Gene replacement with the human BRCA1 locus: tissue specific expression and rescue of embryonic lethality in mice

We have generated transgenic mice that harbor a 140 kb genomic fragment of the human BRCA1 locus (TgN.BRCA1(GEN)). We find that the transgene directs appropriate expression of human BRCA1 transcripts in multiple mouse tissues, and that human BRCA1 protein is expressed and stabilized following exposure to DIVA damage, Such mice are completely normal, with no overt signs of BRCA1 toxicity commonly observed when BRCA1 is expressed from heterologous promoters. Most importantly, however, the transgene rescues the otherwise lethal phenotype associated with the targeted hypomorphic allele (Brca1(Delta exIISA)). Brca1(-/-); TgN.BRCA1(GEN) bigenic animals develop normally and can be maintained as a distinct line. These results show that a 140 kb fragment of chromosome 17 contains all elements necessary for the correct expression, localization, and function of the BRCA1 protein, Further, the model provides evidence that function and regulation of the human BRCA1 gene can be studied and manipulated in a genetically tractable mammalian system.

Document retrieval for e-mail search and discovery using Formal Concept Analysis

This paper discusses a document discovery tool based on Conceptual Clustering by Formal Concept Analysis. The program allows users to navigate e-mail using a visual lattice metaphor rather than a tree. It implements a virtual. le structure over e-mail where files and entire directories can appear in multiple positions. The content and shape of the lattice formed by the conceptual ontology can assist in e-mail discovery. The system described provides more flexibility in retrieving stored e-mails than what is normally available in e-mail clients. The paper discusses how conceptual ontologies can leverage traditional document retrieval systems and aid knowledge discovery in document collections.

Breadth-first search and the Andrews-Curtis conjecture

Andrews and Curtis conjectured in 1965 that every balanced presentation of the trivial group can be transformed into a standard presentation by a finite sequence of elementary transformations. Recent computational work by Miasnikov and Myasnikov on this problem has been based on genetic algorithms. We show that a computational attack based on a breadth-first search of the tree of equivalent presentations is also viable, and seems to outperform that based on genetic algorithms. It allows us to extract shorter proofs (in some cases, provably shortest) and to consider the length thirteen case for two generators. We prove that, up to equivalence, there is a unique minimum potential counterexample.

Structured ontology and information retrieval for email search and discovery

This paper discusses an document discovery tool based on formal concept analysis. The program allows users to navigate email using a visual lattice metaphor rather than a tree. It implements a virtual file structure over email where files and entire directories can appear in multiple positions. The content and shape of the lattice formed by the conceptual ontology can assist in email discovery. The system described provides more flexibility in retrieving stored emails than what is normally available in email clients. The paper discusses how conceptual ontologies can leverage traditional document retrieval systems.

El Nino and arboviral disease prediction

Recent El Nino events have stimulated interest in the development of modeling techniques to forecast extremes of climate and related health events. Previous studies have documented associations between specific climate variables (particularly temperature and rainfall) and outbreaks of arboviral disease. In some countries, such diseases are sensitive to Fl Nino. Here we describe a climate-based model for the prediction of Ross River virus epidemics in Australia. From a literature search and data on case notifications, we determined in which years there were epidemics of Ross River virus in southern Australia between 1928 and 1998. Predictor variables were monthly Southern Oscillation index values for the year of an epidemic or lagged by 1 year. We found that in southeastern states, epidemic years were well predicted by monthly Southern Oscillation index values in January and September in the previous year. The model forecasts that there is a high probability of epidemic Ross River virus in the southern states of Australia in 1999. We conclude that epidemics of arboviral disease can, at least in principle, be predicted on the basis of climate relationships.

Reciprocal changes in forebrain contents of glycogen and of glutamate/glutamine during early memory consolidation in the day-old chick

