The 1.8 A crystal structure of a proteinase K-like enzyme from a psychrotroph Serratia species

Proteins from organisms living in extreme conditions are of particular interest because of their potential for being templates for redesign of enzymes both in biotechnological and other industries. The crystal structure of a proteinase K-like enzyme from a psychrotroph Serratia species has been solved to 1.8 A. The structure has been compared with the structures of proteinase K from Tritirachium album Limber and Vibrio sp. PA44 in order to reveal structural explanations for differences in biophysical properties. The Serratia peptidase shares around 40 and 64% identity with the Tritirachium and Vibrio peptidases, respectively. The fold of the three enzymes is essentially identical, with minor exceptions in surface loops. One calcium binding site is found in the Serratia peptidase, in contrast to the Tritirachium and Vibrio peptidases which have two and three, respectively. A disulfide bridge close to the S2 site in the Serratia and Vibrio peptidases, an extensive hydrogen bond network in a tight loop close to the substrate binding site in the Serratia peptidase and different amino acid sequences in the S4 sites are expected to cause different substrate specificity in the three enzymes. The more negative surface potential of the Serratia peptidase, along with a disulfide bridge close to the S2 binding site of a substrate, is also expected to contribute to the overall lower binding affinity observed for the Serratia peptidase. Clear electron density for a tripeptide, probably a proteolysis product, was found in the S' sites of the substrate binding cleft.     

Life in the slow lane revisited: ontogenetic separation between chimpanzees and humans

This study investigates the evolution of human growth by analyzing differences in body mass growth trajectories among three populations: the Ache of eastern Paraguay, the US (NHANES, 1999-2000), and captive chimpanzees. The relative growth statistic "A" from the mammalian growth law is allowed to vary with age and proves useful for comparing growth across different ages, populations, and species. We demonstrate ontogenetic separation between chimpanzees and humans, and show that interspecific differences are robust to variable environmental conditions. The human pattern of slow growth during the lengthened period from weaning to the beginning of the adolescent growth spurt is found among the Ache (low energy availability and high disease load) and also in the US (high energy availability and low disease load). The human growth pattern contrasts with that of the chimpanzee, where absolute growth rates and relative "A" values are faster and less prolonged. We suggest that selection has acted to decrease human growth rates to allow more time for increased cognitive development with lower body-maintenance costs.     

Surfactant protein D (Sp-D) binds to membrane-proximal domain (D3) of signal regulatory protein α (SIRPα), a site distant from binding domain of CD47, while also binding to analogous region on signal regulatory protein β (SIRPβ)

Signal regulatory protein α (SIRPα), a highly glycosylated type-1 transmembrane protein, is composed of three immunoglobulin-like extracellular loops as well as a cytoplasmic tail containing three classical tyrosine-based inhibitory motifs. Previous reports indicate that SIRPα binds to humoral pattern recognition molecules in the collectin family, namely surfactant proteins D and A (Sp-D and Sp-A, respectively), which are heavily expressed in the lung and constitute one of the first lines of innate immune defense against pathogens. However, little is known about molecular details of the structural interaction of Sp-D with SIRPs. In the present work, we examined the molecular basis of Sp-D binding to SIRPα using domain-deleted mutant proteins. We report that Sp-D binds to the membrane-proximal Ig domain (D3) of SIRPα in a calcium- and carbohydrate-dependent manner. Mutation of predicted N-glycosylation sites on SIRPα indicates that Sp-D binding is dependent on interactions with specific N-glycosylated residues on the membrane-proximal D3 domain of SIRPα. Given the remarkable sequence similarity of SIRPα to SIRPβ and the lack of known ligands for the latter, we examined Sp-D binding to SIRPβ. Here, we report specific binding of Sp-D to the membrane-proximal D3 domain of SIRPβ. Further studies confirmed that Sp-D binds to SIRPα expressed on human neutrophils and differentiated neutrophil-like cells. Because the other known ligand of SIRPα, CD47, binds to the membrane-distal domain D1, these findings indicate that multiple, distinct, functional ligand binding sites are present on SIRPα that may afford differential regulation of receptor function.     

Comparison of particle image velocimetry and phase contrast MRI in a patient-specific extracardiac total cavopulmonary connection

Particle image velocimetry (PIV) and phase contrast magnetic resonance imaging (PC-MRI) have not been compared in complex biofluid environments. Such analysis is particularly useful to investigate flow structures in the correction of single ventricle congenital heart defects, where fluid dynamic efficiency is essential. A stereolithographic replica of an extracardiac total cavopulmonary connection (TCPC) is studied using PIV and PC-MRI in a steady flow loop. Volumetric two-component PIV is compared to volumetric three-component PC-MRI at various flow conditions. Similar flow structures are observed in both PIV and PC-MRI, where smooth flow dominates the extracardiac TCPC, and superior vena cava flow is preferential to the right pulmonary artery, while inferior vena cava flow is preferential to the left pulmonary artery. Where three-component velocity is available in PC-MRI studies, some helical flow in the extracardiac TCPC is observed. Vessel cross sections provide an effective means of validation for both experiments, and velocity magnitudes are of the same order. The results highlight similarities to validate flow in a complex patient-specific extracardiac TCPC. Additional information obtained by velocity in three components further describes the complexity of the flow in anatomic structures.     

