Dynamic Allostery Mediated by a Conserved Tryptophan in the Tec Family Kinases

Bruton’s tyrosine kinase (Btk) is a Tec family non-receptor tyrosine kinase that plays a critical role in immune signaling and is associated with the immunological disorder X-linked agammaglobulinemia (XLA). Our previous findings showed that the Tec kinases are allosterically activated by the adjacent N-terminal linker. A single tryptophan residue in the N-terminal 17-residue linker mediates allosteric activation, and its mutation to alanine leads to the complete loss of activity. Guided by hydrogen/deuterium exchange mass spectrometry results, we have employed Molecular Dynamics simulations, Principal Component Analysis, Community Analysis and measures of node centrality to understand the details of how a single tryptophan mediates allostery in Btk. A specific tryptophan side chain rotamer promotes the functional dynamic allostery by inducing coordinated motions that spread across the kinase domain. Either a shift in the rotamer population, or a loss of the tryptophan side chain by mutation, drastically changes the coordinated motions and dynamically isolates catalytically important regions of the kinase domain. This work also identifies a new set of residues in the Btk kinase domain with high node centrality values indicating their importance in transmission of dynamics essential for kinase activation. Structurally, these node residues appear in both lobes of the kinase domain. In the N-lobe, high centrality residues wrap around the ATP binding pocket connecting previously described Catalytic-spine residues. In the C-lobe, two high centrality node residues connect the base of the R- and C-spines on the αF-helix. We suggest that the bridging residues that connect the catalytic and regulatory architecture within the kinase domain may be a crucial element in transmitting information about regulatory spine assembly to the catalytic machinery of the catalytic spine and active site.     

Effects of Probiotic Yogurt on Serum Omentin-1, Adropin,and Nesfatin-1 Concentrations in Overweight and Obese Participants Under Low-Calorie Diet

Probiotics and Antimicrobial Proteins - Data on the effects of probiotics on adipokines such as omentin-1, nesfatin-1, and adropin are limited. The aim of this study was to evaluate the effects of...     

Bradyrhizobial inoculation and P application effects on haricot and mung beans in the Ethiopian Rift Valley

Plant and Soil - Natural and managed soils have been identified as the largest sources of atmospheric nitrous oxide (N2O). However, the quantification of N2O emissions from soils under natural...     

Finite element method analysis of the tooth movement induced by orthodontic forces

The finite element method is a useful technique for measuring structural stress and for movement analyses. The objective of this investigation was to get a more accurate estimation of tooth movement depending on application point when a tipping orthodontic force is applied. The three-dimensional model of un upper canine, consisting of 4,000 hexahedron elements with 2,367 nodes was obtained. Horizontal, orally directed 1N tipping orthodontic force was applied to the model on five different levels of the tooth crown. The three-dimensional mathematical finite element model is useful in analyzing the tooth movement in response to orthodontic forces. The tipping tooth movement is greater if the force is applied closer to its neck, or more gingivally.     

Structure-based design of novel nonpeptide inhibitors of the Src SH2 domain:phosphotyrosine mimetics exploiting multifunctional group replacement chemistry

A series of novel nonpeptide inhibitors of the pp60(c-Src) (Src) SH2 domain is described that exploit multifunctional group replacement of the phenylphosphate moiety of phosphotyrosine (pTyr). Relative to an x-ray structure of citrate complexed to the pTyr binding site of the Src SH2 domain, these nonpeptide ligands illustrate the systematic replacement of the phosphate group by multiple nonhydrolyzable, mono- or dianionic functionalities. Specifically, several phenylalanine (Phe) analogs incorporating key 4' and 3' substituents were synthesized and incorporated into a bicyclic benzamide template previously reported (W. C. Shakespeare et al., Proceedings of the National Academy of Science USA, 2000, Vol. 97, pp. 9373-9378). These pTyr mimetics included 4',3'-diphosphono-Phe (Dpp), 4',3'-dicarboxymethyloxy-Phe (Dcp), and 4'-phosphono-3'-carboxymethyloxy-Phe (Cpp). Noteworthy were nonpeptide inhibitors 8-11 that were 5- to 10-fold more potent than the cognate tetrapeptide ligand Ac-pTyr-Glu-Glu-Ile-NH(2) in binding to the Src SH2 domain.     

Interferometry in the assessment of biomechanical features of the masticatory system hard segments

Biomechanical studies have found wide application and solved many problems in dental medicine. An interdisciplinary approach has allowed an ever-faster progress in the field. The aim of this study was to point out the advantages of holographic interferometry. With the use of this method, the study object is observed as a whole rather than as a substrate, thus providing a three-dimensional holographic image visualizing the load transmission from one jaw to another, tooth pressure against the alveolus, and strain of Sharpey's fibers, and yielding precise data on deformities, dislocations and force distribution.     

Trends in dental caries in 12-year old children in Croatia

In this epidemiological study the caries status of 12-year-old children was compared over time for the years 1968, 1973, 1980, 1985, 1990, 1991 and 1999. The mean number of decayed, missing and filled teeth (DMFT) decreased from 7.0 in 1968 to 2.6 in 1991. From 1991 to 1999 and increase of DMFT 2.6 in 1991, to 3.5 in 1999) has been seen which is result of war in Croatia and reorganisation of health care delivery system. With the expected continuing decline in the prevalence and severity of oral diseases, one of the main problems in the future seems to be the transition of the oral health care delivery system from a disease-oriented system to a health-oriented one.     

Spondylodiscitis and an aortic aneurysm due to Campylobacter coli

The aim of the current study was to evaluate the prevalence of stump infections after major amputations of the lower extremities. Patients rehospitalized in Hospital de Base of the Medicine School in São José do Rio Preto in the period from January 2005 to January 2007 due to stump infection after major amputations of lower extremities were evaluated in a retrospective study. All the patients underwent prophylactic antibiotic therapy at the time of the surgery. The Fisher exact test was utilized for statistical analysis with an alpha error of 5% (p-value < 0.05) being considered acceptable. A total of 231 patients were submitted to major amputations during this period and 17 (7.3%) were rehospitalized due to amputation stump infections of which 5 (29.4%) died within one month. The association between death due to stump infection and other causes of death during rehospitalizations was not significant (Fisher exact test: p < 0.1). However, death during rehospitalizations was significantly higher than in the initial hospitalization.