451 research outputs found
Glucose lowering effect of transgenic human insulin-like growth factor-I from rice: in vitro and in vivo studies
<p>Abstract</p> <p>Background</p> <p>Human insulin-like growth factor-I (hIGF-I) is a growth factor which is highly resemble to insulin. It is essential for cell proliferation and has been proposed for treatment of various endocrine-associated diseases including growth hormone insensitivity syndrome and diabetes mellitus. In the present study, an efficient plant expression system was developed to produce biologically active recombinant hIGF-I (rhIGF-I) in transgenic rice grains.</p> <p>Results</p> <p>The plant-codon-optimized hIGF-I was introduced into rice via <it>Agrobacterium</it>-mediated transformation. To enhance the stability and yield of rhIGF-I, the endoplasmic reticulum-retention signal and glutelin signal peptide were used to deliver rhIGF-I to endoplasmic reticulum for stable accumulation. We found that only glutelin signal peptide could lead to successful expression of hIGF-I and one gram of hIGF-I rice grain possessed the maximum activity level equivalent to 3.2 micro molar of commercial rhIGF-I. <it>In vitro </it>functional analysis showed that the rice-derived rhIGF-I was effective in inducing membrane ruffling and glucose uptake on rat skeletal muscle cells. Oral meal test with rice-containing rhIGF-I acutely reduced blood glucose levels in streptozotocin-induced and Zucker diabetic rats, whereas it had no effect in normal rats.</p> <p>Conclusion</p> <p>Our findings provided an alternative expression system to produce large quantities of biologically active rhIGF-I. The provision of large quantity of recombinant proteins will promote further research on the therapeutic potential of rhIGF-I.</p
P11-04. PEGylated poly [2-(N,N-dimethylamino) ethyl methacrylate] as mucosal DNA delivery vector improves HIV-1-specific immune responses
On Robustness Computation and Optimization in BIOCHAM-4
Long version with appendicesInternational audienceBIOCHAM-4 is a tool for modeling, analyzing and synthesizing biochemical reaction networks with respect to some formal, yet possibly imprecise, specification of their behavior. We focus here on one new capability of this tool to optimize the robustness of a parametric model with respect to a specification of its dynamics in quantitative temporal logic. More precisely, we present two complementary notions of robustness: the statistical notion of model robustness to parameter perturbations, defined as its mean functionality, and a metric notion of formula satisfaction robustness, defined as the penetration depth in the validity domain of the temporal logic constraints. We show how the formula robustness can be used in BIOCHAM-4 with no extra cost as an objective function in the parameter optimization procedure, to actually improve the model robustness. We illustrate these unique features with a classical example of the hybrid systems community and provide some performance figures on a model of MAPK signalling with 37 parameters
Comparison of DNA testing strategies in monitoring human papillomavirus infection prevalence through simulation
Observation of a ppb mass threshoud enhancement in \psi^\prime\to\pi^+\pi^-J/\psi(J/\psi\to\gamma p\bar{p}) decay
The decay channel
is studied using a sample of events collected
by the BESIII experiment at BEPCII. A strong enhancement at threshold is
observed in the invariant mass spectrum. The enhancement can be fit
with an -wave Breit-Wigner resonance function with a resulting peak mass of
and a
narrow width that is at the 90% confidence level.
