Showing papers by "University of Alberta published in 1998"

Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination

Abstract: A new software suite, called Crystallography & NMR System (CNS), has been developed for macromolecular structure determination by X-ray crystallography or solution nuclear magnetic resonance (NMR) spectroscopy. In contrast to existing structure-determination programs the architecture of CNS is highly flexible, allowing for extension to other structure-determination methods, such as electron microscopy and solid-state NMR spectroscopy. CNS has a hierarchical structure: a high-level hypertext markup language (HTML) user interface, task-oriented user input files, module files, a symbolic structure-determination language (CNS language), and low-level source code. Each layer is accessible to the user. The novice user may just use the HTML interface, while the more advanced user may use any of the other layers. The source code will be distributed, thus source-code modification is possible. The CNS language is sufficiently powerful and flexible that many new algorithms can be easily implemented in the CNS language without changes to the source code. The CNS language allows the user to perform operations on data structures, such as structure factors, electron-density maps, and atomic properties. The power of the CNS language has been demonstrated by the implementation of a comprehensive set of crystallographic procedures for phasing, density modification and refinement. User-friendly task-oriented input files are available for nearly all aspects of macromolecular structure determination by X-ray crystallography and solution NMR.

Stated Preference Approaches for Measuring Passive Use Values: Choice Experiments and Contingent Valuation

Abstract: The measurement of passive use values has become an important issue in environmental economics. In this paper we examine an extension or variant of contingent valuation, the choice experiment, which employs a series of questions with more than two alternatives that are designed to elicit responses that allow the estimation of preferences over attributes of an environmental state. We also combine the information from choice experiments and contingent valuation to test for differences in preferences and error variances arising from the two methods. Our results show that choice experiments have considerable merit in measuring passive use values.

Outcome measures for low back pain research. A proposal for standardized use.

Abstract: Study Design. An international group of back pain researchers considered recommendations for standardized measures in clinical outcomes research in patients with back pain. Objectives. To promote more standardization. Summary of outcome measurement in clinical trials and other types of outcomes research, including meta-analyses, cost-effectiveness analyses, and multicenter studies. Summary of Background Data. Better standardization of outcome measurement would facilitate comparison of results among studies, and more complete reporting of relevant outcomes. Because back pain is rarely fatal or completely cured, outcome assessment is complex and involves multiple dimensions. These include symptoms, function, general well-being, work disability, and satisfaction with care. Methods. The panel considered several factors in recommending a standard battery of outcome measures. These included reliability, validity, responsiveness, and practicality of the measures. In addition, compatibility with widely used and promoted batteries such as the American Academy of Orthopaedic Surgeons Lumbar Cluster were considered to minimize the need for changes when these instruments are used. Results. First, a six-item set was proposed, which is sufficiently brief that it could be used in routine care settings for quality improvement and for research purposes. An expanded outcome set, which would provide more precise measurement for research purposes, includes measures of severity and frequency of symptoms, either the Roland or the Oswestry Disability Scale, either the SF-12 or the EuroQol measure of general health status, a question about satisfaction with symptoms, three types of disability days, and an optional single item on overall satisfaction with medical care. Conclusion. Standardized measurement of outcomes would facilitate scientific advances in clinical care. A short, 6-item questionnaire and a somewhat expanded, more precise battery of questionnaires can be recommended. Although many considerations support such recommendations, more data on responsiveness and the minimally important change in scores are needed for most of the instruments.

The eyes have it! Reflexive orienting is triggered by nonpredictive gaze

Abstract: Normal subjects were presented with a simple line drawing of a face looking left, right, or straight ahead. A target letter F or T then appeared to the left or the right of the face. All subjects participated in target detection, localization, and identification response conditions. Although subjects were told that the line drawing’s gaze direction (the cue) did not predict where the target would occur, response time in all three conditions was reliably faster when gaze was toward versus away from the target. This study provides evidence for covert, reflexive orienting to peripheral locations in response to uninformative gaze shifts presented at fixation. The implications for theories of social attention and visual orienting are discussed, and the brain mechanisms that may underlie this phenomenon are considered.

