134 resultados para Containing Peptide


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This study examines a matrix of synthetic water samples designed to include conditions that favour brominated disinfection by-product (Br-DBP) formation, in order to provide predictive models suitable for high Br-DBP forming waters such as salinity-impacted waters. Br-DBPs are known to be more toxic than their chlorinated analogues, in general, and their formation may be favoured by routine water treatment practices such as coagulation/flocculation under specific conditions; therefore, circumstances surrounding their formation must be understood. The chosen factors were bromide concentration, mineral alkalinity, bromide to dissolved organic carbon (Br/DOC) ratio and Suwannee River natural organic matter concentration. The relationships between these parameters and DBP formation were evaluated by response surface modelling of data generated using a face-centred central composite experimental design. Predictive models for ten brominated and/or chlorinated DBPs are presented, as well as models for total trihalomethanes (tTHMs) and total dihaloacetonitriles (tDHANs), and bromide substitution factors for the THMs and DHANs classes. The relationships described revealed that increasing alkalinity and increasing Br/DOC ratio were associated with increasing bromination of THMs and DHANs, suggesting that DOC lowering treatment methods that do not also remove bromide such as enhanced coagulation may create optimal conditions for Br-DBP formation in waters in which bromide is present.

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The focus of this paper is two-dimensional computational modelling of water flow in unsaturated soils consisting of weakly conductive disconnected inclusions embedded in a highly conductive connected matrix. When the inclusions are small, a two-scale Richards’ equation-based model has been proposed in the literature taking the form of an equation with effective parameters governing the macroscopic flow coupled with a microscopic equation, defined at each point in the macroscopic domain, governing the flow in the inclusions. This paper is devoted to a number of advances in the numerical implementation of this model. Namely, by treating the micro-scale as a two-dimensional problem, our solution approach based on a control volume finite element method can be applied to irregular inclusion geometries, and, if necessary, modified to account for additional phenomena (e.g. imposing the macroscopic gradient on the micro-scale via a linear approximation of the macroscopic variable along the microscopic boundary). This is achieved with the help of an exponential integrator for advancing the solution in time. This time integration method completely avoids generation of the Jacobian matrix of the system and hence eases the computation when solving the two-scale model in a completely coupled manner. Numerical simulations are presented for a two-dimensional infiltration problem.

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Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-(X)18-E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K 528R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.

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Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

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In-plane shear capacity formulation of reinforced masonry is commonly conceived as the sum of the capacities of three parameters, viz, the masonry, the reinforcement, and the precompression. The term “masonry” incorporates the aspect ratio of the wall without any regard to the aspect ratio of the panels inscribed (and hence confined) by the vertical and the horizontal reinforced grout cores. This paper proposes design expressions in which the aspect ratio of such panels is explicitly included. For this purpose, the grouted confining cores are regarded as a grid of confining elements within which the panels are positioned. These confined masonry panels are then considered as building blocks for multi-bay, multi-storied confined masonry shear walls and analyzed using an experimentally validated macroscopic finite-element model. Results of the analyzes of 161 confined masonry walls containing panels of height to length ratio less than 1.0 have been regressed to formulate design expressions. These expressions have been first validated using independent test data sets and then compared with the existing equations in some selected international design standards. The concept of including the unreinforced masonry panel aspect ratio as an additional term in the design expression for partially grouted/confined masonry shear walls is recommended based on the conclusions from this paper.

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The repeat unit of the K12 capsular polysaccharide isolated from the Acinetobacter baumannii global clone 1 clinical isolate, D36, was elucidated by means of chemical and spectroscopical methods. The structure was shown to contain N-acetyl-D-galactosamine (D-GalpNAc), N-acetyl-D-fucosamine and N-acetyl-L-fucosamine linked together in the main chain, with the novel sugar, 5,7-diacetamido-3,5,7,9-tetradeoxy-L-glycero-L-altro-non-2-ulosonic acid (5,7-di-N-acetylacinetaminic acid or Aci5Ac7Ac), attached to D-GalpNAc as a side branch. This matched the sugar composition of the K12 capsule and the genetic content of the KL12 capsule gene cluster reported previously. D-FucpNAc was predicted to be the substrate for the initiating transferase, ItrB3, with the Wzy polymerase making a α-D-FucpNAc-(1 → 3)-D-GalpNAc linkage between the repeat units. The three glycosyltransferases encoded by KL12 are all retaining glycosyltransferases and were predicted to form specific linkages between the sugars in the K12 repeat unit.

