Pulse Width Evolution of Late Time X-rays Flares in GRBs: Evidence For Internal Shocks

We study the duration and variability of late time X-ray flares following gamma-ray bursts (GRBs) observed by the narrow field X-ray telescope (XRT) aboard the {\it Swift} spacecraft. These flares are thought to be indicative of late time activity by the central engine that powers the GRB and produced by means similar to those which produce the prompt emission. We use a non-parametric procedure to study the overall temporal properties of the flares and a structure function analysis to look for an evolution of the fundamental variability time-scale between the prompt and late time emission. We find a strong correlation in 28 individual x-ray flares in 18 separate GRBs between the flare duration and their time of peak flux since the GRB trigger. We also find a qualitative trend of decreasing variability as a function of time since trigger, with a characteristic minimum variability timescale $\Delta t/t=0.1$ for most flares. We interpret these results as evidence of internal shocks at collision radii that are larger than those that produced the prompt emission. Contemporaneous detections of high energy emission by GLAST could be a crucial test in determining if indeed these X-ray flares originate as internal shocks behind the afterglow, as any X-ray emission originating from behind the afterglow is expected to undergo inverse Compton scattering as it passes through the external shock.Comment: 26 pages, 5 figures, 1 table. Submitted to ApJ. This work expands upon and formalizes our previous report at the October 2006 AAS HEAD Meeting of the discovery of pulse width evolutio

Why high-error-rate random mutagenesis libraries are enriched in functional and improved proteins

Recently, several groups have used error-prone polymerase chain reactions to construct mutant libraries containing up to 27 nucleotide mutations per gene on average, and reported a striking observation: although retention of protein function initially declines exponentially with mutations as has previously been observed, orders of magnitude more proteins remain viable at the highest mutation rates than this trend would predict. Mutant proteins having improved or novel activity were isolated disproportionately from these heavily mutated libraries, leading to the suggestion that distant regions of sequence space are enriched in useful cooperative mutations and that optimal mutagenesis should target these regions. If true, these claims have profound implications for laboratory evolution and for evolutionary theory. Here, we demonstrate that properties of the polymerase chain reaction can explain these results and, consequently, that average protein viability indeed decreases exponentially with mutational distance at all error rates. We show that high-error-rate mutagenesis may be useful in certain cases, though for very different reasons than originally proposed, and that optimal mutation rates are inherently protocol-dependent. Our results allow optimal mutation rates to be found given mutagenesis conditions and a protein of known mutational robustness.Comment: Optimality results improved. 26 pages, 4 figures, 3 table

Modulation of T Cell Function by Combination of Epitope Specific and Low Dose Anticytokine Therapy Controls Autoimmune Arthritis

Innate and adaptive immunity contribute to the pathogenesis of autoimmune arthritis by generating and maintaining inflammation, which leads to tissue damage. Current biological therapies target innate immunity, eminently by interfering with single pro-inflammatory cytokine pathways. This approach has shown excellent efficacy in a good proportion of patients with Rheumatoid Arthritis (RA), but is limited by cost and side effects. Adaptive immunity, particularly T cells with a regulatory function, plays a fundamental role in controlling inflammation in physiologic conditions. A growing body of evidence suggests that modulation of T cell function is impaired in autoimmunity. Restoration of such function could be of significant therapeutic value. We have recently demonstrated that epitope-specific therapy can restore modulation of T cell function in RA patients. Here, we tested the hypothesis that a combination of anti-cytokine and epitope-specific immunotherapy may facilitate the control of autoimmune inflammation by generating active T cell regulation. This novel combination of mucosal tolerization to a pathogenic T cell epitope and single low dose anti-TNFα was as therapeutically effective as full dose anti-TNFα treatment. Analysis of the underlying immunological mechanisms showed induction of T cell immune deviation

Axonal Regeneration and Neuronal Function Are Preserved in Motor Neurons Lacking ß-Actin In Vivo

The proper localization of ß-actin mRNA and protein is essential for growth cone guidance and axon elongation in cultured neurons. In addition, decreased levels of ß-actin mRNA and protein have been identified in the growth cones of motor neurons cultured from a mouse model of Spinal Muscular Atrophy (SMA), suggesting that ß-actin loss-of-function at growth cones or pre-synaptic nerve terminals could contribute to the pathogenesis of this disease. However, the role of ß-actin in motor neurons in vivo and its potential relevance to disease has yet to be examined. We therefore generated motor neuron specific ß-actin knock-out mice (Actb-MNsKO) to investigate the function of ß-actin in motor neurons in vivo. Surprisingly, ß-actin was not required for motor neuron viability or neuromuscular junction maintenance. Skeletal muscle from Actb-MNsKO mice showed no histological indication of denervation and did not significantly differ from controls in several measurements of physiologic function. Finally, motor axon regeneration was unimpaired in Actb-MNsKO mice, suggesting that ß-actin is not required for motor neuron function or regeneration in vivo

Spatial Modeling of Vesicle Transport and the Cytoskeleton: The Challenge of Hitting the Right Road

The membrane trafficking machinery provides a transport and sorting system for many cellular proteins. We propose a mechanistic agent-based computer simulation to integrate and test the hypothesis of vesicle transport embedded into a detailed model cell. The method tracks both the number and location of the vesicles. Thus both the stochastic properties due to the low numbers and the spatial aspects are preserved. The underlying molecular interactions that control the vesicle actions are included in a multi-scale manner based on the model of Heinrich and Rapoport (2005). By adding motor proteins we can improve the recycling process of SNAREs and model cell polarization. Our model also predicts that coat molecules should have a high turnover at the compartment membranes, while the turnover of motor proteins has to be slow. The modular structure of the underlying model keeps it tractable despite the overall complexity of the vesicle system. We apply our model to receptor-mediated endocytosis and show how a polarized cytoskeleton structure leads to polarized distributions in the plasma membrane both of SNAREs and the Ste2p receptor in yeast. In addition, we can couple signal transduction and membrane trafficking steps in one simulation, which enables analyzing the effect of receptor-mediated endocytosis on signaling

Ustekinumab as Induction and Maintenance Therapy for Crohn’s 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 Crohn’s 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 Crohn’s Disease Activity Index [CDAI] score of ≥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 P≤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 Crohn’s 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.

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201

Search for exotic resonances decaying into WZ/ZZ in pp collisions at √s=7 TeV

Journal of High Energy Physics 2013.2 (2013): 036 reproduced by permission of Scuola Internazionale Superiore di Studi Avanzati (SISSA)Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAMA search for new exotic particles decaying to the VZ final state is performed, where V is either a W or a Z boson decaying into two overlapping jets and the Z decays into a pair of electrons, muons or neutrinos. The analysis uses a data sample of pp collisions corresponding to an integrated luminosity of 5 fb-1 collected by the CMS experiment at the LHC at √s=7 TeV in 2011. No significant excess is observed in the mass distribution of the VZ candidates compared with the background expectation from standard model processes. Model-dependent upper limits at the 95% confidence level are set on the product of the cross section times the branching fraction of hypothetical particles decaying to the VZ final state as a function of mass. Sequential standard model W′ bosons with masses between 700 and 940 GeV are excluded. In the Randall-Sundrum model for graviton resonances with a coupling parameter of 0.05, masses between 750 and 880 GeV are also exclude