227 research outputs found
A first insight into the developability of an IgG3 : a combined computational and experimental approach
Immunoglobulin G 3 (IgG3) monoclonal antibodies (mAbs) are high value scaffolds for developing novel therapies. Despite their wide-ranging therapeutic potential, IgG3 physicochemical properties and developability characteristics remain largely under-characterised. Protein-protein interactions elevate solution viscosity in high-concentration formulations impacting physico-chemical stability, manufacturability, and injectability of mAbs. Therefore, in this manuscript, the key molecular descriptors and biophysical properties of a model anti-IL-8 IgG1 and its IgG3 ortholog are characterised. A computational and experimental framework was applied to measure molecular descriptors impacting on their downstream developability. Findings from this approach underpin a detailed understanding of the molecular characteristics of IgG3 mAbs as potential therapeutic entities. This work is the first report examining the manufacturability of IgG3 for high concentration mAb formulations. While poorer conformational and colloidal stability, and elevated solution viscosity was observed for IgG3, future efforts controlling surface potential through sequence-engineering of solvent-accessible patches can be used to improve biophysical parameters that dictate mAb developability
Gravitational waves from coalescing binaries and Doppler experiments
Doppler tracking of interplanetary spacecraft provides the only method
presently available for broad-band searches of low frequency gravitational
waves. The instruments have a peak sensitivity around the reciprocal of the
round-trip light-time T of the radio link connecting the Earth to the
space-probe and therefore are particularly suitable to search for coalescing
binaries containing massive black holes in galactic nuclei. A number of Doppler
experiments -- the most recent involving the probes ULYSSES, GALILEO and MARS
OBSERVER -- have been carried out so far; moreover, in 2002-2004 the CASSINI
spacecraft will perform three 40 days data acquisition runs with expected
sensitivity about twenty times better than that achieved so far. Central aims
of this paper are: (i) to explore, as a function of the relevant instrumental
and astrophysical parameters, the Doppler output produced by in-spiral signals
-- sinusoids of increasing frequency and amplitude (the so-called chirp); (ii)
to identify the most important parameter regions where to concentrate intense
and dedicated data analysis; (iii) to analyze the all-sky and all-frequency
sensitivity of the CASSINI's experiments, with particular emphasis on possible
astrophysical targets, such as our Galactic Centre and the Virgo Cluster.Comment: 52 pages, LaTeX, 19 Postscript Figures, submitted to Phys. Rev.
Socioeconomic Position and Adolescent Trajectories in Smoking, Drinking, and Psychiatric Distress
Purpose: Smoking, drinking, and psychiatric distress are inter-related and may also be associated with socioeconomic position (SEP). This paper investigates the role of SEP in adolescent development across all three of these outcomes. Methods: Data were self-reported by adolescents in the Twenty-07 Study (N = 1,515) at ages 15, 17, and 18 years. Latent class analysis was used to identify homogeneous subgroups of adolescents with distinct developmental patterns. Associations between developmental patterns and a range of socioeconomic indicators were then tested. Results: Five classes were identified. A Low Risk class had low levels for all outcomes. A High Distress class had persistently high levels of distress, but was otherwise similar to the Low Risk group. A High Drinking class drank alcohol earlier and more heavily but also had higher levels of distress than the Low Risk group. Smokers were grouped in two classes, Early Smokers and Late Smokers, and both also had raised levels of drinking and distress. Early Smokers tended to begin earlier and smoke more heavily than Late Smokers. Relative to the Low Risk class, adolescents in a disadvantaged SEP were more likely to be Early Smokers and somewhat less likely to be in the High Drinking class. SEP was not consistently associated with membership in the High Distress or Late Smokers classes. Conclusions: Associations with SEP are evident in opposing directions or absent depending on the combination and timing of outcomes, suggesting that a disadvantaged SEP is not a simple common cause for all three outcomes. © 2013 Society for Adolescent Health and Medicine. All rights reserved
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Inflation and Dark Energy from spectroscopy at z > 2
The expansion of the Universe is understood to have accelerated during two
epochs: in its very first moments during a period of Inflation and much more
recently, at z < 1, when Dark Energy is hypothesized to drive cosmic
acceleration. The undiscovered mechanisms behind these two epochs represent
some of the most important open problems in fundamental physics. The large
cosmological volume at 2 < z < 5, together with the ability to efficiently
target high- galaxies with known techniques, enables large gains in the
study of Inflation and Dark Energy. A future spectroscopic survey can test the
