A hierarchical distributed approach for mining molecular fragments

Recently, two approaches have been introduced that distribute the molecular fragment mining problem. The first approach applies a master/worker topology, the second approach, a completely distributed peer-to-peer system, solves the scalability problem due to the bottleneck at the master node. However, in many real world scenarios the participating computing nodes cannot communicate directly due to administrative policies such as security restrictions. Thus, potential computing power is not accessible to accelerate the mining run. To solve this shortcoming, this work introduces a hierarchical topology of computing resources, which distributes the management over several levels and adapts to the natural structure of those multi-domain architectures. The most important aspect is the load balancing scheme, which has been designed and optimized for the hierarchical structure. The approach allows dynamic aggregation of heterogenous computing resources and is applied to wide area network scenarios.

Distributed mining of molecular fragments

In real world applications sequential algorithms of data mining and data exploration are often unsuitable for datasets with enormous size, high-dimensionality and complex data structure. Grid computing promises unprecedented opportunities for unlimited computing and storage resources. In this context there is the necessity to develop high performance distributed data mining algorithms. However, the computational complexity of the problem and the large amount of data to be explored often make the design of large scale applications particularly challenging. In this paper we present the first distributed formulation of a frequent subgraph mining algorithm for discriminative fragments of molecular compounds. Two distributed approaches have been developed and compared on the well known National Cancer Institute’s HIV-screening dataset. We present experimental results on a small-scale computing environment.

Efficient mining of discriminative molecular fragments

Frequent pattern discovery in structured data is receiving an increasing attention in many application areas of sciences. However, the computational complexity and the large amount of data to be explored often make the sequential algorithms unsuitable. In this context high performance distributed computing becomes a very interesting and promising approach. In this paper we present a parallel formulation of the frequent subgraph mining problem to discover interesting patterns in molecular compounds. The application is characterized by a highly irregular tree-structured computation. No estimation is available for task workloads, which show a power-law distribution in a wide range. The proposed approach allows dynamic resource aggregation and provides fault and latency tolerance. These features make the distributed application suitable for multi-domain heterogeneous environments, such as computational Grids. The distributed application has been evaluated on the well known National Cancer Institute’s HIV-screening dataset.

Detection of transgenic and endogenous plant DNA fragments in the blood, tissues, and digesta of broilers

The aim was to determine the fate of transgenic and endogenous plant DNA fragments in the blood, tissues, and digesta of broilers. Male broiler chicks (n = 24) were allocated at 1 day old to each of four treatment diets designated T1-T4. T1 and T2 contained the near isogenic nongenetically modified (GM) maize grain, whereas T3 and T4 contained GM maize grain [cry1a(b) gene]; T1 and T3 also contained the near isogenic non-GM soybean meal, whereas T2 and T4 contained GM soybean meal (cp4epsps gene). Four days prior to slaughter at 39-42 days old, 50% of the broilers on T2-T4 had the source(s) of GM ingredients replaced by their non-GM counterparts. Detection of specific DNA sequences in feed, tissue, and digesta samples was completed by polymerase chain reaction analysis. Seven primer pairs were used to amplify fragments (similar to 200 bp) from single copy genes (maize high mobility protein, soya lectin, and transgenes in the GM feeds) and multicopy genes (poultry mitochondrial cytochrome b, maize, and soya rubisco). There was no effect of treatment on the measured growth performance parameters. Except for a single detection of lectin (nontransgenic single copy gene; unsubstantiated) in the extracted DNA from one bursa tissue sample, there was no positive detection of any endogenous or transgenic single copy genes in either blood or tissue DNA samples. However, the multicopy rubisco gene was detected in a proportion of samples from all tissue types (23% of total across all tissues studied) and in low numbers in blood. Feed-derived DNA was found to survive complete degradation up to the large intestine. Transgenic DNA was detected in gizzard digesta but not in intestinal digesta 96 h after the last feeding of treatment diets containing a source of GM maize and/or soybean meal.

Cross-sectional estimation of Babesia bovis antibody prevalence in cattle in two contrasting dairying areas in Tanzania

The crude prevalence of antibodies to Babesia bovis infection in cattle was estimated by serology using indirect ELISA during the period January to April, 1999. Sera were obtained from 1395 dairy cattle (of all ages, sexes and breeds) on smallholder farms, the majority being kept under a zero grazing regime. The crude prevalence of antibodies to Babesia bovis was 6 % for Tanga and 12 % for Iringa. The forces of infection based on the age sero-prevalence profile, were estimated at six for Iringa and four for Tanga per 100 cattle years-risk, respectively. Using random effect logistic regression as the analytical method, the factors (variables) of age, source of animals and geographic location were hypothesised to be associated with sero-positivity of Babesia bovis in the two regions.

