2,757 research outputs found
Site-specific identification and quantitation of endogenous SUMO modifications under native conditions.
Small ubiquitin-like modifier (SUMO) modification regulates numerous cellular processes. Unlike ubiquitin, detection of endogenous SUMOylated proteins is limited by the lack of naturally occurring protease sites in the C-terminal tail of SUMO proteins. Proteome-wide detection of SUMOylation sites on target proteins typically requires ectopic expression of mutant SUMOs with introduced tryptic sites. Here, we report a method for proteome-wide, site-level detection of endogenous SUMOylation that uses α-lytic protease, WaLP. WaLP digestion of SUMOylated proteins generates peptides containing SUMO-remnant diglycyl-lysine (KGG) at the site of SUMO modification. Using previously developed immuno-affinity isolation of KGG-containing peptides followed by mass spectrometry, we identified 1209 unique endogenous SUMO modification sites. We also demonstrate the impact of proteasome inhibition on ubiquitin and SUMO-modified proteomes using parallel quantitation of ubiquitylated and SUMOylated peptides. This methodological advancement enables determination of endogenous SUMOylated proteins under completely native conditions
Conformally Flat Smoothed Particle Hydrodynamics: Application to Neutron Star Mergers
We present a new 3D SPH code which solves the general relativistic field +
hydrodynamics equations in the conformally flat approximation. Several test
cases are considered to test different aspects of the code. We finally apply
then the code to the coalescence of a neutron star binary system. The neutron
stars are modeled by a polytropic equation of state (EoS) with adiabatic
indices , and . We calculate the
gravitational wave signals, luminosities and frequency spectra by employing the
quadrupole approximation for emission and back reaction in the slow motion
limit. In addition, we consider the amount of ejected mass.Comment: 23 pages, 12 figures. Accepted for publication in Phys. Rev. D. v3:
Final Versio
The Nature of Infrared Emission in the Local Group Dwarf Galaxy NGC 6822 As Revealed by Spitzer
We present Spitzer imaging of the metal-deficient (Z ~30% Z_sun) Local Group
dwarf galaxy NGC 6822. On spatial scales of ~130 pc, we study the nature of IR,
H alpha, HI, and radio continuum emission. Nebular emission strength correlates
with IR surface brightness; however, roughly half of the IR emission is
associated with diffuse regions not luminous at H alpha (as found in previous
studies). The global ratio of dust to HI gas in the ISM, while uncertain at the
factor of ~2 level, is ~25 times lower than the global values derived for
spiral galaxies using similar modeling techniques; localized ratios of dust to
HI gas are about a factor of five higher than the global value in NGC 6822.
There are strong variations (factors of ~10) in the relative ratios of H alpha
and IR flux throughout the central disk; the low dust content of NGC 6822 is
likely responsible for the different H alpha/IR ratios compared to those found
in more metal-rich environments. The H alpha and IR emission is associated with
high-column density (> ~1E21 cm^-2) neutral gas. Increases in IR surface
brightness appear to be affected by both increased radiation field strength and
increased local gas density. Individual regions and the galaxy as a whole fall
within the observed scatter of recent high-resolution studies of the radio-far
IR correlation in nearby spiral galaxies; this is likely the result of depleted
radio and far-IR emission strengths in the ISM of this dwarf galaxy.Comment: ApJ, in press; please retrieve full-resolution version from
http://www.astro.wesleyan.edu/~cannon/pubs.htm
Massive-Star Supernovae as Major Dust Factories
We present late-time optical and mid-infrared observations of the Type-II
supernova 2003gd in NGC 628. Mid-infrared excesses consistent with cooling dust
in the ejecta are observed 499-678 days after outburst, and are accompanied by
increasing optical extinction and growing asymmetries in the emission-line
profiles. Radiative-transfer models show that up to 0.02 solar masses of dust
has formed within the ejecta, beginning as early as 250 days after outburst.
