A mathematical model for the adenylosuccinate synthetase reaction involved in purine biosynthesis

BACKGROUND: Development of the mathematical models that adequately describe biochemical reactions and molecular-genetic mechanisms is one of the most important tasks in modern bioinformatics. Because the enzyme adenylosuccinate synthetase (AdSS) has long been extensively studied, a wealth of kinetic data has been accumulated. RESULTS: We describe a mathematical model for the reaction catalyzed by AdSS. The model's parameters were fitted to experimental data obtained from published literature. The advantage of our model is that it includes relationships between the reaction rate, the concentrations of three substrates (GTP, IMP and ASP), the effects of five inhibitors (GMP, GDP, AMP, ASUC and SUCC), and the influence of Mg(2+ )ions. CONCLUSION: Our model describes the reaction catalyzed by AdSS as a fully random process. The model structure implies that each of the inhibitors included in it is only competitive to one of the substrates. The model was tested for adequacy using experimental data published elsewhere. The values obtained for the parameters are as follows: V(max )= 1.35·10(-3 )mM/min, Km(GTP )= 0.023 mM, Km(IMP )= 0.02 mM, Km(ASP )= 0.3 mM, Ki(GMP )= 0.024 mM, Ki(GDP )= 8·10(-3 )mM, Ki(AMP )= 0.01 mM, Ki(ASUC )= 7.5·10(-3 )mM, Ki(SUCC )= 8 mM, Km(Mg )= 0.08 mM

Interactions among mitochondrial proteins altered in glioblastoma

Mitochondrial dysfunction is putatively central to glioblastoma (GBM) pathophysiology but there has been no systematic analysis in GBM of the proteins which are integral to mitochondrial function. Alterations in proteins in mitochondrial enriched fractions from patients with GBM were defined with label-free liquid chromatography mass spectrometry. 256 mitochondrially-associated proteins were identified in mitochondrial enriched fractions and 117 of these mitochondrial proteins were markedly (fold-change ≥2) and significantly altered in GBM (p ≤ 0.05). Proteins associated with oxidative damage (including catalase, superoxide dismutase 2, peroxiredoxin 1 and peroxiredoxin 4) were increased in GBM. Protein–protein interaction analysis highlighted a reduction in multiple proteins coupled to energy metabolism (in particular respiratory chain proteins, including 23 complex-I proteins). Qualitative ultrastructural analysis in GBM with electron microscopy showed a notably higher prevalence of mitochondria with cristolysis in GBM. This study highlights the complex mitochondrial proteomic adjustments which occur in GBM pathophysiology

An evaluation of the hypolipidemic effect of an extract of Hibiscus Sabdariffa leaves in hyperlipidemic Indians: a double blind, placebo controlled trial

<p>Abstract</p> <p>Background</p> <p>Hibiscus sabdariffa is used regularly in folk medicine to treat various conditions.</p> <p>Methods</p> <p>The study was a double blind, placebo controlled, randomized trial. Sixty subjects with serum LDL values in the range of 130-190 mg/dl and with no history of coronary heart disease were randomized into experimental and placebo groups. The experimental group received 1 gm of the extract for 90 days while the placebo received a similar amount of maltodextrin in addition to dietary and physical activity advice for the control of their blood lipids. Anthropometry, blood biochemistry, dietary and physical activity were assessed at baseline, day 45 and day 90.</p> <p>Results</p> <p>While body weight, serum LDL cholesterol and triglyceride levels decreased in both groups, there were no significant differences between the experimental and placebo group.</p> <p>Conclusions</p> <p>It is likely that the observed effects were as a result of the patients following the standard dietary and physical activity advice. At a dose of 1 gm/day, hibiscus sabdariffa leaf extract did not appear to have a blood lipid lowering effect.</p> <p>Trial Registration</p> <p>REFCTRI2009000472</p

