Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse

Recent clinical evidence suggests important role of lipid and amino acid metabolism in early pre-autoimmune stages of type 1 diabetes pathogenesis. We study the molecular paths associated with the incidence of insulitis and type 1 diabetes in the Non-Obese Diabetic (NOD) mouse model using available gene expression data from the pancreatic tissue from young pre-diabetic mice. We apply a graph-theoretic approach by using a modified color coding algorithm to detect optimal molecular paths associated with specific phenotypes in an integrated biological network encompassing heterogeneous interaction data types. In agreement with our recent clinical findings, we identified a path downregulated in early insulitis involving dihydroxyacetone phosphate acyltransferase (DHAPAT), a key regulator of ether phospholipid synthesis. The pathway involving serine/threonine-protein phosphatase (PP2A), an upstream regulator of lipid metabolism and insulin secretion, was found upregulated in early insulitis. Our findings provide further evidence for an important role of lipid metabolism in early stages of type 1 diabetes pathogenesis, as well as suggest that such dysregulation of lipids and related increased oxidative stress can be tracked to beta cells.     

It's all in your head: the role of quantity estimation in sperm competition

The study of animal cognition has provided valuable data throughout the years, yet its reliance on laboratory work leaves some open questions. The main question is whether animals employ cognition in daily decision-making. The following discussion uses sperm competition (SC) as a test case for demonstrating the effect of cognition on routine choices, in this case, sexual selection. Cognition is manifested here by males' ability to represent the number of rivals competing with them. I claim that response to SC is driven by quantity estimation and the ability to assess competition magnitude cognitively. Hence, cognition can determine males' response to SC, and consequentially it can be selected within this context. This supports the argument that cognition constitutes an integral part of an individual's toolbox in solving real-life problems, and shows that physical and behavioural phenomena can expose cognition to selection and facilitate its evolution.     

Chitosan-pentaglycine-phenylboronic acid conjugate: a potential colon-specific platform for calcitonin

Novel drug delivery vehicles based on the biodegradable, mucoadhesive polysaccharide chitosan covalently linked to a boronic acid protease inhibitor have been prepared and characterized. It was anticipated that these conjugates could protect a proteinaceous drug, such as salmon calcitonin, against proteolysis by serine proteases, an obstacle that prevents its oral administration. Specifically, 4-formylphenylboronic acid was linked to chitosan. Three types of conjugates were prepared. In the first, 4-formylphenylboronic acid was directly linked to chitosan. The other two conjugates employed glycylglycine and pentaglycine spacers. Enzyme-inhibition assays toward trypsin and elastase, in the presence of the enzyme chitosanase, demonstrated a strong inhibitory effect for the chitosan-pentaglycine-phenylboronic acid conjugates, while no inhibitory effect could be detected without chitosanase. The chitosan-pentaglycine-phenylboronic acid conjugate with the highest degree of substitution of 4-formylphenylboronic acid was able to decrease the salmon calcitonin degradation rate by trypsin. It is concluded that chitosan-pentaglycine-phenylboronic acid conjugates are a potential multifunctional, colon-specific vehicle for orally administered salmon calcitonin.     

'Genome order index' should not be used for defining compositional constraints in nucleotide sequences - a case study of the Z-curve

Background  

The Z-curve is a three dimensional representation of DNA sequences proposed over a decade ago and has been extensively applied to sequence segmentation, horizontal gene transfer detection, and sequence analysis. Based on the Z-curve, a "genome order index," was proposed, which is defined as S = a ²+ c ²+t ²+g ², where a, c, t, and g are the nucleotide frequencies of A, C, T, and G, respectively. This index was found to be smaller than 1/3 for almost all tested genomes, which was taken as support for the existence of a constraint on genome composition. A geometric explanation for this constraint has been suggested. Each genome was represented by a point P whose distance from the four faces of a regular tetrahedron was given by the frequencies a, c, t, and g. They claimed that an inscribed sphere of radius r = 1/ contains almost all points corresponding to various genomes, implying that S <r ². The distribution of the points P obtained by S was studied using the Z-curve.     