Using choice experiments to value the environment

Abstract: This paper we outline the “choice experiment” approach to environmental valuation. This approach has its roots in Lancaster's characteristics theory of value, in random utility theory and in experimental design. We show how marginal values for the attributes of environmental assets, such as forests and rivers, can be estimated from pair-wise choices, as well as the value of the environmental asset as a whole. These choice pairs are designed so as to allow efficient statistical estimation of the underlying utility function, and to minimise required sample size. Choice experiments have important advantages over other environmental valuation methods, such as contingent valuation and travel cost-type models, although many design issues remain unresolved. Applications to environmental issues have so far been relatively limited. We illustrate the use of choice experiments with reference to a recent UK study on public preferences for alternative forest landscapes. This study allows us to perform a convergent validity test on the choice experiment estimates of willingness to pay.

An introduction to fuzzy sets : analysis and design

Abstract: Part 1 Fundamentals of fuzzy sets: basic notions and concepts of fuzzy sets - set membership and fuzzy sets, basic definitions of a fuzzy set, types of membership functions, characteristics of a fuzzy set, basic relationships between fuzzy sets - equality and inclusion, fuzzy sets and sets - the representation theorem, the extension principles, membership function determination, generalizations of fuzzy sets, chapter summary, problems, references fuzzy set operations - set theory operations and their properties, triangular norms, aggregation operations on fuzzy sets, sensitivity of fuzzy sets operators, negations, comparison operations on fuzzy sets, chapter summary, problems, references information-based characterization of fuzzy sets -entropy measures of fuzziness, energy measures of fuzziness, specificity of a fuzzy set, frames of cognition, information encoding and decoding using linguistic landmarks, decoding mechanisms for pointwise data, decoding using membership functions of the linguistic terms of the codebook, general possibility-necessity decoding, distance between fuzzy sets based on their internal, linguistic representation, chapter summary, problems, references fuzzy relations and their calculus -relations and fuzzy relations, operations on fuzzy relations, compositions of fuzzy relations, projections and cylindric extensions of fuzzy relations, binary fuzzy relations, some classes of fuzzy relations, fuzzy-relational equations, estimation and inverse problem in fuzzy relational equations, solving fuzzy-relational equations with the sup-t composition, solutions to dual fuzzy-relational equations, adjoint fuzzy-relational equations, generaliations of fuzzy relational equations, approximate solutions to fuzzy-relational equations, chapter summary, problems, references fuzzy numbers - defining fuzzy numbers, interval analysis and fuzzy numbers, computing with fuzzy numbers, triangular fuzzy numbers and basic operations, general formulas for LR fuzzy numbers, accumulation of fuzziness in computing with fuzzy numbers, inverse problem in computation with fuzzy numbers, fuzzy numbers and approximate operations, chapter summary, problems, references fuzzy modelling - fuzzy models - beyond numerical computations, main phases of system modelling, fundamental design objectives in system modelling, general topology of fuzzy models, compatibility of encoding and decoding modules, classes of fuzzy models, verification and validation of fuzzy models, chapter summary, problems, references. Part 3 Problem solving with fuzzy sets: methodology -analysis and design, fuzzy controllers and fuzzy control, mathematical programming and fuzzy optimization, chapter summary, problems, references case studies - traffic intersection control, distributed traffic control, elevator group control, induction motor control, communication network planning, neurocomputation in fault diagnosis of dynamic systems, multicommodity transportation planning in railways.

Interleukin-2–Receptor Blockade with Daclizumab to Prevent Acute Rejection in Renal Transplantation

Abstract: Background Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen-reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the α chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation. Methods We administered daclizumab (1.0 mg per kilogram of body weight) or placebo intravenously before transplantation and once every other week afterward, for a total of five doses, to 260 patients receiving first cadaveric kidney grafts and immunosuppressive therapy with cyclosporine, azathioprine, and prednisone. The patients were followed at regular intervals for 12 months. The primary end point was the incidence of biopsy-confirmed acute rejection within six months after transplantation. Results Of the 126 patients given daclizumab, 28 (22 percent) had biopsy-confirmed episodes of acute rejection, as compared with 47 of the ...