CNx-modified Fe3O4 as Pt nanoparticle support for the oxygen reduction reaction

A novel electrocatalyst support material, nitrogendoped carbon (CNx)-modified Fe3O4 (Fe3O4-CNx), was synthesized through carbonizing a polypyrrole-Fe3O4 hybridized precursor. Subsequently, Fe3O4-CNx-supported Pt (Pt/Fe3O4-CNx) nanocomposites were prepared by reducing Pt precursor in ethylene glycol solution and evaluated for the oxygen reduction reaction (ORR). The Pt/Fe3O4-CNx catalysts were characterized by X-ray diffraction, Raman spectra, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The electrocatalytic activity and stability of the as-prepared electrocatalysts toward ORR were studied by cyclic voltammetry and steady-state polarization measurements. The results showed that Pt/ Fe3O4-CNx catalysts exhibited superior catalytic performance for ORR to the conventional Pt/C and Pt/C-CNx catalysts.Web of Scienc

Delta neutrophil index as an early marker of disease severity in critically ill patients with sepsis

BACKGROUND: The immature granulocyte count has been reported to be a marker of infection and sepsis. The difference in leukocyte subfractions (delta neutrophil index, DNI) in ADVIA 2120 reflects the fraction of circulating immature granulocytes in the blood. This study evaluated the clinical utility of DNI as a severity and prediction marker in critically ill patients with sepsis. METHODS: One hundred and three patients admitted to the medical intensive care unit with sepsis were studied. DNI (the difference in leukocyte subfractions identified by myeloperoxidase and nuclear lobularity channels) was determined using a specific blood cell analyzer. RESULTS: Forty four patients (42.7%) were diagnosed with severe sepsis/septic shock. Overt disseminated intravascular coagulation (DIC) occurred in 40 (38.8%). DNI was significantly higher in patients with severe sepsis/septic shock and overt DIC than in patients without (p 6.5% was a better indicator of severe sepsis/septic shock than C-reactive protein, lactate, white blood cell count, and absolute neutrophil count (sensitivity, 81.3%; specificity, 91.0%; positive predictive value, 88.6%; and negative predictive value, 84.7%). In 36 (82%) of the 44 patients with severe sepsis/septic shock, DNI values were already elevated up to 12 hours before the onset of organ/circulatory failure. CONCLUSIONS: DNI may be used as a marker of disease severity in critically ill patients with sepsis. High levels of DNI may help to identify patients with an impending risk of developing severe sepsis/septic shock.ope

The Aspartate-Semialdehyde Dehydrogenase of Edwardsiella ictaluri and Its Use as Balanced-Lethal System in Fish Vaccinology

asdA mutants of Gram-negative bacteria have an obligate requirement for diaminopimelic acid (DAP), which is an essential constituent of the peptidoglycan layer of the cell wall of these organisms. In environments deprived of DAP, i.e., animal tissues, they will undergo lysis. Deletion of the asdA gene has previously been exploited to develop antibiotic-sensitive strains of live attenuated recombinant bacterial vaccines. Introduction of an Asd+ plasmid into a ΔasdA mutant makes the bacterial strain plasmid-dependent. This dependence on the Asd+ plasmid vector creates a balanced-lethal complementation between the bacterial strain and the recombinant plasmid. E. ictaluri is an enteric Gram-negative fish pathogen that causes enteric septicemia in catfish. Because E. ictaluri is a nasal/oral invasive intracellular pathogen, this bacterium is a candidate to develop a bath/oral live recombinant attenuated Edwardsiella vaccine (RAEV) for the catfish aquaculture industry. As a first step to develop an antibiotic-sensitive RAEV strain, we characterized and deleted the E. ictaluri asdA gene. E. ictaluri ΔasdA01 mutants exhibit an absolute requirement for DAP to grow. The asdA gene of E. ictaluri was complemented by the asdA gene from Salmonella. Several Asd+ expression vectors with different origins of replication were transformed into E. ictaluri ΔasdA01. Asd+ vectors were compatible with the pEI1 and pEI2 E. ictaluri native plasmids. The balanced-lethal system was satisfactorily evaluated in vivo. Recombinant GFP, PspA, and LcrV proteins were synthesized by E. ictaluri ΔasdA01 harboring Asd+ plasmids. Here we constructed a balanced-lethal system, which is the first step to develop an antibiotic-sensitive RAEV for the aquaculture industry

Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target