Immunogenicity of the outer domain of a HIV-1 clade C gp120

Background: The possibility that a sub domain of a C clade HIV-1 gp120 could act as an effective immunogen was investigated. To do this, the outer domain ( OD) of gp120(CN54) was expressed and characterized in a construct marked by a re-introduced conformational epitope for MAb 2G12. The expressed sequence showed efficient epitope retention on the isolated ODCN54 suggesting authentic folding. To facilitate purification and subsequent immunogenicity ODCN54 was fused to the Fc domain of human IgGl. Mice were immunised with the resulting fusion proteins and also with gp120(CN54)-Fc and gp120 alone. Results: Fusion to Fc was found to stimulate antibody titre and Fc tagged ODCN54 was substantially more immunogenic than non-tagged gp120. Immunogenicity appeared the result of Fc facilitated antigen processing as immunisation with an Fc domain mutant that reduced binding to the FcR lead to a reduction in antibody titre when compared to the parental sequence. The breadth of the antibody response was assessed by serum reaction with five overlapping fragments of gp120(CN54) expressed as GST fusion proteins in bacteria. A predominant anti-inner domain and anti-V3C3 response was observed following immunisation with gp120(CN54)-Fc and an anti-V3C3 response to the ODCN54-Fc fusion. Conclusion: The outer domain of gp120(CN54) is correctly folded following expression as a C terminal fusion protein. Immunogenicity is substantial when targeted to antigen presenting cells but shows V3 dominance in the polyvalent response. The gp120 outer domain has potential as a candidate vaccine component.

Burkholderia Hep_Hag autotransporter (BuHA) proteins elicit a strong antibody response during experimental glanders but not human melioidosis

BACKGROUND: The bacterial biothreat agents Burkholderia mallei and Burkholderia pseudomallei are the cause of glanders and melioidosis, respectively. Genomic and epidemiological studies have shown that B. mallei is a recently emerged, host restricted clone of B. pseudomallei. RESULTS: Using bacteriophage-mediated immunoscreening we identified genes expressed in vivo during experimental equine glanders infection. A family of immunodominant antigens were identified that share protein domain architectures with hemagglutinins and invasins. These have been designated Burkholderia Hep_Hag autotransporter (BuHA) proteins. A total of 110/207 positive clones (53%) of a B. mallei expression library screened with sera from two infected horses belonged to this family. This contrasted with 6/189 positive clones (3%) of a B. pseudomallei expression library screened with serum from 21 patients with culture-proven melioidosis. CONCLUSION: Members of the BuHA proteins are found in other Gram-negative bacteria and have been shown to have important roles related to virulence. Compared with other bacterial species, the genomes of both B. mallei and B. pseudomallei contain a relative abundance of this family of proteins. The domain structures of these proteins suggest that they function as multimeric surface proteins that modulate interactions of the cell with the host and environment. Their effect on the cellular immune response to B. mallei and their potential as diagnostics for glanders requires further study.

Malacosporean-like spores in urine of rainbow trout react with antibody and DNA probes to Tetracapsuloides bryosalmonae

Tetracapsuloides bryosalmonae is the myxozoan parasite causing proliferative kidney disease (PKD) of salmonid fishes in Europe and North America. The complete life cycle of the parasite remains unknown despite recent discoveries that the stages infectious for fish develop in freshwater bryozoans. During the course of examinations of the urine of rainbow trout (Oncorhynchus mykiss) with or recovering from PKD we identified spores with features similar to those of T. bryosalmonae found in the bryozoan host. Spores found in the urine were subspherical, with a width of 16 mum and height of 14 mum, and possessed two soft valves surrounding two spherical polar capsules (2 mum in diameter) and a single sporoplasm. The absence of hardened valves is a distinguishing characteristic of the newly established class Malacosporea that includes T. bryosalmonae as found in the bryozoan host. The parasite in the urine of rainbow trout possessed only two polar capsules and two valve cells compared to the four polar capsules and four valves observed in the spherical spores of 19 mum in diameter from T. bryosalmonae from the bryozoan host. Despite morphological differences, a relationship between the spores in the urine of rainbow trout and T. bryosalmonae was demonstrated by binding of monoclonal and polyclonal antibodies and DNA probes specific to T. bryosalmonae.