Solute Diffusion within Hydrogels. Mechanisms and Models

Abstract: Solute diffusion in hydrogels is important in many biotechnology fields. Solute behavior in hydrogels has been explained in terms of reduction in hydrogel free volume, enhanced hydrodynamic drag on the solute, increased path length due to obstruction, and a combination of hydrodynamic drag and obstruction effects. In this article the various mathematical models derived to explain and predict solute diffusion in hydrogels are reviewed and tested against literature data. These models can be divided into those applicable to hydrogels composed of flexible polymer chains (i.e., homogeneous hydrogels) and those composed of rigid polymer chains (i.e., heterogeneous hydrogels). For homogeneous hydrogels it was determined that a scaling hydrodynamic model provided the best explanation for solute diffusion, while for heterogeneous hydrogels obstruction models were more consistent with the experimental data. Both the scaling hydrodynamic model and the most appropriate obstruction model contain undefined parameters w...

Geometric morphometrics of developmental instability: analyzing patterns of fluctuating asymmetry with procrustes methods

Abstract: Although fluctuating asymmetry has become popular as a measure of developmental instability, few studies have examined its developmental basis. We propose an approach to investigate the role of development for morphological asymmetry by means of morphometric methods. Our approach combines geometric morphometrics with the two-way ANOVA customary for conventional analyses of fluctuating asymmetry and can discover localized features of shape variation by examining the patterns of covariance among landmarks. This approach extends the notion of form used in studies of fluctuating asymmetry from collections of distances between morphological landmarks to an explicitly geometric concept of shape characterized by the configuration of landmarks. We demonstrate this approach with a study of asymmetry in the wings of tsetse flies (Glossina palpalis gambiensis). The analysis revealed significant fluctuating and directional asymmetry for shape as well as ample shape variation among individuals and between the offspring of young and old females. The morphological landmarks differed markedly in their degree of variability but multivariate patterns of landmark covariation identified by principal component analysis were generally similar between fluctuating asymmetry (within-individual variability) and variation among individuals. Therefore there is no evidence that special developmental processes control fluctuating asymmetry. We relate some of the morphometric patterns to processes known to be involved in the development of fly wings.

RasGRP, a Ras Guanyl Nucleotide- Releasing Protein with Calcium- and Diacylglycerol-Binding Motifs

Abstract: RasGRP, a guanyl nucleotide-releasing protein for the small guanosine triphosphatase Ras, was characterized. Besides the catalytic domain, RasGRP has an atypical pair of "EF hands" that bind calcium and a diacylglycerol (DAG)-binding domain. RasGRP activated Ras and caused transformation in fibroblasts. A DAG analog caused sustained activation of Ras-Erk signaling and changes in cell morphology. Signaling was associated with partitioning of RasGRP protein into the membrane fraction. Sustained ligand-induced signaling and membrane partitioning were absent when the DAG-binding domain was deleted. RasGRP is expressed in the nervous system, where it may couple changes in DAG and possibly calcium concentrations to Ras activation.

Buccal mucosa as a route for systemic drug delivery: a review.

Abstract: Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable. It is the objective of this article to review buccal drug delivery by discussing the structure and environment of the oral mucosa and the experimental methods used in assessing buccal drug permeation/absorption. Buccal dosage forms will also be reviewed with an emphasis on bioadhesive polymeric based delivery systems

A Comparison of Physical Therapy, Chiropractic Manipulation, and Provision of an Educational Booklet for the Treatment of Patients with Low Back Pain

Abstract: Background and Methods There are few data on the relative effectiveness and costs of treatments for low back pain. We randomly assigned 321 adults with low back pain that persisted for seven days after a primary care visit to the McKenzie method of physical therapy, chiropractic manipulation, or a minimal intervention (provision of an educational booklet). Patients with sciatica were excluded. Physical therapy or chiropractic manipulation was provided for one month (the number of visits was determined by the practitioner but was limited to a maximum of nine); patients were followed for a total of two years. The bothersomeness of symptoms was measured on an 11-point scale, and the level of dysfunction was measured on the 24-point Roland Disability Scale. Results After adjustment for base-line differences, the chiropractic group had less severe symptoms than the booklet group at four weeks (P=0.02), and there was a trend toward less severe symptoms in the physical-therapy group (P=0.06). However, these diff...