Passive avoidance learning is with advantage studied in day-old chicks trained to distinguish between beads of two different colors, of which one at training was associated with aversive taste. During the first 30-min post-training, two periods of glutamate release occur in the forebrain. One period is immediately after the aversive experience, when glutamate release is confined to the left hemisphere. A second release, 30 min later, may be bilateral, perhaps with preponderance of the right hemisphere. The present study showed increased pool sizes of glutamate and glutamine, specifically in the left hemisphere, at the time when the first glutamate release occurs, indicating de novo synthesis of glutamate/glutamine from glucose or glycogen, which are the only possible substrates. Behavioral evidence that memory is extinguished by intracranial administration at this time of iodoacetate, an inhibitor of glycolysis and glycogenolysis, and that the extinction of memory is counteracted by injection of glutamine, supports this concept. A decrease in forebrain glycogen of similar magnitude and coinciding with the increase in glutamate and glutamine suggests that glycogen rather than glucose is the main source of newly synthesized glutamate/glutamine. The second activation of glutamatergic activity 30 min after training, when memory is consolidated into stable, long-term memory, is associated with a bilateral increase in pool size of glutamate/glutamine. No glycogenolysis was observed at this time, but again there is a temporal correlation with sensitivity to inhibition by iodoacetate and rescue by glutamine, indicating the importance of de novo synthesis of glutamate/glutamine from glucose or glycogen. (C) 2003 Elsevier B.V All rights reserved.

The chemistry and biology of human relaxin-3

A novel member of the human relaxin subclass of the insulin superfamily was recently discovered during a genomics database search and named relaxin-3. Like human relaxin-1 and relaxin-2, relaxin-3 is predicted to consist of a two-chain structure and three disulfide bonds in a disposition identical to that of insulin. To undertake detailed biophysical and biological characterization of the peptide, its chemical synthesis was undertaken. In contrast to human relaxin-1 and relaxin-2, however, relaxin-3 could not be successfully prepared by simple combination of the individual chains, thus necessitating recourse to the use of a regioselective disulfide bond formation strategy. Solid phase synthesis of the separate, selectively S-protected A and B chains followed by their purification and the subsequent stepwise formation of each of the three disulfides led to the successful acquisition of human relaxin-3. Comprehensive chemical characterization confirmed both the correct chain orientation and the integrity of the synthetic product. Relaxin-3 was found to bind to and activate native relaxin receptors in vitro and stimulate water drinking through central relaxin receptors in vivo. Recent studies have demonstrated that relaxin-3 will bind to and activate human LGR7, but not LGR8, in vitro. Secondary structural analysis showed it to adopt a less ordered confirmation than either relaxin-1 or relaxin-2, reflecting the presence in the former of a greater percentage of nonhelical forming amino acids. NMR spectroscopy and simulated annealing calculations were used to determine the three-dimensional structure of relaxin-3 and to identify key structural differences between the human relaxins.

Tourists and beach safety in Queensland, Australia

Surf Life Saving Queensland (SLSQ) is a leading authority on beach safety, providing patrol, education, and rescue services to both tourists and local residents along the coast of Queensland, Australia. SLSQ recognizes that tourists are a target group requiring special attention due to their unfamiliarity with ocean beaches and surfing activities, and in some cases having the additional challenge of poor swimming skills, language barriers, and disorientation in a foreign vacation environment. This article describes SLSQ initiatives to provide beach safety for tourists through a focus on service delivery and partnerships with the tourism industry and relevant government agencies. The positive involvement of SLSQ in tourism is a model for other coastal destinations, given that drowning is the second most frequent cause of injury death among international travelers.

Acquisition of negative valence and modified attentional processing by non fear relevant stimuli

The current research examined valence and attentional processing of a priori fear relevant stimuli and investigated the extent to which these characteristics can be acquired by non fear relevant stimuli across an aversive learning episode. The first experiment compared pictures of snakes and spiders with pictures of birds and fish using affective priming, visual search and detection of a dot probe. Snakes and spiders were more negative than birds and fish as indexed by affective priming, and were preferentially attended to in the visual search task. The second experiment exposed the non fear relevant animal pictures, birds and fish, in an aversive learning episode involving an aversive shock US. Skin conductance responding was measured during acquisition. After acquisition, conditioned non fear relevant animal stimuli, CS1, and non conditioned, non fear relevant animal stimuli, CS, were compared across affective priming, visual search and dot probe tasks. During acquisition, skin conductance responses were larger during CS1 than during CS across all three response intervals. After acquisition, CS1 non fear relevant animal pictures were more negative than CS non fear relevant animal pictures as indexed by affective priming, and were preferentially attended to in a dot probe task. These studies provide evidence that negative valence and modified attentional processing can be acquired in a brief aversive learning episode.

