moreover, the addition of noise can improve a bundle's ability to detect the stimulus. Although, mechanical activity has not yet been observed in mammalian hair bundles, a related model predicts that active but quiescent bundles can oscillate spontaneously when they are loaded by a sufficiently massive object such as the tectorial membrane. Overall, this work indicates that auditory systems rely on active elements, composed of hair cells and their mechanical environment, that operate on the brink of self-oscillation.

Drawing upon sources in neuroethics, civil rights, and disability rights law, we argue for the reintegration of people with severe brain injury back into the nexus of their families and communities consistent with the Americans with Disabilities Act (ADA) and the UN Convention on the Rights of Persons with Disabilities, both of which call for the maximal integration of people with disability into society. To this end, we offer a rights-based argument to address the care of people with severe brain injury. Instead of viewing the provision of rehabilitation as a reimbursement issue, which it surely is, we argue that it can be productively understood as a question of civil rights for a population generally segregated from the medical mainstream and from society itself. Their segregation in the chronic care sector constitutes disrespect for persons, made all the more consequential because recent advances in brain injury rehabilitation make reintegration into civil society an aspirational, if not achievable goal.

Cell division involves mechanical processes, such as chromosome

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

Manganese superoxide dismutase (MnSOD) is a key enzyme in the protection of cells from oxidative stress. A tandem duplication of the MnSOD gene (NbMnSOD1 and NbMnSOD2) in the genome of Nosema bombycis, a parasite of the silkworm Bombyx mori, was previously identified. Here, we compare the protein structures of NbMnSOD1 and NbMnSOD2 and characterize these two proteins in terms of cellular localization, timing of transcription, protein structure, and enzyme activity. Despite a similarity in the primary sequence of NbMnSOD1 and NbMnSOD2, the latter shows a remarkable degree of amino acid sequence difference on the protein's surface and in the active site, where there is a substitution of a phenylalanine for a histidine in NbMnSOD2. Immuno-electron microscopy demonstrates that NbMnSOD1 is present in the cytosol of mature spores, whereas NbMnSOD2 is localized on the polar tube and the spore wall. Immunofluorescence confirms the localization of NbMnSOD2 on the polar tube of the germinated spore. Quantitative measurement of gene expression (qRT-PCR) demonstrates production of both alleles during the first day of infection followed by a dramatic decrease during the second to fourth day of infection. From the fifth day onward, the two alleles show a complementary pattern of expression. The qRT-PCR of the host manganese superoxide dismutase (BmMnSOD) shows a notable increase in transcription upon infection, leading to a three-fold spike by the first day of infection, followed by a decrease in transcription. Measurement of overall MnSOD activity shows a similar peak at day 1 followed by a decrease to a constant rate of enzyme activity. The differences in cellular localization and pattern of gene expression of NbMnSOD2 compared to NbMnSOD1, as well as the differences in protein structure seen for NbMnSOD2 compared to other microsporidial MnSODs, strongly suggest a unique, recently evolved role for NbMnSOD2.

Huntington's disease (HD) is a fatal neurodegenerative disease caused by expansion of CAG repeats in the Huntingtin gene (HTT). Neither its pathogenic mechanisms nor the normal functions of HTT are well understood. To model HD in humans, we engineered a genetic allelic series of isogenic human embryonic stem cell (hESC) lines with graded increases in CAG repeat length. Neural differentiation of these lines unveiled a novel developmental HD phenotype: the appearance of giant multinucleated telencephalic neurons at an abundance directly proportional to CAG repeat length, generated by a chromosomal instability and failed cytokinesis over multiple rounds of DNA replication. We conclude that disrupted neurogenesis during development is an important, unrecognized aspect of HD pathogenesis. To address the function of normal HTT protein we generated HTT+/- and HTT-/- lines. Surprisingly, the same phenotype emerged in HTT-/- but not HTT+/- lines. We conclude that HD is a developmental disorder characterized by chromosomal instability that impairs neurogenesis, and that HD represents a genetic dominant-negative loss of function, contrary to the prevalent gain-of-toxic-function hypothesis. The consequences of developmental alterations should be considered as a new target for HD therapies.

Objective: To provide an overview of studies contributing to the understanding of immunologic, microbial, and epithelial interactions in atopic dermatitis. Data Sources: PubMed literature review (2000-2017) and meeting abstracts from recent international dermatology conferences. Study Selections: Articles discussing primarily human disease. Results: Clinical studies showed that atopic dermatitis is a type 2 immune-centered disease with a systemic inflammatory component but with heterogeneous treatment responses. This suggests that other factors are likely involved in shaping the skin disease phenotype, including microbial dysbiosis and epidermal barrier dysfunction. Conclusion: Recent clinical investigation has significantly expanded our knowledge on disease pathogenesis in atopic dermatitis, and current and future clinical trials will most likely further help to elucidate this complex, heterogeneous skin disease. (C) 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.