ZO-3, a Novel Member of the MAGUK Protein Family Found at the Tight Junction, Interacts with ZO-1 and Occludin

Abstract: A 130-kD protein that coimmunoprecipitates with the tight junction protein ZO-1 was bulk purified from Madin-Darby canine kidney (MDCK) cells and subjected to partial endopeptidase digestion and amino acid sequencing. A resulting 19–amino acid sequence provided the basis for screening canine cDNA libraries. Five overlapping clones contained a single open reading frame of 2,694 bp coding for a protein of 898 amino acids with a predicted molecular mass of 98,414 daltons. Sequence analysis showed that this protein contains three PSD-95/SAP90, discs-large, ZO-1 (PDZ) domains, a src homology (SH3) domain, and a region similar to guanylate kinase, making it homologous to ZO-1, ZO-2, the discs large tumor suppressor gene product of Drosophila , and other members of the MAGUK family of proteins. Like ZO-1 and ZO-2, the novel protein contains a COOH-terminal acidic domain and a basic region between the first and second PDZ domains. Unlike ZO-1 and ZO-2, this protein displays a proline-rich region between PDZ2 and PDZ3 and apparently contains no alternatively spliced domain. MDCK cells stably transfected with an epitope-tagged construct expressed the exogenous polypeptide at an apparent molecular mass of ∼130 kD. Moreover, this protein colocalized with ZO-1 at tight junctions by immunofluorescence and immunoelectron microscopy. In vitro affinity analyses demonstrated that recombinant 130-kD protein directly interacts with ZO-1 and the cytoplasmic domain of occludin, but not with ZO-2. We propose that this protein be named ZO-3.

Computational Intelligence: A Logical Approach

Abstract: Preface 1.1 What is Computational Intelligence? 1.2 Agents in the World 1.3 Representation and Reasoning 1.4 Applications 1.5 Overview 1.6 References and Further Reading 1.7 Exercises 2.1 Introduction 2.2 Representation and Reasoning Systems 2.3 Simplifying assumptions of the initial RRS 2.4 Datalog 2.5 Semantics 2.6 Questions and Answers 2.7 Proofs 2.8 Extending the Language with Functional Symbols 2.9 References and Further Reading 2.10 Exercises 3.1 Introduction 3.2 Case Study: House Wiring 3.3 Discussion 3.5 Case-Study: Repesenting Abstract Concepts 3.6 Applications in Natural Language Processing 3.7 References and Further Reading 3.8 Exercises 4.1 Why Search? 4.2 Graph Searching 4.3 A Generic Searching Algorithm 4.4 Blind Search Strategies 4.5 Heuristic Search 4.6 Refinements to Search Strategies 4.7 Constraint Satisfaction Problems 4.8 References and Further Reading 4.9 Exercises 5.1 Introduction 5.2 Defining a solution 5.3 Choosing a Representation Language 5.4 Mapping a problem to representation 5.5 Choosing an inference procedure 5.6 References and Further Reading 5.7 Exercises 6.1 Introduction 6.2 Knowledge-Based System Architecture 6.3 Meta-Interpreters 6.4 Querying the User 6.5 Explanation 6.6 Debugging Knowledge Bases 6.7 A Meta-Interpreter with Search 6.8 Unification 6.9 References and Further Reading 6.10 Exercises 7.1 Equality 7.2 Integrity Constraints 7.3 Complete Knowledge Assumption 7.4 Disjunctive Knowledge 7.5 Explicit Quantification 7.6 First-order predicate calculus 7.7 Modal Logic 7.8 References and Further Reading 7.9 Exercises 8.1 Introduction 8.2 Representations of Actions and Change 8.3 Reasoning with World Representations 8.4 References and Further Reading 8.5 Exercises 9.1 Introduction 9.2 An Assumption-Based Reasoning Framework 9.3 Default Reasoning 9.4 Abduction 9.5 Evidential and Causal Reasoning 9.6 Algorithms for Assumption-based Reasoning 9.7 References and Further Reading 9.8 Exercises 10.1 Introduction 10.2 Probability 10.3 Independence Assumptions 10.4 Making Decisions Under Uncertainty 10.5 References and Further Reading 10.6 Exercises 11.1 Introduction 11.2 Learning as choosing the best representation 11.3 Case-based reasoning 11.4 Learning as refining the hypothesis space 11.5 Learning Under Uncertainty 11.6 Explanation-based Learning 11.7 References and Further Reading 11.8 Exercises 12.1 Introduction 12.2 Robotic Systems 12.3 The Agent function 12.4 Designing Robots 12.5 Uses of Agent models 12.6 Robot Architectures 12.7 Implementing a Controller 12.8 Robots Modelling the World 12.9 Reasoning in Situated Robots 12.10 References and Further Reading 12.11 Exercises Appendices A Glossary B The Prolog Programming Language B.1 Introduction B.2 Interacting with Prolog B.3 Syntax B.5 Database Relations B.6 Returning All Answers B.7 Input and Output B.8 Controlling Search C.Some more Implemented Systems C.1 Bottom-Up Interpreters C.2 Top-down Interpreters C.3 A Constraint Satisfaction Problem Solver C.4 Neural Network Learner C.5 Partial-Order Planner C.6 Implementing Belief Networks C.7 Robot Controller

