195 research outputs found
Boundedness properties of fermionic operators
The fermionic second quantization operator is shown to be
bounded by a power of the number operator given that the operator
belongs to the -th von Neumann-Schatten class, . Conversely,
number operator estimates for imply von Neumann-Schatten
conditions on . Quadratic creation and annihilation operators are treated as
well.Comment: 15 page
Transient deSUMOylation of IRF2BP proteins controls early transcription in EGFR signaling
Molecular switches are essential modules in signaling networksand transcriptional reprogramming. Here, we describe a role forsmall ubiquitin-related modifier SUMO as a molecular switch inepidermal growth factor receptor (EGFR) signaling. Using quantita-tive mass spectrometry, we compare the endogenous SUMOproteomes of HeLa cells before and after EGF stimulation. Thereby,we identify a small group of transcriptional coregulators includingIRF2BP1, IRF2BP2, and IRF2BPL as novel players in EGFR signaling.Comparison of cells expressing wild type or SUMOylation-deficientIRF2BP1indicates that transient deSUMOylation of IRF2BP proteinsis important for appropriate expression of immediate early genesincludingdual specificity phosphatase1(DUSP1, MKP-1) and thetranscription factor ATF3. We find that IRF2BP1is a repressor,whose transient deSUMOylation on the DUSP1promoter allowsâand whose timely reSUMOylation restrictsâDUSP1transcription.Our work thus provides a paradigm how comparative SUMOproteome analyses serve to reveal novel regulators in signal trans-duction and transcription
Explicit Stabilised Gradient Descent for Faster Strongly Convex Optimisation
This paper introduces the Runge-Kutta Chebyshev descent method (RKCD) for
strongly convex optimisation problems. This new algorithm is based on explicit
stabilised integrators for stiff differential equations, a powerful class of
numerical schemes that avoid the severe step size restriction faced by standard
explicit integrators. For optimising quadratic and strongly convex functions,
this paper proves that RKCD nearly achieves the optimal convergence rate of the
conjugate gradient algorithm, and the suboptimality of RKCD diminishes as the
condition number of the quadratic function worsens. It is established that this
optimal rate is obtained also for a partitioned variant of RKCD applied to
perturbations of quadratic functions. In addition, numerical experiments on
general strongly convex problems show that RKCD outperforms Nesterov's
accelerated gradient descent
Exact Hybrid Particle/Population Simulation of Rule-Based Models of Biochemical Systems
Detailed modeling and simulation of biochemical systems is complicated by the problem of combinatorial complexity, an explosion in the number of species and reactions due to myriad protein-protein interactions and post-translational modifications. Rule-based modeling overcomes this problem by representing molecules as structured objects and encoding their interactions as pattern-based rules. This greatly simplifies the process of model specification, avoiding the tedious and error prone task of manually enumerating all species and reactions that can potentially exist in a system. From a simulation perspective, rule-based models can be expanded algorithmically into fully-enumerated reaction networks and simulated using a variety of network-based simulation methods, such as ordinary differential equations or Gillespie's algorithm, provided that the network is not exceedingly large. Alternatively, rule-based models can be simulated directly using particle-based kinetic Monte Carlo methods. This "network-free" approach produces exact stochastic trajectories with a computational cost that is independent of network size. However, memory and run time costs increase with the number of particles, limiting the size of system that can be feasibly simulated. Here, we present a hybrid particle/population simulation method that combines the best attributes of both the network-based and network-free approaches. The method takes as input a rule-based model and a user-specified subset of species to treat as population variables rather than as particles. The model is then transformed by a process of "partial network expansion" into a dynamically equivalent form that can be simulated using a population-adapted network-free simulator. The transformation method has been implemented within the open-source rule-based modeling platform BioNetGen, and resulting hybrid models can be simulated using the particle-based simulator NFsim. Performance tests show that significant memory savings can be achieved using the new approach and a monetary cost analysis provides a practical measure of its utility. © 2014 Hogg et al
Network centrality and organizational aspirations: A behavioral interaction in the context of international strategic alliances
Whereas social network analysis has been associated with organizational aspirations, little is known on how firm's structural positioning, and particularly network centrality, affects organizational aspirations to engage in international strategic alliances (ISA). This study examines the impact of network centrality on firm's internationalization behavior within the ISA domain in response to the performance-aspiration gap. We build on social and behavioral perspectives to predict that network centrality and performance-based aspirations will be associated with the number of ISA the firm engages in. Using a sample of 7760 alliance collaborations from the top 81 global pharmaceutical firms for the period of 1991-2012, we find supporting evidence for most of our arguments
Ustekinumab as Induction and Maintenance Therapy for Crohnâs Disease
BACKGROUND
Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohnâs disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.