These observations show that dust formation in supernova ejecta can be
efficient and that massive-star supernovae can be major dust producers
throughout the history of the Universe.Comment: 11 pages, 1 figure. Accepted 2006 May 30 for publication in Science;
Published in 2006 Jun 8 edition of Science Express; 2nd version fixes minor
change in conclusion made in pres
A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.
BACKGROUND
The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T).
METHODS/DESIGN
The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase.
DISCUSSION
The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases.
TRIAL REGISTRATION
The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511)
Search for composite and exotic fermions at LEP 2
A search for unstable heavy fermions with the DELPHI detector at LEP is
reported. Sequential and non-canonical leptons, as well as excited leptons and
quarks, are considered. The data analysed correspond to an integrated
luminosity of about 48 pb^{-1} at an e^+e^- centre-of-mass energy of 183 GeV
and about 20 pb^{-1} equally shared between the centre-of-mass energies of 172
GeV and 161 GeV. The search for pair-produced new leptons establishes 95%
confidence level mass limits in the region between 70 GeV/c^2 and 90 GeV/c^2,
depending on the channel. The search for singly produced excited leptons and
quarks establishes upper limits on the ratio of the coupling of the excited
fermio
Search for supersymmetry in events with b-quark jets and missing transverse energy in pp collisions at 7 TeV
Results are presented from a search for physics beyond the standard model
based on events with large missing transverse energy, at least three jets, and
at least one, two, or three b-quark jets. The study is performed using a sample
of proton-proton collision data collected at sqrt(s) = 7 TeV with the CMS
detector at the LHC in 2011. The integrated luminosity of the sample is 4.98
inverse femtobarns. The observed number of events is found to be consistent
with the standard model expectation, which is evaluated using control samples
in the data. The results are used to constrain cross sections for the
production of supersymmetric particles decaying to b-quark-enriched final
states in the context of simplified model spectra.Comment: Submitted to Physical Review
Search for lightest neutralino and stau pair production in light gravitino scenarios with stau NLSP
Promptly decaying lightest neutralinos and long-lived staus are searched for
in the context of light gravitino scenarios. It is assumed that the stau is the
next to lightest supersymmetric particle (NLSP) and that the lightest
neutralino is the next to NLSP (NNLSP). Data collected with the Delphi detector
at centre-of-mass energies from 161 to 183 \GeV are analysed. No evidence of
the production of these particles is found. Hence, lower mass limits for both
kinds of particles are set at 95% C.L.. The mass of gaugino-like neutralinos is
found to be greater than 71.5 GeV/c^2. In the search for long-lived stau,
masses less than 70.0 to 77.5 \GeVcc are excluded for gravitino masses from 10
to 150 \eVcc . Combining this search with the searches for stable heavy leptons
and Minimal Supersymmetric Standard Model staus a lower limit of 68.5 \GeVcc
may be set for the stau mas
Heavy quarkonium: progress, puzzles, and opportunities
A golden age for heavy quarkonium physics dawned a decade ago, initiated by
the confluence of exciting advances in quantum chromodynamics (QCD) and an
explosion of related experimental activity. The early years of this period were
chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in
2004, which presented a comprehensive review of the status of the field at that
time and provided specific recommendations for further progress. However, the
broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles
could only be partially anticipated. Since the release of the YR, the BESII
program concluded only to give birth to BESIII; the -factories and CLEO-c
flourished; quarkonium production and polarization measurements at HERA and the
Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the
deconfinement regime. All these experiments leave legacies of quality,
precision, and unsolved mysteries for quarkonium physics, and therefore beg for
continuing investigations. The plethora of newly-found quarkonium-like states
unleashed a flood of theoretical investigations into new forms of matter such
as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the
spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b},
and b\bar{c} bound states have been shown to validate some theoretical
approaches to QCD and highlight lack of quantitative success for others. The
intriguing details of quarkonium suppression in heavy-ion collisions that have
emerged from RHIC have elevated the importance of separating hot- and
cold-nuclear-matter effects in quark-gluon plasma studies. This review
systematically addresses all these matters and concludes by prioritizing
directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K.
Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D.
Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A.
Petrov, P. Robbe, A. Vair
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