Cycle-oriented distributed preconfiguration: ring-like speed with mesh-like capacity for self-planning network restoration

Abstract: Cycle-oriented preconfiguration of spare capacity is a new idea for the design and operation of mesh-restorable networks. It offers a sought-after goal: to retain the capacity-efficiency of a mesh-restorable network, while approaching the speed of line-switched self-healing rings. We show that through a strategy of pre-failure cross-connection between the spare links of a mesh network, it is possible to achieve 100% restoration with little, if any, additional spare capacity than in a mesh network. In addition, we find that this strategy requires the operation of only two cross-connections per restoration path. Although spares are connected into cycles, the method is different than self-healing rings because each preconfigured cycle contributes to the restoration of more failure scenarios than can a ring. Additionally, two restoration paths may be obtained from each pre-formed cycle, whereas a ring only yields one restoration path for each failure it addresses. We give an optimal design formulation and results for preconfiguration of spare capacity and describe a distributed self-organizing protocol through which a network can continually approximate the optimal preconfiguration state.

Online Social Interchange, Discord, and Knowledge Construction

Abstract: Online forums provide potential for new forms of collaborative work, study, and community that reduce barriers of time and distance. Yet the types of interaction and means by which individuals create new knowledge in online environments are not well understood. This study presents the results of an exploratory multimethod evaluation study and transcript analysis of an online forum. The researchers used a constructivist interaction analysis model developed by Gunawardena, Lowe, and Anderson (1997) to help understand and assess online learning. The model describes the phases that are attributed to learning development in an online forum. Analysis of the transcripts revealed that most of the online interactions during the forum were at the lower phases of the interaction analysis model. In addition, the researchers studied the interaction patterns that occurred during the online forum. Social-cognitive processes were observed among participants in the forum. The processes included significant time engaged in social interchange followed occasionally by social discord. The social discord served as a catalyst to the knowledge construction process observed. The results of the study illustrate that there are many types of structures, motivations, and applications of online interaction that make the understanding of this communication medium both challenging and exciting. La conference electronique est une application technologique qui peut susciter des formes inedites de travail et d’apprentissage collaboratifs, de meme que de nouveaux types de communautes, en reduisant les obstacles que representent le temps et la distance. Cependant, les types d’interaction et les modes de construction des connaissances adoptes par les usagers des environnements virtuels sont encore mal compris. La presente etude rapporte les resultats d’une etude d’evaluation preliminaire appliquant plusieurs methodes d’analyse aux interactions et a la transcription d’une conference electronique. Les chercheurs ont applique un modele constructiviste d’analyse des processus d’interaction, propose par Gunawardena, Lowe et Anderson (1997), pour tenter de comprendre et d’evaluer l’apprentissage en milieu virtuel. Ce modele decrit les phases attribuees au developpement de l’apprentissage au cours d’une conference electronique. Une analyse des transcriptions revele que la plupart des interactions electroniques au cours de la conference se situaient aux niveaux inferieurs du modele d’analyse des interactions. Les chercheurs se sont egalement penches sur la configuration des interactions au cours de la conference electronique. On a pu observer des processus sociocognitifs entre les participants, notamment un temps significatif accorde a des echanges sociaux, suivis a l’occasion par une discorde sociale; celle-ci servait de catalyseur au processus de construction des connaissances. Nos resultats illustrent le fait que les types de structures, de motivations et d’applications de l’interaction electronique sont multiples et font de celle-ci un objet d’etude a la fois exigeant et stimulant.

