The rockefeller university

Aims: Mineralo-organic nanoparticles (NPs) detected in biological fluids have been described as precursors of physiological and pathological calcifications in the body. Our main objective was to examine the early stages of mineral NP formation in body fluids. Materials & methods: A nanomaterial approach based on atomic force microscopy, dynamic light scattering, electron microscopy and spectroscopy was used. Results: The mineral particles, which contain the serum proteins albumin and fetuin-A, initially precipitate in the form of round amorphous NPs that gradually grow in size, aggregate and coalesce to form crystalline mineral films similar to the structures observed in calcified human arteries. Conclusion: Our study reveals the early stages of particle formation and provides a platform to analyze the role(s) of mineralo-organic NPs in human tissues.

Variation in the presentation of hereditary immunodeficiencies may be explained by genetic or environmental factors. Patients with mutations in HOIL1 (RBCK1) present with amylopectinosis-associated myopathy with or without hyper-inflammation and immunodeficiency. We report that barrier-raised HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium but show minimal signs of hyper-inflammation. However, they show immunodeficiency upon acute infection with Listeria monocytogenes, Toxoplasma gondii or Citrobacter rodentium. Increased susceptibility to Listeria was due to HOIL-1 function in hematopoietic cells and macrophages in production of protective cytokines. In contrast, HOIL-1-deficient mice showed enhanced control of chronic Mycobacterium tuberculosis or murine.-herpesvirus 68 (MHV68), and these infections conferred a hyper-inflammatory phenotype. Surprisingly, chronic infection with MHV68 complemented the immunodeficiency of HOIL-1, IL-6, Caspase-1 and Caspase-1; Caspase-11-deficient mice following Listeria infection. Thus chronic herpesvirus infection generates signs of auto-inflammation and complements genetic immunodeficiency in mutant mice, highlighting the importance of accounting for the virome in genotype-phenotype studies.

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.

Prokaryotic CRISPR-Cas loci encode proteins that function as an adaptive immune system against infectious viruses and plasmids. Immunity is mediated by Cas nucleases and small RNA guides, which specify a cleavage site within the genome of the invader. In type II CRISPR-Cas systems, the RNA-guided Cas9 nuclease cleaves the DNA. Cas9 can be reprogrammed to create double-strand DNA breaks in the genomes of a variety of organisms, from bacteria to human cells. Repair of Cas9 lesions by homologous recombination or nonhomologous end joining mechanisms can lead to the introduction of specific nucleotide substitutions or indel mutations, respectively. Furthermore, a nuclease-null Cas9 has been developed to regulate endogenous gene expression and to label genomic loci in living cells. Targeted genome editing and gene regulation mediated by Cas9 are easy to program, scale, and multiplex, allowing researchers to decipher the causal link between genetic and phenotypic variation. In this review, we describe the most notable applications of Cas9 in basic biology, translational medicine, synthetic biology, biotechnology, and other fields.

The following is an edited transcript of a recorded discussion session on the topics of "Middle Ear Mechanics" and "Progress in Cochlear Modeling". The discussion, moderated by the authors, took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. All participants knew that the session was being recorded. In view of both the spontaneous nature of the discussion and the editing, however, this transcript may not represent the considered or final views of the participants, and may not represent a consensus of experts in the field. The reader is advised to consult additional independent publications.

A measurement of the inclusive ZZ production cross section and constraints on anomalous triple gauge couplings in proton-proton collisions at root s = 8 TeV are presented. The analysis is based on a data sample, corresponding to an integrated luminosity of 19.6 fb(-1), collected with the CMS experiment at the LHC. The measurements are performed in the leptonic decay modes ZZ -> lll'l', where = e, mu and l' = e, mu, tau. The measured total cross section sigma(pp -> ZZ) = 7.7 +/- 0.5 (stat) (0)(-0.4)(+0.5) (syst) +/- 0.4 (theo) +/- 0.2 (lumi) pb, for both Z bosons produced in the mass range 60 < m(z) < 120 GeV, is consistent with standard model predictions. Differential cross sections are measured and well described by the theoretical predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ gamma couplings at the 95% confidence level: -0.004 < f(4)(Z), < 0.004, -0.004 < f(5)(Z) < 0.004, -0.005 < f(5)(Z) < 0.005, and -0.005 < f(5)(Y) < 0.005. (C) 2014 The Authors. Published by Elsevier B.V.

Sterols are a critical component of cell membranes of eukaryotes. In mammalian cells there is approximately a six-fold range in the cholesterol content in various organelles. The cholesterol content of membranes plays an important role in organizing membranes for signal transduction and protein trafficking as well as in modulating the physiochemical properties of membranes. Cholesterol trafficking among organelles is highly dynamic and is mediated by both vesicular and non-vesicular processes. Several proteins have been proposed to mediate inter-organelle trafficking of cholesterol. However, several aspects of the mechanisms involved in regulating trafficking and distribution of cholesterol remain to be elucidated. In the present chapter, we discuss the cellular mechanisms involved in cholesterol distribution and the trafficking processes involved in maintaining sterol homoeostasis.

A measurement of the W boson helicity is presented, where the W boson originates from the decay of a top quark produced in pp collisions. The event selection, optimized for reconstructing a single top quark in the final state, requires exactly one isolated lepton (muon or electron) and exactly two jets, one of which is likely to originate from the hadronization of a bottom quark. The analysis is performed using data recorded at a center-of-mass energy of 8 TeV with the CMS detector at the CERN LHC in 2012. The data sample corresponds to an integrated luminosity of 19.7 fb(-1). The measured helicity fractions are F-L = 0.298 +/- 0.028 (stat) +/- 0.032(syst), F-0 = 0.720 +/- 0.039 (stat) +/- 0.037(syst), and F-R = -0.018 +/- 0.019 (stat) +/- 0.011(syst). These results are used to set limits on the real part of the tWb anomalous couplings, g(L) and g(R).

The following summarizes the key points addressed during a tutorial session on the Micromechanics of Hearing that took place at the 12th International Workshop on the Mechanics of Hearing held at Cape Sounio, Greece, in June 2014. The tutorial was intended to present an overview of basic ideas and to address topics of current interest relevant to the Workshop. The session was recorded, and the audio file and accompanying visual content of the presentation can be found in the Mechanics of Hearing Digital Library (www.mechanicsofhearing.org).