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This project was a step forward in improving the voltage profile of traditional low voltage distribution networks with high photovoltaic generation or high peak demand. As a practical and economical solution, the developed methods use a Dynamic Voltage Restorer or DVR, which is a series voltage compensator, for continuous and communication-less power quality enhancement. The placement of DVR in the network is optimised in order to minimise its power rating and cost. In addition, new approaches were developed for grid synchronisation and control of DVR which are integrated with the voltage quality improvement algorithm for stable operation.

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The peptide hormone ghrelin is a potent orexigen produced predominantly in the stomach. It has a number of other biological actions, including roles in appetite stimulation, energy balance, the stimulation of growth hormone release and the regulation of cell proliferation. Recently, several ghrelin gene splice variants have been described. Here, we attempted to identify conserved alternative splicing of the ghrelin gene by cross-species sequence comparisons. We identified a novel human exon 2-deleted variant and provide preliminary evidence that this splice variant and in1-ghrelin encode a C-terminally truncated form of the ghrelin peptide, termed minighrelin. These variants are expressed in humans and mice, demonstrating conservation of alternative splicing spanning 90 million years. Minighrelin appears to have similar actions to full-length ghrelin, as treatment with exogenous minighrelin peptide stimulates appetite and feeding in mice. Forced expression of the exon 2-deleted preproghrelin variant mirrors the effect of the canonical preproghrelin, stimulating cell proliferation and migration in the PC3 prostate cancer cell line. This is the first study to characterise an exon 2-deleted preproghrelin variant and to demonstrate sequence conservation of ghrelin gene-derived splice variants that encode a truncated ghrelin peptide. This adds further impetus for studies into the alternative splicing of the ghrelin gene and the function of novel ghrelin peptides in vertebrates.

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Purification of drinking water is routinely achieved by use of conventional coagulants and disinfection procedures. However, there are instances such as flood events when the level of turbidity reaches extreme levels while NOM may be an issue throughout the year. Consequently, there is a need to develop technologies which can effectively treat water of high turbidity during flood events and natural organic matter (NOM) content year round. It was our hypothesis that pebble matrix filtration potentially offered a relatively cheap, simple and reliable means to clarify such challenging water samples. Therefore, a laboratory scale pebble matrix filter (PMF) column was used to evaluate the turbidity and natural organic matter (NOM) pre-treatment performance in relation to 2013 Brisbane River flood water. Since the high turbidity was only a seasonal and short term problem, the general applicability of pebble matrix filters for NOM removal was also investigated. A 1.0 m deep bed of pebbles (the matrix) partly in-filled with either sand or crushed glass was tested, upon which was situated a layer of granular activated carbon (GAC). Turbidity was measured as a surrogate for suspended solids (SS), whereas, total organic carbon (TOC) and UV Absorbance at 254 nm were measured as surrogate parameters for NOM. Experiments using natural flood water showed that without the addition of any chemical coagulants, PMF columns achieved at least 50% turbidity reduction when the source water contained moderate hardness levels. For harder water samples, above 85% turbidity reduction was obtained. The ability to remove 50% turbidity without chemical coagulants may represent significant cost savings to water treatment plants and added environmental benefits accrue due to less sludge formation. A TOC reduction of 35-47% and UV-254 nm reduction of 24-38% was also observed. In addition to turbidity removal during flood periods, the ability to remove NOM using the pebble matrix filter throughout the year may have the benefit of reducing disinfection by-products (DBP) formation potential and coagulant demand at water treatment plants. Final head losses were remarkably low, reaching only 11 cm at a filtration velocity of 0.70 m/h.