Surgeon-related factors and outcome in rectal cancer.

Abstract: OBJECTIVE: To determine whether surgical subspecialty training in colorectal surgery or frequency of rectal cancer resection by the surgeon are independent prognostic factors for local recurrence (LR) and survival. SUMMARY BACKGROUND DATA: Variation in patient outcome in rectal cancer has been shown among centers and among individual surgeons. However, the prognostic importance of surgeon-related factors is largely unknown. METHODS: All patients undergoing potentially curative low anterior resection or abdominoperineal resection for primary adenocarcinoma of the rectum between 1983 and 1990 at the five Edmonton general hospitals were reviewed in a historic-prospective study design. Preoperative, intraoperative, pathologic, adjuvant therapy, and outcome variables were obtained. Outcomes of interest included LR and disease-specific survival (DSS). To determine survival rates and to control both confounding and interaction, multivariate analysis was performed using Cox proportional hazards regression. RESULTS: The study included 683 patients involving 52 surgeons, with > 5-year follow-up obtained on 663 (97%) patients. There were five colorectal-trained surgeons who performed 109 (16%) of the operations. Independent of surgeon training, 323 operations (47%) were done by surgeons performing < 21 rectal cancer resections over the study period. Multivariate analysis showed that the risk of LR was increased in patients of both noncolorectal trained surgeons (hazard ratio (HR) = 2.5, p = 0.001) and those of surgeons performing < 21 resections (HR = 1.8, p < 0.001). Stage (p < 0.001), use of adjuvant therapy (p = 0.002), rectal perforation or tumor spill (p < 0.001), and vascular/neural invasion (p = 0.002) also were significant prognostic factors for LR. Similarly, decreased disease-specific survival was found to be independently associated with noncolorectal-trained surgeons (HR = 1.5, p = 0.03) and surgeons performing < 21 resections (HR = 1.4, p = 0.005). Stage (p < 0.001), grade (p = 0.02), age (p = 0.02), rectal perforation or tumor spill (p < 0.001), and vascular or neural invasion (p < 0.001) were other significant prognostic factors for DSS. CONCLUSION: Outcome is improved with both colorectal surgical subspecialty training and a higher frequency of rectal cancer surgery. Therefore, the surgical treatment of rectal cancer patients should rely exclusively on surgeons with such training or surgeons with more experience.

Evidence in Favor of a Broad Framework for Pronunciation Instruction

Abstract: We had native English-speaking (NS) listeners evaluate the effects of 3types of instruction (segmental accuracy; general speaking habits and prosodic factors; and nospecific pronunciation instruction) on the speech of 3 groups of English as a second language(ESL) learners. We recorded their sentences and extemporaneously produced narratives at thebeginning and end of a 12-week course of instruction. In a blind rating task, 48 native Englishlisteners judged randomized sentences for accentedness and comprehensibility. Six experiencedESL teachers evaluated narratives for accent, comprehensibility, and fluency. Although bothgroups instructed in pronunciation showed significant improvement in comprehensibility andaccentedness on the sentences, only the global group showed improvement in comprehensibilityand fluency in the narratives. We argue that the focus of instruction and the attentional demandson speakers and listeners account for these findings.

