Glucagon-like peptide-1, glucose homeostasis and diabetes

Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor beta-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying and food intake, leading to weight loss. GLP-1 mimetics, which are stable-peptide-based activators of the GLP-1 receptor, and incretin enhancers, which inhibit the incretin-degrading enzyme dipeptidyl peptidase-4, have emerged as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here.     

Comparison of rates of natural senescence of the root cortex of wheat (with and without mildew infection), barley,oats and rye

Summary In comparative tests in a glasshouse, the cortex of oat and rye roots senesced more slowly than the cortex of wheat and barley roots. Of the cereals tested, wheat showed the most rapid rate of root cortical senescence, and the rate was unaffected by inoculation of leaves withErysiphe graminis. The results are discussed in relation to infection by root pathogens.     

Chronic renal failure alters endothelial function in cerebral circulation in mice

We examined structure, composition, and endothelial function in cerebral arterioles after 4 wk of chronic renal failure (CRF) in a well-defined murine model (C57BL/6J and apolipoprotein E knockout female mice). We also determined quantitative expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (on serine 1177 and threonine 495), and caveolin-1; quantitative expression of markers of vascular inflammation or oxidative stress [Rock-1, Rock-2, VCAM-1, and peroxisome proliferator-activated receptor-γ (PPARγ)]; and the plasma concentration of L-arginine and asymmetric dimethylarginine (ADMA). Our hypothesis was that endothelial function would be impaired in cerebral arterioles during CRF following either a decrease in NO production (through alteration of eNOS expression or regulation) or an increase in NO degradation (due to oxidative stress or vascular inflammation). Endothelium-dependent relaxation was impaired during CRF, but endothelium-independent relaxation was not. CRF had no effect on cerebral arteriolar structure and composition. Quantitative expressions of eNOS, eNOS phosphorylated on serine 1177, caveolin-1, Rock-1, Rock-2, and VCAM-1 were similar in CRF and non-CRF mice. In contrast, quantitative expression of PPARγ (which exercises a protective role on blood vessels) was significantly lower in CRF mice, whereas quantitative expression of eNOS phosphorylated on the threonine 495 (the inactive form of eNOS) was significantly higher. Lastly, the plasma concentration of ADMA (a uremic toxin and an endogenous inhibitor of eNOS) was elevated and plasma concentration of L-arginine was low in CRF. In conclusion, endothelial function is impaired in a mouse model of early stage CRF. These alterations may be related (at least in part) to a decrease in NO production.     

Reconsidering Darwin’s “Several Powers”

Contemporary textbooks often define evolution in terms of the replication, mutation, and selective retention of DNA sequences, ignoring the contribution of the physical processes involved. In the closing line of The Origin of Species, however, Darwin recognized that natural selection depends on prior more basic living functions, which he merely described as life’s “several powers.” For Darwin these involved the organism’s capacity to maintain itself and to reproduce offspring that preserve its critical functional organization. In modern terms we have come to recognize that this involves the continual generation of complex organic molecules in complex configurations accomplished with the aid of persistent far-from-equilibrium chemical self-organizing and self-assembling processes. But reliable persistence and replication of these processes also requires constantly available constraints and boundary conditions. Organism autonomy further requires that these constraints and co-dependent dynamics are reciprocally produced, each by the other. In this paper I argue that the different constraint-amplifying dynamics of two or more self-organizing processes can be coupled so that they reciprocally generate each other’s critical supportive boundary conditions. This coupling is a higher-order constraint (which can be distributed among components or offloaded onto molecular structures) that effectively constitutes a sign vehicle “interpreted” by the synergistic dynamics of these co-dependent self-organizing process so that they reconstitute this same semiotic-dynamic relationship and its self-reconstituting potential in new substrates. This dynamical co-dependence constitutes Darwin’s “several powers” and is the basis of the biosemiosis that enables evolution.     

Structural genomics: from genes to structures with valuable materials and many questions in between

The Protein Structure Initiative (PSI), funded by the US National Institutes of Health (NIH), provides a framework for the development and systematic evaluation of methods to solve protein structures. Although the PSI and other structural genomics efforts around the world have led to the solution of many new protein structures as well as the development of new methods, methodological bottlenecks still exist and are being addressed in this 'production phase' of PSI.     

Crystal structure of a heat-resilient phytase from Aspergillus fumigatus, carrying a phosphorylated histidine

In order to understand the structural basis for the high thermostability of phytase from Aspergillus fumigatus, its crystal structure was determined at 1.5 A resolution. The overall fold resembles the structure of other phytase enzymes. Aspergillus niger phytase shares 66% sequence identity, however, it is much less heat-resistant. A superimposition of these two structures reveals some significant differences. In particular, substitutions with polar residues appear to remove repulsive ion pair interactions and instead form hydrogen bond interactions, which stabilize the enzyme; the formation of a C-terminal helical capping, induced by arginine residue substitutions also appears to be critical for the enzyme's ability to refold to its active form after denaturation at high temperature. The heat-resilient property of A.fumigatus phytase could be due to the improved stability of regions that are critical for the refolding of the protein; and a heat-resistant A.niger phytase may be achieved by mutating certain critical residues with the equivalent residues in A.fumigatus phytase. Six predicted N-glycosylation sites were observed to be glycosylated from the experimental electron density. Furthermore, the enzyme's catalytic residue His59 was found to be partly phosphorylated and thus showed a reaction intermediate, providing structural insight, which may help understand the catalytic mechanism of the acid phosphatase family. The trap of this catalytic intermediate confirms the two-step catalytic mechanism of the acid histidine phosphatase family.