Convergence properties of the degree distribution of some growing network models

In this article we study a class of randomly grown graphs that includes some preferential attachment and uniform attachment models, as well as some evolving graph models that have been discussed previously in the literature. The degree distribution is assumed to form a Markov chain; this gives a particularly simple form for a stochastic recursion of the degree distribution. We show that for this class of models the empirical degree distribution tends almost surely and in norm to the expected degree distribution as the size of the graph grows to infinity and we provide a simple asymptotic expression for the expected degree distribution. Convergence of the empirical degree distribution has consequences for statistical analysis of network data in that it allows the full data to be summarized by the degree distribution of the nodes without losing the ability to obtain consistent estimates of parameters describing the network.     

The prognostic value of different glucose abnormalities in patients with acute myocardial infarction treated invasively

ABSTRACT: BACKGROUND: Diabetes (DM) deteriorates the prognosis in patients with coronary heart disease. However, the prognostic value of different glucose abnormalities (GA) other than DM in subjects with acute myocardial infarction (AMI) treated invasively remains unclear. AIMS: To assess the incidence and impact of GA on clinical outcomes in AMI patients treated with percutaneous coronary intervention (PCI). METHODS: A single-center, prospective registry encompassed 2733 consecutive AMI subjects treated with PCI. In all in-hospital survivors (n = 2527, 92.5 %) without the history of DM diagnosed before or during index hospitalization standard oral glucose tolerance test (OGTT) was performed during stable condition before hospital discharge and interpreted according to WHO criteria. The mean follow-up period was 37.5 months. RESULTS: The incidence of GA was as follows: impaired fasting glycaemia - IFG (n = 376, 15 %); impaired glucose tolerance - IGT (n = 560, 22 %); DM (n = 425, 17 %); new onset DM (n = 384, 15 %); and normal glucose tolerance NGT (n = 782, 31 %). During the long-term follow-up, death rate events for previously known DM, new onset DM and IGT were significantly more frequent than those for IFG and NGT (12.3; 9.6 and 9.4 vs. 5.6 and 6.4 %, respectively, P < 0.05). The strongest and common independent predictors of death in GA patients were glomerular filtration rate < 60 ml/min/1,73 m^2 (HR 2.0 and 2.8) and left ventricle ejection fraction < 35 % (HR 2.5 and 1.8, all P < 0.05) respectively. CONCLUSIONS: Glucose abnormalities are very common in AMI patients. DM, new onset DM and IGT increase remote mortality. Impaired glucose tolerance bears similar long-term prognosis as diabetes.     

Enhanced consumption of an aversively conditioned taste following the presentation of a “medicine” taste

Rats given presentations of a citric acid solution while recovering from LiCl-induced illness (i.e., a “medicine effect” treatment) subsequently drank more of an aversively conditioned NaCl solution at test, when the NaCl presentation was immediately preceded by citric acid. That is, citric acid passed a summation test of conditioned inhibition. Such an effect was not observed in a group given explicitly unpaired presentations of LiCl and citric acid. It is proposed that enhanced consumption of an aversive taste due to the previous presentation of a “medicine” taste can provide an animal model of human maladaptive behavior in regards to food consumption.     

LIFE AT THE FRONT OF AN EXPANDING POPULATION

Environmental changes have caused episodes of habitat expansions in the evolutionary history of many species. These range changes affect the dynamics of biological evolution in multiple ways. Recent microbial experiments as well as simulations suggest that enhanced genetic drift at the frontier of a two-dimensional range expansion can cause genetic sectoring patterns with fractal domain boundaries. Here, we propose and analyze a simple model of asexual biological evolution at expanding frontiers that explains these neutral patterns and predicts the effect of natural selection. We find that beneficial mutations give rise to sectors with an opening angle that depends sensitively on the selective advantage of the mutants. Deleterious mutations, on the other hand, are not able to establish a sector permanently. They can, however, temporarily surf on the population front, and thereby reach unusually high frequencies. As a consequence, expanding frontiers are loaded with a high fraction of mutants at mutation–selection balance. Numerically, we also determine the condition at which the wild type is lost in favor of deleterious mutants (genetic meltdown) at a growing front. Our prediction for this error threshold differs qualitatively from existing well-mixed theories, and sets tight constraints on sustainable mutation rates for populations that undergo frequent range expansions.