Gaussianity of the initial conditions up to a factor of ~50 better than our
current bounds, crossing the crucial theoretical threshold of
of order unity that separates single field and
multi-field models. Simultaneously, it can measure the fraction of Dark Energy
at the percent level up to , thus serving as an unprecedented test of
the standard model and opening up a tremendous discovery space
Measurement of the production cross section for W-bosons in association with jets in pp collisions at s=7 TeV with the ATLAS detector
This Letter reports on a first measurement of the inclusive W + jets cross section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC, with the ATLAS detector. Cross sections, in both the electron and muon decay modes of the W-boson, are presented as a function of jet multiplicity and of the transverse momentum of the leading and next-to-leading jets in the event. Measurements are also presented of the ratio of cross sections sigma (W + >= n)/sigma(W + >= n - 1) for inclusive jet multiplicities n = 1-4. The results, based on an integrated luminosity of 1.3 pb(-1), have been corrected for all known detector effects and are quoted in a limited and well-defined range of jet and lepton kinematics. The measured cross sections are compared to particle-level predictions based on perturbative QCD. Next-to-leading order calculations, studied here for n <= 2, are found in good agreement with the data. Leading-order multiparton event generators, normalized to the NNLO total cross section, describe the data well for all measured jet multiplicitie
Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector
The inclusive and dijet production cross-sections have been measured for jets
containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass
energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The
measurements use data corresponding to an integrated luminosity of 34 pb^-1.
The b-jets are identified using either a lifetime-based method, where secondary
decay vertices of b-hadrons in jets are reconstructed using information from
the tracking detectors, or a muon-based method where the presence of a muon is
used to identify semileptonic decays of b-hadrons inside jets. The inclusive
b-jet cross-section is measured as a function of transverse momentum in the
range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet
cross-section is measured as a function of the dijet invariant mass in the
range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets
and the angular variable chi in two dijet mass regions. The results are
compared with next-to-leading-order QCD predictions. Good agreement is observed
between the measured cross-sections and the predictions obtained using POWHEG +
Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet
cross-section. However, it does not reproduce the measured inclusive
cross-section well, particularly for central b-jets with large transverse
momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final
version published in European Physical Journal
Universal WBC reduction
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75583/1/j.1537-2995.2000.40060751.x.pd
Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study
Raised risks of several cancers have been found in patients with type II diabetes, but there are few data on cancer risk in type I diabetes. We conducted a cohort study of 28 900 UK patients with insulin-treated diabetes followed for 520 517 person-years, and compared their cancer incidence and mortality with national expectations. To analyse by diabetes type, we examined risks separately in 23 834 patients diagnosed with diabetes under the age of 30 years, who will almost all have had type I diabetes, and 5066 patients diagnosed at ages 30–49 years, who probably mainly had type II. Relative risks of cancer overall were close to unity, but ovarian cancer risk was highly significantly raised in patients with diabetes diagnosed under age 30 years (standardised incidence ratio (SIR)=2.14; 95% confidence interval (CI) 1.22–3.48; standardised mortality ratio (SMR)=2.90; 95% CI 1.45–5.19), with greatest risks for those with diabetes diagnosed at ages 10–19 years. Risks of cancer at other major sites were not substantially raised for type I patients. The excesses of obesity- and alcohol-related cancers in type II diabetes may be due to confounding rather than diabetes per se
WASA-FRS experiments in FAIR Phase-0 at GSI
We have developed a new and unique experimental setup integrating the central part of the Wide Angle Shower Apparatus (WASA) into the Fragment Separator (FRS) at GSI. This combination opens up possibilities of new experiments with high-resolution spectroscopy at forward and measurements of light decay particles with nearly full solid-angle acceptance in coincidence. The first series of the WASA-FRS experiments have been successfully carried out in 2022. The developed experimental setup and two physics experiments performed in 2022 including the status of the preliminary data analysis are introduced
A comparative genomics multitool for scientific discovery and conservation
A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.Peer reviewe
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