Highlights • Maintenance of intra/extracellular force balance is essential for cell integrity. • LIM domain proteins are broadly mechanosensitive. • LIM proteins mediate SF assembly and repair. • ...Zyxin provides a tractable model for understanding LIM protein mechanoresponse.
Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, ...suggesting genetic or environmental modifiers.
Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied.
Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003).
Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
The discovery and characterization of broadly neutralizing antibodies (bnAbs) against influenza viruses have raised hopes for the development of monoclonal antibody (mAb)-based immunotherapy and the ...design of universal influenza vaccines. Only one human bnAb (CR8020) specifically recognizing group 2 influenza A viruses has been previously characterized that binds to a highly conserved epitope at the base of the hemagglutinin (HA) stem and has neutralizing activity against H3, H7, and H10 viruses. Here, we report a second group 2 bnAb, CR8043, which was derived from a different germ-line gene encoding a highly divergent amino acid sequence. CR8043 has in vitro neutralizing activity against H3 and H10 viruses and protects mice against challenge with a lethal dose of H3N2 and H7N7 viruses. The crystal structure and EM reconstructions of the CR8043-H3 HA complex revealed that CR8043 binds to a site similar to the CR8020 epitope but uses an alternative angle of approach and a distinct set of interactions. The identification of another antibody against the group 2 stem epitope suggests that this conserved site of vulnerability has great potential for design of therapeutics and vaccines.
The unclear relationship between cuprate superconductivity and the pseudogap state remains an impediment to understanding the high transition temperature (Tc) superconducting mechanism. Here, we used ...magnetic field–dependent scanning tunneling microscopy to provide phase-sensitive proof that d-wave superconductivity coexists with the pseudogap on the antinodal Fermi surface of an overdoped cuprate. Furthermore, by tracking the hole-doping (p) dependence of the quasi-particle interference pattern within a single bismuth-based cuprate family, we observed a Fermi surface reconstruction slightly below optimal doping, indicating a zero-field quantum phase transition in notable proximity to the maximum superconducting Tc. Surprisingly, this major reorganization of the system's underlying electronic structure has no effect on the smoothly evolving pseudogap.
In January 2016, Asia and North America experienced unusual cold temperatures, although the global average of surface air temperature broke the warmest record during a strong El Niño event. This was ...closely related to the remarkable phase transition of the Arctic Oscillation (AO), which can be explained by stratosphere‐troposphere interactions. First, the quasi‐biennial oscillation changed to its westerly phase in summer 2015 and the stratospheric polar vortex was stronger in early to midwinter 2015/2016. As blocking did not occur in December, the associated downward propagation signal resulted in a strongly positive AO in late December 2015. Second, after late December, the positive phase of Pacific‐North America pattern became apparent in El Niño event, which strengthened the Aleutian anticyclone in the stratosphere. In addition, an equivalent barotropic (“blocking”) anticyclone was established in the troposphere over Asia. The coexistence of blocking over Asia and North America characterized the negative AO and a strong zonal wave number 2 pattern. Due to stronger zonal wave number 2 signals from the troposphere, the stronger stratospheric polar vortex was elongated, with two cyclonic centers over Asia and the North Atlantic in January. The resultant southward displacement of polar vortices was followed by rare snowfall in the subtropical region of East Asia and a heavy snowstorm on the East Coast of the United States.
Key Points
The strongly positive Arctic Oscillation was due to the westerly quasi‐biennial oscillation and no blocking
An El Niño event and the Asian blocking coincided with the elongation of the stratospheric polar vortex in January 2016
Blocking and the elongated polar vortex were linked to the strongly negative Arctic Oscillation and extreme cold spells
We present the result of a search of the Milagro sky map for spatial correlations with sources from a subset of the recent Fermi Bright Source List (BSL). The BSL consists of the 205 most significant ...sources detected above 100 MeV by the Fermi Large Area Telescope. We select sources based on their categorization in the BSL, taking all confirmed or possible Galactic sources in the field of view of Milagro. Of the 34 Fermi sources selected, 14 are observed by Milagro at a significance of 3 standard deviations or more. We conduct this search with a new analysis which employs newly optimized gamma-hadron separation and utilizes the full eight-year Milagro data set. Milagro is sensitive to gamma rays with energy from 1 to 100 TeV with a peak sensitivity from 10 to 50 TeV depending on the source spectrum and declination. These results extend the observation of these sources far above the Fermi energy band. With the new analysis and additional data, multi-TeV emission is definitively observed associated with the Fermi pulsar, J2229.0+6114, in the Boomerang pulsar wind nebula (PWN). Furthermore, an extended region of multi-TeV emission is associated with the Fermi pulsar, J0634.0+1745, the Geminga pulsar.
(ProQuest: ... denotes formulae and/or non-USASCII text omitted) The Cygnus region is a very bright and complex portion of the TeV sky, host to unidentified sources and a diffuse excess with respect ...to conventional cosmic-ray propagation models. Two of the brightest TeV sources, MGRO J2019+37 and MGRO J2031+41, are analyzed using Milagro data with a new technique, and their emission is tested under two different spectral assumptions: a power law and a power law with an exponential cutoff. The new analysis technique is based on an energy estimator that uses the fraction of photomultiplier tubes in the observatory that detect the extensive air shower. The photon spectrum is measured in the range 1-100 TeV using the last three years of Milagro data (2005-2008), with the detector in its final configuration. An F-test indicates that MGRO J2019+37 is better fit by a power law with an exponential cutoff than by a simple power law. The best-fitting parameters for the power law with exponential cutoff model are a normalization at 10 TeV of ... x 10 super(-10) s super(-1) m super(-2) TeV super(-1), a spectral index of ... and a cutoff energy of ... TeV. MGRO J2031+41 shows no evidence of a cutoff. The best-fitting parameters for a power law are a normalization of ... x 10 super(-10) s super(-1) m super(-2) TeV super(-1) and a spectral index of ... The overall flux is subject to a ~30% systematic uncertainty. The systematic uncertainty on the power-law indices is ~0.1. Both uncertainties have been verified with cosmic-ray data. A comparison with previous results from TeV J2032+4130, MGRO J2031+41, and MGRO J2019+37 is also presented.
Most of the world's crops depend on pollinators, so declines in both managed and wild bees raise concerns about food security. However, the degree to which insect pollination is actually limiting ...current crop production is poorly understood, as is the role of wild species (as opposed to managed honeybees) in pollinating crops, particularly in intensive production areas. We established a nationwide study to assess the extent of pollinator limitation in seven crops at 131 locations situated across major crop-producing areas of the USA. We found that five out of seven crops showed evidence of pollinator limitation. Wild bees and honeybees provided comparable amounts of pollination for most crops, even in agriculturally intensive regions. We estimated the nationwide annual production value of wild pollinators to the seven crops we studied at over $1.5 billion; the value of wild bee pollination of all pollinator-dependent crops would be much greater. Our findings show that pollinator declines could translate directly into decreased yields or production for most of the crops studied, and that wild species contribute substantially to pollination of most study crops in major crop-producing regions.
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