Expression of Main Toll-Like Receptors in Patients with Different Types of Colorectal Polyps and Their Relationship with Gut Microbiota

Abnormal activation of Toll-like receptor (TLRs) signaling can result in colon cancer development. The aim of this study was to investigate the expression of important TLRs in different histological types of colorectal polyps and evaluate their relationship with intestinal microbiota. The expression levels of TLR2, 3, 4, and 5 were analyzed in intestinal biopsy specimens of 21 hyperplastic polyp (HP), 16 sessile serrated adenoma (SSA), 29 tubular adenoma (TA), 21 villous/tubulovillous (VP/TVP) cases, and 31 normal controls. In addition, selected gut bacteria including Streptococcus bovis, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Fusobacterium nucleatum, Porphyromonas spp., Lactobacillus spp., Roseburia spp., and Bifidobacterium spp. were quantified in fecal samples using absolute qRT PCR, and, finally, the association between TLRs and these gut microbiota- was evaluated by Spearman’s correlation coefficient. Higher expression of TLR2 and TLR4 in VP/TVP and TA, and lower expression levels of TLR3 and TLR5 in all type of polyps were observed. The differences in TLR expression patterns was not only dependent on the histology, location, size, and dysplasia grade of polyps but also related to the intestinal microbiota patterns. TLR2 and TLR4 expression was directly associated with the F. nucleatum, E. faecalis, S. bovis, Porphyromonas, and inversely to Bifidobacterium, Lactobacillus, and Roseburia quantity. Furthermore, TLR3 and TLR5 expression was directly associated with Bifidobacterium, Roseburia, and Lactobacillus quantity. Our results suggest a possible critical role of TLRs during colorectal polyp progression. An abnormal regulation of TLRs in relation to gut microbial quantity may contribute to carcinogenesis.     

Profile-Driven Component Placement for Cluster-Based Online Services

The growth of the Internet and of various intranets has spawned a wealth of online services, most of which are implemented on local-area clusters using remote invocation (for example, remote procedure call/remote method invocation) among manually placed application components. Component placement can be a significant challenge for large-scale services, particularly when application resource needs are workload dependent. Automatic component placement has the potential to maximize overall system throughput. The key idea is to construct (offline) a mapping between input workload and individual-component resource consumption. Such mappings, called component profiles, then support high-performance placement. Preliminary results on an online auction benchmark based on J2EE (Java 2 Platform, Enterprise Edition) suggest that profile-driven tools can identify placements that achieve near-optimal overall throughput.     

Management gaps analysis: a case study of groundwater resource management in New Zealand

The primary objective of this project is to identify gaps, whether real or perceived, that hinder effective groundwater management in New Zealand. These gaps show as gaps in information, gaps in implementation, gaps in technological and management tools, and gaps in understanding of fundamental processes. The secondary objective is to propose a management strategy to close the identified gaps. Several methods are used to meet these objectives: surveys distributed to selected staff in each regional council; the review of various written reports; the analysis of land-use databases; and private consultation within each regional council. Results show that groundwater management in New Zealand is generally reactionary with the main gaps being in strategic planning and national guidelines. Most gaps appear to be predominantly information and implementation issues. In some cases there are gaps in the understanding of fundamental processes within an aquifer system, including the long-term effects of land-use on groundwater quality. An adaptive management approach is suggested as a means of closing these gaps.     

Interior symmetry and local bifurcation in coupled cell networks

A coupled cell system is a network of dynamical systems, or 'cells', coupled together. Such systems can be represented schematically by a directed graph whose nodes correspond to cells and whose edges represent couplings. A symmetry of a coupled cell system is a permutation of the cells and edges that preserves all internal dynamics and all couplings. It is well known that symmetry can lead to patterns of synchronized cells, rotating waves, multirhythms, and synchronized chaos. Recently, the introduction of a less stringent form of symmetry, the 'symmetry groupoid', has shown that global group-theoretic symmetry is not the only mechanism that can create such states in a coupled cell system. The symmetry groupoid consists of structure-preserving bijections between certain subsets of the cell network, the input sets. Here, we introduce a concept intermediate between the groupoid symmetries and the global group symmetries of a network: 'interior symmetry'. This concept is closely related to the groupoid structure, but imposes stronger constraints of a group-theoretic nature. We develop the local bifurcation theory of coupled cell systems possessing interior symmetries, by analogy with symmetric bifurcation theory. The main results are analogues for 'synchrony-breaking' bifurcations of the Equivariant Branching Lemma for steady-state bifurcation, and the Equivariant Hopf Theorem for bifurcation to time-periodic states.     