Hierarchical indexing structure for efficient similarity search in video retrieval

With the rapid increase in both centralized video archives and distributed WWW video resources, content-based video retrieval is gaining its importance. To support such applications efficiently, content-based video indexing must be addressed. Typically, each video is represented by a sequence of frames. Due to the high dimensionality of frame representation and the large number of frames, video indexing introduces an additional degree of complexity. In this paper, we address the problem of content-based video indexing and propose an efficient solution, called the Ordered VA-File (OVA-File) based on the VA-file. OVA-File is a hierarchical structure and has two novel features: 1) partitioning the whole file into slices such that only a small number of slices are accessed and checked during k Nearest Neighbor (kNN) search and 2) efficient handling of insertions of new vectors into the OVA-File, such that the average distance between the new vectors and those approximations near that position is minimized. To facilitate a search, we present an efficient approximate kNN algorithm named Ordered VA-LOW (OVA-LOW) based on the proposed OVA-File. OVA-LOW first chooses possible OVA-Slices by ranking the distances between their corresponding centers and the query vector, and then visits all approximations in the selected OVA-Slices to work out approximate kNN. The number of possible OVA-Slices is controlled by a user-defined parameter delta. By adjusting delta, OVA-LOW provides a trade-off between the query cost and the result quality. Query by video clip consisting of multiple frames is also discussed. Extensive experimental studies using real video data sets were conducted and the results showed that our methods can yield a significant speed-up over an existing VA-file-based method and iDistance with high query result quality. Furthermore, by incorporating temporal correlation of video content, our methods achieved much more efficient performance.

Engineered T cell receptors and their potential in molecular medicine

T cell receptors are among the most specific biological structures found in nature and are therefore excellent candidates for the molecular targeting of antigen. It is becoming increasingly apparent that common sets of T cell receptors are frequently used in humans to combat pathogen and cancer derived threats. Given that many of these conserved T cell receptors have high affinity for their target ligands, there is potential to amass virtual banks of “off-the-shelf” receptors for use in a wide range of immunotherapeutic strategies. Additionally, such T cell receptors could become basic blueprints for artificial enhancement through mutagenesis, thereby creating an even better 3-dimensional fit for their cognate targets. Indeed, preliminary approaches using both “natural” and “supernatural” T cell receptors have shown promise in treating autoimmunity and malignancy. This review will discuss these studies and other approaches through which T cell receptors can be exploited in immunodiagnostics, pathogen control and gene therapy.

Consumer search of the web: An exploratory analysis of antecedents of web search satisfaction

This article explores consumer Web-search satisfaction. It commences with a brief overview of the concepts consumer information search and consumer satisfaction. Consumer Web adoption issues are then briefly discussed and the importance of consumer search satisfaction is highlighted in relation to the adoption of the Web as an additional source of consumer information. Research hypotheses are developed and the methodology of a large scale consumer experiment to record consumer Web search behaviour is described. The hypotheses are tested and the data explored in relation to post-Web-search satisfaction. The results suggest that consumer post-Web-search satisfaction judgments may be derived from subconscious judgments of Web search efficiency, an empirical calculation of which is problematic in unlimited information environments such as the Web. The results are discussed and a future research agenda is briefly outlined.

A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22)

Familial hyperaldosteronism type II (FH-II) is caused by adrenocortical hyperplasia or aldosteronoma or both and is frequently transmitted in an autosomal dominant fashion. Unlike FH type I (FI-I-I), which results from fusion of the CYP11B1 and CYP11B2 genes, hyperaldosteronism in FH-II is not glucocorticoid remediable. A large family with FH-II was used for a genome wide search and its members were evaluated by measuring the aldosterone:renin ratio. In those with an increased ratio, FH-II was confirmed by fludrocortisone suppression testing. After excluding most of the genome, genetic linkage was identified with a maximum two point lod score of 3.26 at theta =0, between FH-II in this family and the polymorphic markers D7S511, D7S517, and GATA24F03 on chromosome 7,a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II; its molecular elucidation may provide further insight into the aetiology of primary aldosteronism.

Ways of using evidence-based medicine in general practice

General practitioners wanting to practise evidence-based medicine (EBM) are constrained by time factors and the great diversity of clinical problems they deal with. They need experience in knowing what questions to ask, in locating and evaluating the evidence, and in applying it. Conventional searching for the best evidence can be achieved in daily general practice. Sometimes the search can be performed during the consultation, but more often it can be done later and the patient can return for the result. Case-based journal clubs provide a supportive environment for GPs to work together to find the best evidence at regular meetings. An evidence-based literature search service is being piloted to enhance decision-making for individual patients. A central facility provides the search and interprets the evidence in relation to individual cases. A request form and a results format make the service akin to pathology testing or imaging. Using EBM in general practice appears feasible. Major difficulties still exist before it can be practised by all GPs, but it has the potential to change the way doctors update their knowledge.