2,213 research outputs found
Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation
Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2’s recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins
Emission-Line Galaxies from the Hubble Space Telescope Probing Evolution and Reionization Spectroscopically (PEARS) Grism Survey. II: The Complete Sample
We present a full analysis of the Probing Evolution And Reionization
Spectroscopically (PEARS) slitess grism spectroscopic data obtained with the
Advanced Camera for Surveys on HST. PEARS covers fields within both the Great
Observatories Origins Deep Survey (GOODS) North and South fields, making it
ideal as a random survey of galaxies, as well as the availability of a wide
variety of ancillary observations to support the spectroscopic results. Using
the PEARS data we are able to identify star forming galaxies within the
redshift volume 0< z<1.5. Star forming regions in the PEARS survey are
pinpointed independently of the host galaxy. This method allows us to detect
the presence of multiple emission line regions (ELRs) within a single galaxy.
1162 Ha, [OIII] and/or [OII] emission lines have been identified in the PEARS
sample of ~906 galaxies down to a limiting flux of ~1e-18 erg/s/cm^2. The ELRs
have also been compared to the properties of the host galaxy, including
morphology, luminosity, and mass. From this analysis we find three key results:
1) The computed line luminosities show evidence of a flattening in the
luminosity function with increasing redshift; 2) The star forming systems show
evidence of disturbed morphologies, with star formation occurring predominantly
within one effective (half-light) radius. However, the morphologies show no
correlation with host stellar mass; and 3) The number density of star forming
galaxies with M_* > 1e9} M_sun decreases by an order of magnitude at z<0.5
relative to the number at 0.5<z<0.9 in support of the argument for galaxy
downsizing.Comment: Submitted. 48 pages. 19 figures. Accepted to Ap
Genetic Deletion of the Desmosomal Component Desmoplakin Promotes Tumor Microinvasion in a Mouse Model of Pancreatic Neuroendocrine Carcinogenesis
We used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to profile the transcriptome of pancreatic neuroendocrine tumors (PNET) that were either non-invasive or highly invasive, seeking to identify pro- and anti-invasive molecules. Expression of multiple components of desmosomes, structures that help maintain cellular adhesion, was significantly reduced in invasive carcinomas. Genetic deletion of one of these desmosomal components, desmoplakin, resulted in increased local tumor invasion without affecting tumor growth parameters in RT2 PNETs. Expression of cadherin 1, a component of the adherens junction adhesion complex, was maintained in these tumors despite the genetic deletion of desmoplakin. Our results demonstrate that loss of desmoplakin expression and resultant disruption of desmosomal adhesion can promote increased local tumor invasion independent of adherens junction status
Direct Semi-Synthesis of the Anticancer Lead-Drug Protoapigenone from Apigenin, and Synthesis of Further New Cytotoxic Protoflavone Derivatives
Protoapigenone, a natural flavonoid possessing an unusual p-quinol moiety on its B-ring, is a novel prospective anticancer agent with low toxicity that is currently in development. The first economical, one-step synthesis of protoapigenone from apigenin is described on up to gram scale. 13 new 1′-O-alkylflavone analogs were also synthesized, either from apigenin or β-naphthoflavone. The in vitro cytotoxic activity of each compound was tested on six human cancer cell lines (HepG2, Hep3B, Ca9-22, A549, MCF-7 and MDA-MB-231). In the case of 1′-O-alkyl-protoapigenone derivatives, structure-activity relationships were found depending on the side-chain, and protoapigenone 1′-O-butyl ether was found to exert significantly stronger activity against three of the cell lines (Hep3B, MCF-7 and MDA-MB-231) than its non-substituted analog, protoapigenone itself. In contrast to this, all β-naphthoflavone derivatives bearing the same pharmacophore on their B-ring showed decreased cytotoxic activities when substituted with an O-alkyl side-chain at position 1′, comparing to that of the non-substituted compound
MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis
Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization
The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe
The preponderance of matter over antimatter in the early Universe, the
dynamics of the supernova bursts that produced the heavy elements necessary for
life and whether protons eventually decay --- these mysteries at the forefront
of particle physics and astrophysics are key to understanding the early
evolution of our Universe, its current state and its eventual fate. The
Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed
plan for a world-class experiment dedicated to addressing these questions. LBNE
is conceived around three central components: (1) a new, high-intensity
neutrino source generated from a megawatt-class proton accelerator at Fermi
National Accelerator Laboratory, (2) a near neutrino detector just downstream
of the source, and (3) a massive liquid argon time-projection chamber deployed
as a far detector deep underground at the Sanford Underground Research
Facility. This facility, located at the site of the former Homestake Mine in
Lead, South Dakota, is approximately 1,300 km from the neutrino source at
Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino
charge-parity symmetry violation and mass ordering effects. This ambitious yet
cost-effective design incorporates scalability and flexibility and can
accommodate a variety of upgrades and contributions. With its exceptional
combination of experimental configuration, technical capabilities, and
potential for transformative discoveries, LBNE promises to be a vital facility
for the field of particle physics worldwide, providing physicists from around
the globe with opportunities to collaborate in a twenty to thirty year program
of exciting science. In this document we provide a comprehensive overview of
LBNE's scientific objectives, its place in the landscape of neutrino physics
worldwide, the technologies it will incorporate and the capabilities it will
possess.Comment: Major update of previous version. This is the reference document for
LBNE science program and current status. Chapters 1, 3, and 9 provide a
comprehensive overview of LBNE's scientific objectives, its place in the
landscape of neutrino physics worldwide, the technologies it will incorporate
and the capabilities it will possess. 288 pages, 116 figure
Molecular Evolutionary Trends and Feeding Ecology Diversification in the Hemiptera, Anchored by the Milkweed Bug Genome
Background: The Hemiptera (aphids, cicadas, and true bugs) are a key insect order, with high diversity for feeding ecology and excellent experimental tractability for molecular genetics. Building upon recent sequencing of hemipteran pests such as phloem-feeding aphids and blood-feeding bed bugs, we present the genome sequence and comparative analyses centered on the milkweed bug Oncopeltus fasciatus, a seed feeder of the family Lygaeidae.
Results: The 926-Mb Oncopeltus genome is well represented by the current assembly and official gene set. We use our genomic and RNA-seq data not only to characterize the protein-coding gene repertoire and perform isoform-specific RNAi, but also to elucidate patterns of molecular evolution and physiology. We find ongoing, lineage-specific expansion and diversification of repressive C2H2 zinc finger proteins. The discovery of intron gain and turnover specific to the Hemiptera also prompted the evaluation of lineage and genome size as predictors of gene structure evolution. Furthermore, we identify enzymatic gains and losses that correlate with feeding biology, particularly for reductions associated with derived, fluid nutrition feeding.
Conclusions: With the milkweed bug, we now have a critical mass of sequenced species for a hemimetabolous insect order and close outgroup to the Holometabola, substantially improving the diversity of insect genomics. We thereby define commonalities among the Hemiptera and delve into how hemipteran genomes reflect distinct feeding ecologies. Given Oncopeltus’s strength as an experimental model, these new sequence resources bolster the foundation for molecular research and highlight technical considerations for the analysis of medium-sized invertebrate genomes
Sensory Communication
Contains table of contents for Section 2, an introduction and reports on fourteen research projects.National Institutes of Health Grant RO1 DC00117National Institutes of Health Grant RO1 DC02032National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grant R01 DC00126National Institutes of Health Grant R01 DC00270National Institutes of Health Contract N01 DC52107U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-95-K-0014U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0003U.S. Navy - Office of Naval Research Grant N00014-96-1-0379U.S. Air Force - Office of Scientific Research Grant F49620-95-1-0176U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0202U.S. Navy - Office of Naval Research Subcontract 40167U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0002National Institutes of Health Grant R01-NS33778U.S. Navy - Office of Naval Research Grant N00014-92-J-184
Scientists' warning on climate change and insects
Climate warming is considered to be among the most serious of anthropogenic stresses to the environment, because it not only has direct effects on biodiversity, but it also exacerbates the harmful effects of other human-mediated threats. The associated consequences are potentially severe, particularly in terms of threats to species preservation, as well as in the preservation of an array of ecosystem services provided by biodiversity. Among the most affected groups of animals are insects—central components of many ecosystems—for which climate change has pervasive effects from individuals to communities. In this contribution to the scientists' warning series, we summarize the effect of the gradual global surface temperature increase on insects, in terms of physiology, behavior, phenology, distribution, and species interactions, as well as the effect of increased frequency and duration of extreme events such as hot and cold spells, fires, droughts, and floods on these parameters. We warn that, if no action is taken to better understand and reduce the action of climate change on insects, we will drastically reduce our ability to build a sustainable future based on healthy, functional ecosystems. We discuss perspectives on relevant ways to conserve insects in the face of climate change, and we offer several key recommendations on management approaches that can be adopted, on policies that should be pursued, and on the involvement of the general public in the protection effort
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