Specificity grafting of human antibody frameworks selected from a phage display library: generation of a highly stable humanized anti-CD22 single-chain Fv fragment

A prerequisite for the enrichment of antibodies screened from phage display libraries is their stable expression on a phage during multiple selection rounds. Thus, if stringent panning procedures are employed, selection is simultaneously driven by antigen affinity, stability and solubility. To take advantage of robust pre-selected scaffolds of such molecules, we grafted single-chain Fv (scFv) antibodies, previously isolated from a human phage display library after multiple rounds of in vitro panning on tumor cells, with the specificity of the clinically established murine monoclonal anti-CD22 antibody RFB4. We show that a panel of grafted scFvs retained the specificity of the murine monoclonal antibody, bound to the target antigen with high affinity (6.4-9.6 nM), and exhibited exceptional biophysical stability with retention of 89-93% of the initial binding activity after 6 days of incubation in human serum at 37degreesC. Selection of stable human scaffolds with high sequence identity to both the human germline and the rodent frameworks required only a small number of murine residues to be retained within the human frameworks in order to maintain the structural integrity of the antigen binding site. We expect this approach may be applicable for the rapid generation of highly stable humanized antibodies with low immunogenic potential.

Effect of PEG crystallization on the self-assembly of PEG/peptide copolymers containing amyloid peptide fragments

The effect of poly(ethylene glycol) PEG crystallization on P-sheet fibril formation is studied for a series of three peptide/PEG conjugates containing fragments modified from the amyloid P peptide, specifically KLVFF, FFKLVFF, and AAKLVFF. These are conjugated to PEG with M-n = 3300 g mol(-1). It is found, via small-angle X-ray scattering,X-ray diffraction, atomic force microscopy, and polarized optical microscopy, that PEG crystallinity in dried samples can disturb fibrillization, in particular cross-P amyloid structure formation, for the conjugate containing the weak fibrillizer KLVFF, whereas this is retained for the conjugates containing the stronger fibrillizers AAKLVFF and FFKLVFF. For these two samples, the alignment of peptide fibrils also drives the orientation of the attached PEG chains. Our results highlight the importance of the antagonistic effects of PEG crystallization and peptide fibril formation in PEG/peptide conjugates.

The effect of PEG crystallization on the morphology of PEG/peptide block copolymers containing amyloid beta-peptide fragments

Ordered nanostructures are observed in the melt and solid state for a series of three peptide/PEG conjugates containing fragments of amyloid beta-peptides. These are conjugated to PEG with (M) over bar (n) = 3 300 g.mol(-1) and a melting temperature T-m = 45-50 degrees C. The morphology at room temperature is examined by AFM and POM. This shows spherulite formation for the weakly fibrillizing KLVFF-PEG sample but fibril formation for FFKLVFF-PEG. The fibrillization tendency of the latter is enhanced by multiple phenylalanine residues. Simultaneous SAXS and WAXS was used to investigate the morphology as a function of temperature. The secondary structure is probed by FTIR.

The "freedom to frame questions... worth asking" or three stories and three (other) fragments of research

In our state of centralised control of the curriculum and high-stakes testing an examination subject's assessment objectives have become high profile. Some of the anomalous effects of this profile are shown in the teaching, question-setting, and marking of English literature. Glimpses of earlier times are revealed, all three secondary school key stages are considered, examination performances are discussed, and the views of beginning teachers about teaching to the test are sought.

Measles vaccination and antibody response in autism spectrum disorders

Objective: To test the hypothesis that measles vaccination was involved in the pathogenesis of autism spectrum disorders (ASD) as evidenced by signs of a persistent measles infection or abnormally persistent immune response shown by circulating measles virus or raised antibody titres in children with ASD who had been vaccinated against measles, mumps and rubella (MMR) compared with controls. Design: Case-control study, community based. Methods: A community sample of vaccinated children aged 10-12 years in the UK with ASD (n = 98) and two control groups of similar age, one with special educational needs but no ASD (n = 52) and one typically developing group (n = 90), were tested for measles virus and antibody response to measles in the serum. Results: No difference was found between cases and controls for measles antibody response. There was no dose-response relationship between autism symptoms and antibody concentrations. Measles virus nucleic acid was amplified by reverse transcriptase-PCR in peripheral blood mononuclear cells from one patient with autism and two typically developing children. There was no evidence of a differential response to measles virus or the measles component of the MMR in children with ASD, with or without regression, and controls who had either one or two doses of MMR. Only one child from the control group had clinical symptoms of possible enterocolitis. Conclusion: No association between measles vaccination and ASD was shown.