Loss-of-function mutations in a calcium-channel α1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness

Abstract: X-linked congenital stationary night blindness (CSNB) is a recessive non-progressive retinal disorder characterized by night blindness, decreased visual acuity, myopia, nystagmus and strabismus1,2,3 Two distinct clinical entities of X-linked CSNB have been proposed4 Patients with complete CSNB show moderate to severe myopia, undetectable rod function and a normal cone response, whereas patients with incomplete CSNB show moderate myopia to hyperopia and subnormal but measurable rod and cone function The electrophysiological and psychophysical features of these clinical entities suggest a defect in retinal neurotransmission The apparent clinical heterogeneity in X-linked CSNB reflects the recently described genetic heterogeneity in which the locus for complete CSNB (CSNB1) was mapped to Xp114, and the locus for incomplete CSNB (CSNB2) was refined within Xp1123 (ref 5) A novel retina-specific gene mapping to the CSNB2 minimal region was characterized and found to have similarity to voltage-gated L-type calcium channel α1-subunit genes Mutation analysis of this new α1-subunit gene, CACNA1F , in 20 families with incomplete CSNB revealed six different mutations that are all predicted to cause premature protein truncation These findings establish that loss-of-function mutations in CACNA1F cause incomplete CSNB, making this disorder an example of a human channelopathy of the retina

Management Ownership and Market Valuation: An Empirical Analysis

Abstract: Investigates the relationship between management ownership and market valuation of the firm, as measured by Tobin's Q. The convergence-of-interest hypothesis suggests that a firm's market valuation should rise as its management owns an increasingly large portion of the firm. On the other hand, the entrenchment hypothesis suggests that as management increases its ownership, the incentive to maximize value declines as market discipline becomes less effective against a larger shareholding manager. The authors attempt to reconcile these competing theoretical predictions by examining empirical data of firm management ownership and Tobin's Q. The latter variable, equal to the ratio of the firm's market value to the replacement cost of its physical assets, is used as a proxy for market valuation of the firm's assets. A piecewise linear regression reveals a positive correlation between management ownership and Tobin's Q in the 0% to 5% ownership range. From 5% to 25% management ownership, the relationship is negative, but at levels greater than 25% the relationship again is positive. The authors put forward a theory that the convergence-of-interest effect operates over the whole range of ownership, whereas the entrenchment effect reaches a maximum value at some less than 100% management ownership mark. Thus, at low levels, the convergence effect is predominant. At somewhat higher levels, the entrenchment effect becomes predominant. Finally, having reached a maximum value, the still-increasing convergence effect again becomes the predominant factor. Additional analysis further disaggregates the data to determine the effect of founding family member, other insider, and outsider members of the board of directors on Tobin's Q. Family member board membership is found to have a negative effect on the variable. (CAR)

An update on cytokines in the pathogenesis of insulin-dependent diabetes mellitus

Abstract: Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that β-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNFα, and IFNα) and type 1 cytokines (IFNγ, TNFβ, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGFβ). Cytokines (IL-1, TNFα, TNFβ and IFNγ) may be directly cytotoxic to β-cells by inducing nitric oxide and oxygen free radicals in the β-cells. In addition, cytokines may sensitize β-cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the β-cells (an action of IFNγ), and inducing Fas (CD95) expression on β-cells (actions of IL-1, and possibly TNFα and IFNγ). Transgenic expression of cytokines in β-cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFNα, IFNγ, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNFα. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4+ T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFNγ-producing), but other islet-specific Th1 clones that produce TGFβ can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFNγ genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFNγ, also IL-1, TNFα, IL-2, and IL-6—by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs—significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNFα, and IL-6) and type 1 cytokines (IFNγ, IL-2 and IL-12) in IDDM development. © 1998 John Wiley & Sons, Ltd.

Molecular mechanisms for the conversion of zymogens to active proteolytic enzymes

Abstract: Proteolytic enzymes are synthesized as inactive precursors, or "zymogens," to prevent unwanted protein degradation, and to enable spatial and temporal regulation of proteolytic activity. Upon sorting or appropriate compartmentalization, zymogen conversion to the active enzyme typically involves limited proteolysis and removal of an "activation segment." The sizes of activation segments range from dipeptide units to independently folding domains comprising more than 100 residues. A common form of the activation segment is an N-terminal extension of the mature enzyme, or "prosegment," that sterically blocks the active site, and thereby prevents binding of substrates. In addition to their inhibitory role, prosegments are frequently important for the folding, stability, and/or intracellular sorting of the zymogen. The mechanisms of conversion to active enzymes are diverse in nature, ranging from enzymatic or nonenzymatic cofactors that trigger activation, to a simple change in pH that results in conversion by an autocatalytic mechanism. Recent X-ray crystallographic studies of zymogens and comparisons with their active counterparts have identified the structural changes that accompany conversion. This review will focus upon the structural basis for inhibition by activation segments, as well as the molecular events that lead to the conversion of zymogens to active enzymes.

