Toxicoproteomics and its application to human health risk assessment

Toxicoproteomics is the use of proteomic technologies to better understand environmental and genetic factors, toxic mechanisms, and modes of action in response to acute exposure to toxicants and in the long-term development of diseases caused or influenced by these exposures. Use of toxicoproteomic technologies to identify key biochemical pathways, mechanisms, and biomarkers of exposure and toxicity will decrease the uncertainties that are associated with human health risk assessments. This review provides an overview of toxicoproteomics from human health risk assessment perspectives. Key toxicoproteomic technologies such as 2-D gel-based proteomic methods and toxicoproteomic approaches are described, and examples of applications of these technologies and methodologies in the risk assessment context are presented. The discussion includes a focus on challenges and future directions.     

Learning and retention of associations between auditory icons and denotative referents: implications for the design of auditory warnings

OBJECTIVE: This study examined the way in which the type and preexisting strength of association between an auditory icon and a warning event affects the ease with which the icon/event pairing can be learned and retained. BACKGROUND: To be effective, an auditory warning must be audible, identifiable, interpretable, and heeded. Warnings consisting of familiar environmental sounds, or auditory icons, have potential to facilitate identification and interpretation. The ease with which pairings between auditory icons and warning events can be learned and retained is likely to depend on the type and strength of the preexisting icon/event association. METHOD: Sixty-three participants each learned eight auditory-icon/denotative-referent pairings and attempted to recall them 4 weeks later. Three icon/denotative-referent association types (direct, related, and unrelated) were employed. Participants rated the strength of the association for each pairing on a 7-point scale. RESULTS: The number of errors made while learning pairings was greater for unrelated than for either related or direct associations, whereas the number of errors made while attempting to recall pairings 4 weeks later was greater for unrelated than for related associations and for related than for direct associations. Irrespective of association type, both learning and retention performance remained at very high levels, provided the strength of the association was rated greater than 5. CONCLUSION: This suggests that strong preexisting associations are used to facilitate learning and retention of icon/denotative-referent pairings. APPLICATION: The practical implication of this study is that auditory icons having either direct or strong, indirect associations with warning events should be preferred.     

Predicting function from structure: examples of the serine protease inhibitor canonical loop conformation found in extracellular proteins.

The prediction of protein function from structure is becoming of growing importance in the age of structural genomics. We have focused on the problem of identifying sites of potential serine protease inhibitor interactions on the surface of proteins of known structure. Given that there is no sequence conservation within canonical loops from different inhibitor families we first compare representative loops to all fragments of equal length among proteins of known structure by calculating main-chain RMS deviation. Fragments with RMS deviation below a certain threshold (hits) are removed if residues have solvent accessibilities appreciably lower than those observed in the search structure. These remaining hits are further filtered to remove those occurring largely within secondary structure elements. Likely functional significance is restricted further by considering only extracellular protein domains. Also a test is performed to see if the loop can dock into the binding site of the serine protease trypsin without unacceptable steric clashes. By comparing different canonical loop structures to the protein structure database we show that the method was able to detect previously known inhibitors. In addition, we discuss potentially new canonical loop structures found in secreted hydrolases, toxins, viral proteins, cytokines and other proteins. We discuss the possible functional significance of several of the examples found.     

Managing acute care

In the last few years, much medical-facility construction has been driven by what insurers want. Hospitals have built facilities for well-reimbursed procedures and closed money-losing ones. Health-maintenance organizations increasingly expect to hold down costs by making prepayment arrangements with doctors and their hospitals. President Clinton has pledged early action on health-care reform, which will likely change planners' priorities. Whether the nation goes to Clintonian "managed competition" or a Canadian-style nationwide single-payer system (the two most likely options), the projects on these pages reflect two large-scale trends that are likely to continue: the movement of more procedures from inpatient to outpatient facilities and the separation of treatment functions from ordinary office and administrative tasks so that the latter are not performed in the same high-cost buildings as technology-intensive procedures. Various schemes that make care more "patient-centered" have been tried and been shown to speed healing, even for outpatients, but such hard-to-quantify issues get short shrift in an era of knee-jerk cost containment. The challenge in tomorrow's healthcare universe--whatever it becomes--will be to keep these issues on the table.     

