Combining intracellular selection with protein-fragment complementation to derive A interacting peptides

Aggregation of the β-amyloid (Aβ) peptide into toxic oligomers is considered the primary event in the pathogenesis of Alzheimer's disease. Previously generated peptides and mimetics designed to bind to amyloid fibrils have encountered problems in solubility, protease susceptibility and the population of small soluble toxic oligomers oligomers. We present a new method that opens the possibility of deriving new amyloid inhibitors. The intracellular protein-fragment complementation assay (PCA) approach uses a semi-rational design approach to generate peptides capable of binding to Aβ. Peptide libraries are based on Aβ regions responsible for instigating amyloidosis, with screening and selection occurring entirely inside Escherichia coli. Successfully selected peptides must therefore bind Aβ and recombine an essential enzyme while permitting bacterial cell survival. No assumptions are made regarding the mechanism of action for selected binders. Biophysical characterisation demonstrates that binding induces a noticeable reduction in amyloid. Therefore, this amyloid-PCA approach may offer a new pathway for the design of effective inhibitors against the formation of amyloid in general

Uncovering protein interaction in abstracts and text using a novel linear model and word proximity networks

We participated in three of the protein-protein interaction subtasks of the Second BioCreative Challenge: classification of abstracts relevant for protein-protein interaction (IAS), discovery of protein pairs (IPS) and text passages characterizing protein interaction (ISS) in full text documents. We approached the abstract classification task with a novel, lightweight linear model inspired by spam-detection techniques, as well as an uncertainty-based integration scheme. We also used a Support Vector Machine and the Singular Value Decomposition on the same features for comparison purposes. Our approach to the full text subtasks (protein pair and passage identification) includes a feature expansion method based on word-proximity networks. Our approach to the abstract classification task (IAS) was among the top submissions for this task in terms of the measures of performance used in the challenge evaluation (accuracy, F-score and AUC). We also report on a web-tool we produced using our approach: the Protein Interaction Abstract Relevance Evaluator (PIARE). Our approach to the full text tasks resulted in one of the highest recall rates as well as mean reciprocal rank of correct passages. Our approach to abstract classification shows that a simple linear model, using relatively few features, is capable of generalizing and uncovering the conceptual nature of protein-protein interaction from the bibliome. Since the novel approach is based on a very lightweight linear model, it can be easily ported and applied to similar problems. In full text problems, the expansion of word features with word-proximity networks is shown to be useful, though the need for some improvements is discussed

Accurate user directed summarization from existing tools

This paper describes a set of experimental results produced from the TIPSTER SUMMAC initiative on user directed summaries: document summaries generated in the context of an information need expressed as a query. The summarizer that was evaluated was based on a set of existing statistical techniques that had been applied successfully to the INQUERY retrieval system. The techniques proved to have a wider utility, however, as the summarizer was one of the better performing systems in the SUMMAC evaluation. The design of this summarizer is presented with a range of evaluations: both those provided by SUMMAC as well as a set of preliminary, more informal, evaluations that examined additional aspects of the summaries. Amongst other conclusions, the results reveal that users can judge the relevance of documents from their summary almost as accurately as if they had had access to the document’s full text

A 2-pyridone-amide inhibitor targets the glucose metabolism pathway of Chlamydia trachomatis.

UnlabelledIn a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection.ImportanceChlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections

Pre-passage questions: the influence of structural importance

Bibliography: leaves 23-26Supported in part by the National Institute of Education under contract no. 400-76-011

Altered drug susceptibility during host adaptation of a <i>Plasmodium falciparum</i> strain in a non-human primate model

Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model

Atomic trajectory characterization in a fountain clock based on the spectrum of a hyperfine transition

We describe a new method to determine the position of the atomic cloud during its interaction with the microwave field in the cavity of a fountain clock. The positional information is extracted from the spectrum of the F=3,mF=0 to F=4,mF=-1 hyperfine transition, which shows a position dependent asymmetry when the magnetic C-field is tilted by a few degrees with respect to the cavity axis. Analysis of this spectral asymmetry provides the horizontal center-of-mass position for the ensemble of atoms contributing to frequency measurements. With an uncertainty on the order of 0.1 mm, the obtained information is useful for putting limits on the systematic uncertainty due to distributed cavity phase gradients. The validity of the new method is demonstrated through experimental evidence.Comment: 6 figures, submitted to PR

Benefits of Computer Based Content Analysis to Foresight

Purpose of the article: The present manuscript summarizes benefits of the use of computer-based content analysis in a generation phase of foresight initiatives. Possible advantages, disadvantages and limitations of the content analysis for the foresight projects are discussed as well. Methodology/methods: In order to specify the benefits and identify the limitations of the content analysis within the foresight, results of the generation phase of a particular foresight project performed without and subsequently with the use of computer based content analysis tool were compared by two proposed measurements. Scientific aim: The generation phase of the foresight is the most demanding part in terms of analysis duration, costs and resources due to a significant amount of reviewed text. In addition, the conclusions of the foresight evaluation are dependent on personal views and perceptions of the foresight analysts as the evaluation is based merely on reading. The content analysis may partially or even fully replace the reading and provide an important benchmark. Findings: The use of computer based content analysis tool significantly reduced time to conduct the foresight generation phase. The content analysis tool showed very similar results as compared to the evaluation performed by the standard reading. Only ten % of results were not revealed by the use of content analysis tool. On the other hand, several new topics were identified by means of content analysis tool that were missed by the reading. Conclusions: The results of two measurements should be subjected to further testing within more foresight projects to validate them. The computer based content analysis tool provides valuable benchmark to the foresight analysts and partially substitute the reading. However, a complete replacement of the reading is not recommended, as deep understanding to weak signals interpretation is essential for the foresight