These results are consistent with published BESII results. These mass and width
values do not match with those of any known meson resonance.Comment: 5 pages, 3 figures, submitted to Chinese Physics
Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules
Celiac disease is caused by an abnormal intestinal T-cell response to gluten proteins of wheat, barley and rye. Over the last few years, a number of gluten T-cell epitopes restricted by celiac disease associated HLA-DQ molecules have been characterized. In this work, we give an overview of these epitopes and suggest a comprehensive, new nomenclature
Transepithelial Transport and Enzymatic Detoxification of Gluten in Gluten-Sensitive Rhesus Macaques
In a previous report, we characterized a condition of gluten sensitivity in juvenile rhesus macaques that is similar in many respects to the human condition of gluten sensitivity, celiac disease. This animal model of gluten sensitivity may therefore be useful toward studying both the pathogenesis and the treatment of celiac disease. Here, we perform two pilot experiments to demonstrate the potential utility of this model for studying intestinal permeability toward an immunotoxic gluten peptide and pharmacological detoxification of gluten in vivo by an oral enzyme drug candidate.Intestinal permeability was investigated in age-matched gluten-sensitive and control macaques by using mass spectrometry to detect and quantify an orally dosed, isotope labeled 33-mer gluten peptide delivered across the intestinal epithelium to the plasma. The protective effect of a therapeutically promising oral protease, EP-B2, was evaluated in a gluten-sensitive macaque by administering a daily gluten challenge with or without EP-B2 supplementation. ELISA-based antibody assays and blinded clinical evaluations of this macaque and of an age-matched control were conducted to assess responses to gluten.Labeled 33-mer peptide was detected in the plasma of a gluten-sensitive macaque, both in remission and during active disease, but not in the plasma of healthy controls. Administration of EP-B2, but not vehicle, prevented clinical relapse in response to a dietary gluten challenge. Unexpectedly, a marked increase in anti-gliadin (IgG and IgA) and anti-transglutaminase (IgG) antibodies was observed during the EP-B2 treatment phase.Gluten-sensitive rhesus macaques may be an attractive resource for investigating important aspects of celiac disease, including enhanced intestinal permeability and pharmacology of oral enzyme drug candidates. Orally dosed EP-B2 exerts a protective effect against ingested gluten. Limited data suggest that enhanced permeability of short gluten peptides generated by gastrically active glutenases may trigger an elevated antibody response, but that these antibodies are not necessarily causative of clinical illness
A Hidden Feedback in Signaling Cascades Is Revealed
Cycles involving covalent modification of proteins are key components of the intracellular signaling machinery. Each cycle is comprised of two interconvertable forms of a particular protein. A classic signaling pathway is structured by a chain or cascade of basic cycle units in such a way that the activated protein in one cycle promotes the activation of the next protein in the chain, and so on. Starting from a mechanistic kinetic description and using a careful perturbation analysis, we have derived, to our knowledge for the first time, a consistent approximation of the chain with one variable per cycle. The model we derive is distinct from the one that has been in use in the literature for several years, which is a phenomenological extension of the Goldbeter-Koshland biochemical switch. Even though much has been done regarding the mathematical modeling of these systems, our contribution fills a gap between existing models and, in doing so, we have unveiled critical new properties of this type of signaling cascades. A key feature of our new model is that a negative feedback emerges naturally, exerted between each cycle and its predecessor. Due to this negative feedback, the system displays damped temporal oscillations under constant stimulation and, most important, propagates perturbations both forwards and backwards. This last attribute challenges the widespread notion of unidirectionality in signaling cascades. Concrete examples of applications to MAPK cascades are discussed. All these properties are shared by the complete mechanistic description and our simplified model, but not by previously derived phenomenological models of signaling cascades
Effect of Polymorphisms in XPD on Clinical Outcomes of Platinum-Based Chemotherapy for Chinese Non-Small Cell Lung Cancer Patients
PURPOSE: Xeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. EXPERIMENTAL DESIGN: 353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg(156)Arg, Asp(312)Asn, Asp(711)Asp and Lys(751)Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing. RESULTS: Variant genotypes of XPD Asp(312)Asn, Asp(711)Asp and Lys(751)Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp(312)Asn, Asp(711)Asp and Lys(751)Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10(-4), log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0-1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS. CONCLUSIONS: Our study provides evidence for the predictive role of XPD Asp(312)Asn, Asp(711)Asp and Lys(751)Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy
Acute Respiratory Distress Syndrome Induced by a Swine 2009 H1N1 Variant in Mice
Background: Acute respiratory distress syndrome (ARDS) induced by pandemic 2009 H1N1 influenza virus has been widely reported and was considered the main cause of death in critically ill patients with 2009 H1N1 infection. However, no animal model has been developed for ARDS caused by infection with 2009 H1N1 virus. Here, we present a mouse model of ARDS induced by 2009 H1N1 virus. Methodology Principal Findings: Mice were inoculated with A/swine/Shandong/731/2009 (SD/09), which was a 2009 H1N1 influenza variant with a G222D mutation in the hemagglutinin. Clinical symptoms were recorded every day. Lung injury was assessed by lung water content and histopathological observation. Arterial blood gas, leukocyte count in the bronchial alveolar lavage fluid and blood, virus titers, and cytokine levels in the lung were measured at various times post-inoculation. Mice infected with SD/09 virus showed typical ARDS symptoms characterized by 60 % lethality on days 8–10 postinoculation, highly edematous lungs, inflammatory cellular infiltration, alveolar and interstitial edema, lung hemorrhage, progressive and severe hypoxemia, and elevated levels of proinflammatory cytokines and chemokines. Conclusions/Significance: These results suggested that we successfully established an ARDS mouse model induced by a virulent 2009 H1N1 variant without previous adaptation, which may be of benefit for evaluating the pathogenesis or therapy of human ARDS caused by 2009 H1N1 virus
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