Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

© 2019 National Academy of Sciences. All rights reserved. Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation

Electroweak measurements in electron–positron collisions at w-boson-pair energies at lep

Contains fulltext : 121524.pdf (preprint version ) (Open Access

An integrated pan-tropical biomass map using multiple reference datasets (PAN-TROPICAL FUSED BIOMASS MAP)

Abstract We combined two existing datasets of vegetation aboveground biomass (AGB) (Saatchi et al., 2011; Baccini et al., 2012) into a pan-tropical AGB map at 1-km resolution using an independent reference dataset of field observations and locally-calibrated high-resolution biomass maps, harmonized and upscaled to 14,477 1-km AGB estimates. Our data fusion approach uses bias removal and weighted linear averaging that incorporates and spatializes Accepted Article This article is protected by copyright. All rights reserved. existing regional biomass maps as input maps and additional, country-specific reference datasets

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention

Search for Charged Higgs bosons: Combined Results Using LEP Data

The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for pair-produced charged Higgs bosons in the framework of Two Higgs Doublet Models (2HDMs). The data of the four experiments are statistically combined. The results are interpreted within the 2HDM for Type I and Type II benchmark scenarios. No statistically significant excess has been observed when compared to the Standard Model background prediction, and the combined LEP data exclude large regions of the model parameter space. Charged Higgs bosons with mass below 80 GeV/c^2 (Type II scenario) or 72.5 GeV/c^2 (Type I scenario, for pseudo-scalar masses above 12 GeV/c^2) are excluded at the 95% confidence level

BEAM TESTS OF THE ZEUS BARREL CALORIMETER

A fully compensating uranium-scintillator calorimeter was constructed for the ZEUS detector at HERA. Several of the barrel calorimeter modules were subjected to beam tests at Fermilab before shipping them to DESY for installation. The calibrations of the modules used beams of electrons and hadrons, measuring the uniformity of the response, and checking the resolution. The runs also provided opportunity to test a large fraction of the actual ZEUS calorimeter readout system in an integrated beam environment more than one year before HERA turn on. The experiment utilized two computer controlled mechanical structures. one of which was capable of holding up to four modules in order to study shower containment, and a magnetic spectrometer with a high resolution beam tracking system. During two running periods, beams of 6 to 110 GeV containing e, mu, pi, and pBAR were used. The results show energy resolutions of 35%/square-root E for hadrons and 19%/square-root E for electrons, uniformities at the 1% level, energy nonlinearity less than 1%, and equal response for electrons and hadrons