The rockefeller university

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.

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.

CRISPR-Cas systems offer an immune mechanism through which prokaryotic hosts can acquire heritable resistance to genetic parasites, including temperate phages. Co-transcriptional DNA and RNA targeting by type III-A CRISPR-Cas systems restricts temperate phage lytic infections while allowing lysogenic infections to be tolerated under conditions where the prophage targets are transcriptionally repressed. However, long-term consequences of this phenomenon have not been explored. Here we show that maintenance of conditionally tolerant type III-A systems can produce fitness costs within populations of Staphylococcus aureus lysogens. The fitness costs depend on the activity of prophage-internal promoters and type III-A Cas nucleases implicated in targeting, can be more severe in double lysogens, and are alleviated by spacer-target mismatches which do not abrogate immunity during the lytic cycle. These findings suggest that persistence of type III-A systems that target endogenous prophages could be enhanced by spacer-target mismatches, particularly among populations that are prone to polylysogenization.

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory. In this work we propose a model to analyze the effect of T cell dynamics on the performance of prime-boost vaccines. This model suggests that boost doses and timings should be selected according to the T cell response elicited by priming. Specifically, boosting during late stages of clonal contraction would maximize T cell memory production for vaccines using lower doses of irradiated sporozoites. In contrast, single-dose inoculations would be indicated for higher vaccine doses. Experimental data have been obtained that support theoretical predictions of the model.

A search for narrow vector resonances decaying into quark-antiquark pairs is presented. The analysis is based on data collected in proton-proton collisions at root s = 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 35.9 fb(-1). The hypothetical resonance is produced with sufficiently high transverse momentum that its decay products are merged into a single jet with two-prong substructure. A signal would be identified as a peak over a smoothly falling background in the distribution of the invariant mass of the jet, using novel jet substructure techniques. No evidence for such a resonance is observed within the mass range of 50-300 GeV. Upper limits at 95% confidence level are set on the production cross section, and presented in a mass-coupling parameter space. The limits further constrain simplified models of dark matter production involving a mediator interacting between quarks and dark matter particles through a vector or axial-vector current. In the framework of these models, the results are the most sensitive to date, extending for the first time the search region to masses below 100 GeV.

Hair bundles are specialized organelles that transduce mechanical inputs into electrical outputs. To activate hair cells, physiologists have resorted to mechanical methods of hair-bundle stimulation. Here we describe a new method of hair-bundle stimulation, irradiation with ultraviolet light. A hair bundle illuminated by ultraviolet light rapidly moves towards its tall edge, a motion typically associated with excitatory stimulation. The motion disappears upon tip-link rupture and is associated with the opening of mechanotransduction channels. Hair bundles can be induced to move sinusoidally with oscillatory modulation of the stimulation power. We discuss the implications of ultraviolet stimulation as a novel hair-bundle stimulus.