Effects of introduced aspartic and glutamic acid residues on the P'1 substrate specificity, pH dependence and stability of carboxypeptidase Y

Carboxypeptidase Y is a serine carboxypeptidase isolated from Saccharomyces cerevisiae with a preference for C-terminal hydrophobic amino acid residues. In order to alter the inherent substrate specificity of CPD-Y into one for basic amino acid residues in P'1, we have introduced Asp and/or Glu residues at a number of selected positions within the S'1 binding site. The effects of these substitutions on the substrate specificity, pH dependence and protein stability have been evaluated. The results presented here demonstrate that it is possible to obtain significant changes in the substrate preference by introducing charged amino acids into the framework provided by an enzyme with a quite different specificity. The introduced acidic amino acid residues provide a marked pH dependence of the (kcat/Km)FA-A-R-OH/(kcat/Km)FA-A-L-OH ratio. The change in stability upon introduction of Asp/Glu residues can be correlated to the difference in the mean buried surface area between the substituted and the substituting amino acid. Thus, the effects of acidic amino acid residues on the protein stability depend upon whether the introduced amino acid protrudes from the solvent accessible surface as defined by the surrounding residues in the wild type enzyme or is submerged below.     

Structure and stability of an immunoglobulin superfamily domain from twitchin, a muscle protein of the nematode Caenorhabditis elegans

The NMR solution structure of an immunoglobulin superfamily module of twitchin (Ig 18') has been determined and the kinetic and equilibrium folding behaviour characterised. Thirty molecular coordinates were calculated using a hybrid distance geometry-simulated annealing protocol based on 1207 distance and 48 dihedral restraints. The atomic rms distributions about the mean coordinate for the ensemble of structures is 0.55( +/- 0.09) A for backbone atoms and 1.10( +/- 0.08) A for all heavy atoms. The protein has a topology very similar to that of telokin and the titin Ig domains and thus it falls into the I set of the immunoglobulin superfamily. The close agreement between the predicted and observed structures of Ig 18' demonstrates clearly that the I set profile can be applied in the structure prediction of immunoglobulin-like domains of diverse modular proteins. Folding studies reveal that the protein has relatively low thermodynamic stability, deltaG(H2O)U-F = 4.0 kcal mol(-1) at physiological pH. Unfolding studies suggest that the protein has considerable kinetic stability, the half life of the unfolding is greater than 40 minutes in the absence of denaturant.     

Comparative study of monoclonal antibody scan in diagnosing orthopaedic infection

When clinical data are insufficient to diagnose infection of bone or joints, nuclear scanning becomes crucial in making an accurate diagnosis. The efficacy of (99m)technetium antigranulocyte monoclonal antibody Fab' fragment (LeukoScan) is prospectively compared with (111)indium white blood cell and (99m)technetium methylene diphosphonate bone scans in 74 patients with suspected musculoskeletal infections. They were grouped according to site of suspected infection: 33 long bones, 23 prosthetic joints, and 18 diabetic feet. Sixty-two of these 74 patients had surgical verification with histopathology or culture. The remaining 12 patients had clinical followup as proof of absence of infection. The overall sensitivity of LeukoScan, (111)indium white blood cell, and (99m)technetium methylene diphosphonate bone scans was 93%, 85% and 92%, respectively. Specificity was 89%, 75% and 52%, and accuracy was 90%, 79% and 74%, respectively. The conclusion from this study is that LeukoScan is more accurate in detecting osteomyelitis, with better sensitivity and specificity in prosthetic joints. Compared with (111)indium white blood cell scans, LeukoScan++ gives superior images, and results are obtained in 1 to 6 hours without biohazard risk from handling blood products.     

Activity-dependent changes in voltage-dependent calcium currents and transmitter release

The use of capillary electrophoresis (CE) for clinically relevant assays is attractive since it often presents many advantages over contemporary methods. The small-diameter tubing that holds the separation medium has led to the development of multicapillary instruments, and simultaneous sample analysis. Furthermore, CE is compatible with a wide range of detectors, including UV-Vis, fluorescence, laser-induced fluorescence, electrochemistry, mass spectrometry, radiometric, and more recently nuclear magnetic resonance, and laser-induced circular dichroism systems. Selection of an appropriate detector can yield highly specific analyte detection with good mass sensitivity. Another attractive feature of CE is the low consumption of sample and reagents. However, it is paradoxical that this advantage also leads to severe limitation, namely poor concentration sensitivity. Often high analyte concentrations are required in order to have injection of sufficient material for detection. In this regard, a series of devices that are broadly termed 'analyte concentrators' have been developed for analyte preconcentration on-line with the CE capillary. These devices have been used primarily for non-specific analyte preconcentration using packing material of the C18 type. Alternatively, the use of very specific antibody-containing cartridges and enzyme-immobilized microreactors have been demonstrated. In the current report, we review the likely impact of the technology of capillary electrophoresis and the role of the CE analyte concentrator-microreactor on the analysis of biomolecules, present on complex matrices, in a clinical laboratory. Specific examples of the direct analysis of physiologically-derived fluids and microdialysates are presented, and a personal view of the future of CE in the clinical environment is given.