METHODS
We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed
these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohnâs Disease Activity Index [CDAI] score of â„100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150).
RESULTS
The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher
than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with Pâ€0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.
CONCLUSIONS
Among patients with moderately to severely active Crohnâs disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.
Cancer effects of formaldehyde: a proposal for an indoor air guideline value
Formaldehyde is a ubiquitous indoor air pollutant that is classified as âCarcinogenic to humans (Group 1)â (IARC, Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropanol-2-ol. IARC monographs on the evaluation of carcinogenic risks to humans, vol 88. World Health Organization, Lyon, pp 39â325, 2006). For nasal cancer in rats, the exposureâresponse relationship is highly non-linear, supporting a no-observed-adverse-effect level (NOAEL) that allows setting a guideline value. Epidemiological studies reported no increased incidence of nasopharyngeal cancer in humans below a mean level of 1 ppm and peak levels below 4 ppm, consistent with results from rat studies. Rat studies indicate that cytotoxicity-induced cell proliferation (NOAEL at 1 ppm) is a key mechanism in development of nasal cancer. However, the linear unit risk approach that is based on conservative (âworst-caseâ) considerations is also used for risk characterization of formaldehyde exposures. Lymphohematopoietic malignancies are not observed consistently in animal studies and if caused by formaldehyde in humans, they are high-dose phenomenons with non-linear exposureâresponse relationships. Apparently, these diseases are not reported in epidemiological studies at peak exposures below 2 ppm and average exposures below 0.5 ppm. At the similar airborne exposure levels in rodents, the nasal cancer effect is much more prominent than lymphohematopoietic malignancies. Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies. Departing from the rat studies, the guideline value of the WHO (Air quality guidelines for Europe, 2nd edn. World Health Organization, Regional Office for Europe, Copenhagen, pp 87â91, 2000), 0.08 ppm (0.1 mg mâ3) formaldehyde, is considered preventive of carcinogenic effects in compliance with epidemiological findings
The dynamic geophysical environment of (101955) Bennu based on OSIRIS-REx measurements
The top-shaped morphology characteristic of asteroid (101955) Bennu, often found among fast-spinning asteroids and binary asteroid primaries, may have contributed substantially to binary asteroid formation. Yet a detailed geophysical analysis of this morphology for a fast-spinning asteroid has not been possible prior to the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission. Combining the measured Bennu mass and shape obtained during the Preliminary Survey phase of the OSIRIS-REx mission, we find a notable transition in Bennuâs surface slopes within its rotational Roche lobe, defined as the region where material is energetically trapped to the surface. As the intersection of the rotational Roche lobe with Bennuâs surface has been most recently migrating towards its equator (given Bennuâs increasing spin rate), we infer that Bennuâs surface slopes have been changing across its surface within the last million years. We also find evidence for substantial density heterogeneity within this body, suggesting that its interior is a mixture of voids and boulders. The presence of such heterogeneity and Bennuâs top shape are consistent with spin-induced failure at some point in its past, although the manner of its failure cannot yet be determined. Future measurements by the OSIRIS-REx spacecraft will provide insight into and may resolve questions regarding the formation and evolution of Bennuâs top-shape morphology and its link to the formation of binary asteroids
Evidence for widespread hydrated minerals on asteroid (101955) Bennu
Early spectral data from the Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer (OSIRIS-REx) mission reveal evidence for abundant hydrated minerals on the surface of near-Earth asteroid (101955) Bennu in the form of a near-infrared absorption near 2.7â”m and thermal infrared spectral features that are most similar to those of aqueously altered CM-type carbonaceous chondrites. We observe these spectral features across the surface of Bennu, and there is no evidence of substantial rotational variability at the spatial scales of tens to hundreds of metres observed to date. In the visible and near-infrared (0.4 to 2.4â”m) Bennuâs spectrum appears featureless and with a blue (negative) slope, confirming previous ground-based observations. Bennu may represent a class of objects that could have brought volatiles and organic chemistry to Earth
Microglia in the dorsal raphe nucleus plays a potential role in both suicide facilitation and prevention in affective disorders
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