Multifaceted plant responses to circumvent Phe hyperaccumulation by downregulation of flux through the shikimate pathway and by vacuolar Phe sequestration

Detrimental effects of hyperaccumulation of the aromatic amino acid phenylalanine (Phe) in animals, known as phenylketonuria, are mitigated by excretion of Phe derivatives; however, how plants endure Phe accumulating conditions in the absence of an excretion system is currently unknown. To achieve Phe hyperaccumulation in a plant system, we simultaneously decreased in petunia flowers expression of all three Phe ammonia lyase (PAL) isoforms that catalyze the non‐oxidative deamination of Phe to trans‐cinnamic acid, the committed step for the major pathway of Phe metabolism. A total decrease in PAL activity by 81–94% led to an 18‐fold expansion of the internal Phe pool. Phe accumulation had multifaceted intercompartmental effects on aromatic amino acid metabolism. It resulted in a decrease in the overall flux through the shikimate pathway, and a redirection of carbon flux toward the shikimate‐derived aromatic amino acids tyrosine and tryptophan. Accumulation of Phe did not lead to an increase in flux toward phenylacetaldehyde, for which Phe is a direct precursor. Metabolic flux analysis revealed this to be due to the presence of a distinct metabolically inactive pool of Phe, likely localized in the vacuole. We have identified a vacuolar cationic amino acid transporter (PhCAT2) that contributes to sequestering excess of Phe in the vacuole. In vitro assays confirmed PhCAT2 can transport Phe, and decreased PhCAT2 expression in PAL‐RNAi transgenic plants resulted in 1.6‐fold increase in phenylacetaldehyde emission. These results demonstrate mechanisms by which plants maintain intercompartmental aromatic amino acid homeostasis, and provide critical insight for future phenylpropanoid metabolic engineering strategies.     

Vimentin binding to phosphorylated Erk sterically hinders enzymatic dephosphorylation of the kinase

Cleavage fragments of de novo synthesized vimentin were recently reported to interact with phosphorylated Erk1 and Erk2 MAP kinases (pErk) in injured sciatic nerve, thus linking pErk to a signaling complex retrogradely transported on importins and dynein. Here we clarify the structural basis for this interaction, which explains how pErk is protected from dephosphorylation while bound to vimentin. Pull-down and ELISA experiments revealed robust calcium-dependent binding of pErk to the second coiled-coil domain of vimentin, with observed affinities of binding increasing from 180 nM at 0.1 microM calcium to 15 nM at 10 microM calcium. In contrast there was little or no binding of non-phosphorylated Erk to vimentin under these conditions. Geometric and electrostatic complementarity docking generated a number of solutions wherein vimentin binding to pErk occludes the lip containing the phosphorylated residues in the kinase. Binding competition experiments with Erk peptides confirmed a solution in which vimentin covers the phosphorylation lip in pErk, interacting with residues above and below the lip. The same peptides inhibited pErk binding to the dynein complex in sciatic nerve axoplasm, and interfered with protection from phosphatases by vimentin. Thus, a soluble intermediate filament fragment interacts with a signaling kinase and protects it from dephosphorylation by calcium-dependent steric hindrance.     

Arthritis patterns in familial Mediterranean fever patients and association with M694V mutation

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of febrile peritonitis, pleuritis and synovitis. Arthritis is a common and important feature of FMF. The clinical spectrum of arthritis in 71 FMF patients was retrospectively investigated. Mutations in the familial Mediterranean (MEFV) gene were screened. Unlike the previous reports on arthritis of FMF, most of the FMF patients (59%) in this study had symmetric two-joint arthritis whereas monoarticular, oligoarticular and polyarticular arthritis was presented in 20, 8 and 10% of the patients, respectively. Knees were affected in 45 (63%) patients, ankles in 30 (42%), elbows in 11 (15%), wrists in 12 (17%), hips in 12 (17%), small joints of the hands 7 (10%), small joints of the feet 2 (3%) and sacroiliac in 1 (1%). Destruction of the hip was observed in 2 (3%) patients and required hip replacement. Amyloidosis developed in 2 (3%) of our patients. Mutations in the MEFV gene were identified in 50 (71%) patients and the most dominant mutation detected was M694V (64%). Since FMF can be diagnosed by a simple DNA mutation analysis, all arthritis patients of certain origins (Arabs, Turks, Armenians and Jews) should be tested for FMF in order to prevent the complications (amyloidosis and protracted arthritis) by introducing colchicine which is the treatment of choice for FMF.