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CXCL-8 (Interleukin 8) is a CXC chemokine with a central role in the human immune response. We have undertaken extensive in silico analyses to elucidate the interactions of CXCL-8 with its various binding partners, which are crucial for its biological function. Sequence and structure analyses showed that residues in the thirdq β-sheet and basic residues in the heparin binding site are highly variable, while residues in the second β-sheet are highly conserved. Molecular dynamics simulations in aqueous solution of dimeric CXCL-8 have been performed with starting geometries from both X-ray and NMR structures showed shearing movements between the two antiparallel C-terminal helices. Dynamic conservation analyses of these simulations agreed with experimental data indicating that structural differences between the two structures at quaternary level arise from changes in the secondary structure of the N-terminal loop, the 310-helix, the 30s, 40s, and 50s loops and the third β-sheet, resulting in a different interhelical separation. Nevertheless, the observation of these different states indicates that CXCL-8 has the potential to undergo conformational changes, and it seems likely that this feature is relevant to the mode of binding of glycosaminoglycan (GAG) mimetics such as cyclitols. Simulations of the receptor peptide fragment−CXCL-8 complex identified several specific interactions of the receptor peptide with CXCL-8 that could be exploited in the structure-based design of competitive peptides and nonpeptidic molecules targeting CXCL-8 for combating inflammatory diseases. Simulations of the CXCL-8 dimer complexed with a 24-mer heparin fragment and of the CXCL-8−receptor peptide complex revealed that Arg60, Lys64, and Arg68 in the dimer bind to cyclitols in a horseshoe pattern, defining a region which is spatially distinct from the receptor binding site. There appears to be an optimum number of sulfates and an optimum length of alkyl spacers required for the interaction of cyclitol inhibitors with the dimeric form of CXCL-8. Calculation of the binding affinities of cyclitol inhibitors reflected satisfactorily the ranking of experimentally determined inhibitory potencies. The findings of these molecular modeling studies will help in the search for inhibitors which can modulate various CXCL-8 biological activities and serve as an excellent model system to study CXC-inhibitor interactions.

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Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau225−250) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal β-sheet pattern (226VAVVR230 and 244QTAPVP249), replacing it with a range of structures. The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structural characterization, with the observation of a transient α-helix (239AKSRLQT245). PPII helical conformations were only found sporadically throughout the simulations. Proteins 2014; 82:1907–1923. © 2014 Wiley Periodicals, Inc.

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This thesis investigated the basis for availability of iron (Fe) and zinc (Zn) content in different banana fruits grown in Uganda and Australia. Rather than micronutrient content levels in different banana cultivar, genotype and environment interactions explained much of the differences. Such information should provide important insights for future developments in the biofortification of banana. Bananas consumed in Uganda did not contain sufficient levels of Fe and Zn that meet the nutrient requirements for vulnerable groups.

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Standard mechanism inhibitors are attractive design templates for engineering reversible serine protease inhibitors. When optimizing interactions between the inhibitor and target protease, many studies focus on the nonprimed segment of the inhibitor's binding loop (encompassing the contact β-strand). However, there are currently few methods for screening residues on the primed segment. Here, we designed a synthetic inhibitor library (based on sunflower trypsin inhibitor-1) for characterizing the P2′ specificity of various serine proteases. Screening the library against 13 different proteases revealed unique P2′ preferences for trypsin, chymotrypsin, matriptase, plasmin, thrombin, four kallikrein-related peptidases, and several clotting factors. Using this information to modify existing engineered inhibitors yielded new variants that showed considerably improved selectivity, reaching up to 7000-fold selectivity over certain off-target proteases. Our study demonstrates the importance of the P2′ residue in standard mechanism inhibition and unveils a new approach for screening P2′ substitutions that will benefit future inhibitor engineering studies.