Detection of serum antibodies to Chlamydia trachomatis in patients with chlamydial and nonchlamydial pelvic inflammatory disease by the IPAzyme Chlamydia and enzyme immunoassay

A novel serological test, IPAzyme Chlamydia (Savyon Diagnostics Ltd., Beer Sheva, Israel), was compared with an enzyme immunoassay (EIA) for the ability to detect serum immunoglobulin G and A antibodies in the diagnosis of acute chlamydial pelvic inflammatory disease. In comparison with cell culture, which is the "gold standard," IPAzyme Chlamydia and EIA exhibited sensitivities of 63 and 68% and specificities of 76 and 87%, respectively. Thus, IPAzyme Chlamydia offers no advantages over the EIA, and neither serological test can be recommended for the diagnosis of acute Chlamydia trachomatis infection. So far, conventional cell culture remains the most reliable diagnostic test for chlamydial pelvic inflammatory disease.     

Early assessment of diaphragmatic dysfunction in children in the ITU: chest radiology and phrenic nerve stimulation

Diaphragmatic dysfunction is a common postoperative complication of cardiac surgery in children, with important effects on respiratory morbidity. Its early diagnosis, followed by prompt surgical intervention, has been shown to reduce morbidity. However, the commonest method of diagnosis, based on hemi-diaphragmatic elevation on the chest radiograph, may be less accurate than direct techniques for assessing phrenic nerve function. We have compared electrophysiological and radiological diagnoses of diaphragmatic abnormality in 100 children (aged 3 days to 17.5 yrs) undergoing cardiac surgery, looking at respiratory morbidity as assessed by the duration of ventilation, the time spent on the cardiac intensive care unit (CICU), and the requirement for reintubation. Despite showing good reproducibility, radiological diagnosis was neither sensitive nor specific in identifying patients with electrophysiological phrenic nerve damage. Analysis of the measures of outcome supported the electrophysiological technique. Patients with electrophysiological evidence of damage had a longer duration of ventilation, spent longer on the CICU, and had a greater incidence of reintubation than either radiologically abnormal or "normal" patients. Chest X-rays are not a good method for diagnosing phrenic nerve damage in the early postoperative period in children. If early diagnosis is needed, then direct assessment of phrenic nerve function, such as the measurement of phrenic latency, may be a better technique.     

Avoidance of bird repellents by mice (Mus musculus)

It is believed that mammalian chemosensory irritants are not aversive to birds and vice versa. Nevertheless, few avian repellents have been tested against mammals. For that reason, we evaluated the efficacy of 1.0% w/v methyl anthranilate, orthoaminoacetophenone, 2-amino-4,5-methoxyacetophenone, 2-methoxyacetophenone, and veratryl amine as mouse repellents in 3-hr no-choice drinking tests. Relative to ingestion of plain water, all test substances significantly reduced (P < 0.05) intake. Orthoaminoaceto-phenone was the most effective repellent, with intake reduced to levels statistically indistinguishable from zero.     

Exponential lower bounds for the pigeonhole principle

In this paper we prove an exponential lower bound on the size of bounded-depth Frege proofs for the pigeonhole principle (PHP). We also obtain an (loglogn)-depth lower bound for any polynomial-sized Frege proof of the pigeonhole principle. Our theorem nearly completes the search for the exact complexity of the PHP, as S. Buss has constructed polynomial-size, logn-depth Frege proofs for the PHP. The main lemma in our proof can be viewed as a general Håstad-style Switching Lemma for restrictions that are partial matchings. Our lower bounds for the pigeonhole principle improve on previous superpolynomial lower bounds.     

EuLisp in education

We present our experience withEuLisp as a teaching language, focussing on the level of the language which was specifically designed for this purpose (level-0).EuLisp has been used in undergraduate and postgraduate teaching since 1990, in lectures and laboratories, where in many cases it has replaced Scheme or Common Lisp. It has been used extensively in programming courses, parallelism courses, as a vehicle for advanced courses in symbolic computing and programming language design; it has also been used as a platform for final year undergraduate projects. This experience has demonstrated thatEuLisp is well suited to teaching and far reaching in its capabilities: it supports the relevant concepts in a consistent and versatile framework, so that the language serves to facilitate the educational process. The discussion is illustrated with examples, and where appropriate we draw a comparison with the Lisp dialects used previously in these courses.     

Ferrimagnetic resonance and low temperature transition in Ni- and Co-substituted powder magnetite

The effects of nickel and cobalt substitution on ferrimagnetic resonance in high-purity magnetite powder have been investigated. The low-temperature transition temperature and damping parameter, , are found to decrease with increasing solute additions. The linewidth, H, varies in proportion to the anisotropy field of the ferrites, narrowing with increasing nickel content but broadening with increasing cobalt content. Theg factor increases with the dopant concentration, passing through a maximum around room temperature. Decreasing the deviation from stoichiometry by appropriate annealing decreases the transition temperature shift but slightly increases H, g and .