Accumulation of persistent organochlorine compounds in mountains of western Canada

Abstract: Persistent, semi-volatile organochlorine compounds, including toxic industrial pollutants and agricultural pesticides, are found everywhere on Earth, including in pristine polar and near-polar locations1,2,3,4. Higher than expected occurrences of these compounds in remote regions are the result of long-range transport in the atmosphere, precipitation and ‘cold condensation’ — the progressive volatilization in relatively warm locations and subsequent condensation in cooler environments3,4 which leads to enhanced concentrations at high latitudes. The upper reaches of high mountains are similar to high-latitude regions in that they too are characterized by relatively low average temperatures, but the accumulation of organochlorine compounds as a function of altitude has not yet been documented. Here we repororganochlorine deposition in snow from mountain ranges in western Canada that show a 10- to 100-fold increase between 770 and 3,100 m altitude. In the case of less-volatile compounds, the observed increase by a factor of 10 is simply due to a 10-fold increase in snowfall over the altitude range of the sampling sites. In the case of the more-volatile organochlorines, cold-condensation effects further enhance the concentration of these compounds with increasing altitude. These findings demonstrate that temperate-zone mountain regions, which tend to receive high levels of precipitation while being close to pollutant sources, are particularly susceptible to the accumulation of semivolatile organochlorine compounds.

Spatiotemporal evolution of ventricular fibrillation

Abstract: Sudden cardiac death is the leading cause of death in the industrialized world, with the majority of such tragedies being due to ventricular fibrillation1. Ventricular fibrillation is a frenzied and irregular disturbance of the heart rhythm that quickly renders the heart incapable of sustaining life. Rotors, electrophysiological structures that emit rotating spiral waves, occur in several systems that all share with the heart the functional properties of excitability and refractoriness. These re-entrant waves, seen in numerical solutions of simplified models of cardiac tissue2, may occur during ventricular tachycardias3,4. It has been difficult to detect such forms of re-entry in fibrillating mammalian ventricles5,6,7,8. Here we show that, in isolated perfused dog hearts, high spatial and temporal resolution mapping of optical transmembrane potentials can easily detect transiently erupting rotors during the early phase of ventricular fibrillation. This activity is characterized by a relatively high spatiotemporal cross-correlation. During this early fibrillatory interval, frequent wavefront collisions and wavebreak generation9 are also dominant features. Interestingly, this spatiotemporal pattern undergoes an evolution to a less highly spatially correlated mechanism that lacks the epicardial manifestations of rotors despite continued myocardial perfusion.

Structure of the Shiga-like Toxin I B-Pentamer Complexed with an Analogue of Its Receptor Gb3†,‡

Abstract: Shiga-like toxin I (SLT-I) is a virulence factor of Escherichia coli strains that cause disease in humans. Like other members of the Shiga toxin family, it consists of an enzymatic (A) subunit and five copies of a binding subunit (the B-pentamer). The B-pentamer binds to a specific glycolipid, globotriaosylceramide (Gb3), on the surface of target cells and thereby plays a crucial role in the entry of the toxin. Here we present the crystal structure at 2.8 A resolution of the SLT-I B-pentamer complexed with an analogue of the Gb3 trisaccharide. The structure reveals a surprising density of binding sites, with three trisaccharide molecules bound to each B-subunit monomer of 69 residues. All 15 trisaccharides bind to one side of the B-pentamer, providing further evidence that this side faces the cell membrane. The structural model is consistent with data from site-directed mutagenesis and binding of carbohydrate analogues, and allows the rational design of therapeutic Gb3 analogues that block the attachment ...

Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes.

Abstract: Hypoxia initiates pulmonary vasoconstriction (HPV) by inhibiting one or more voltage-gated potassium channels (Kv) in the pulmonary artery smooth muscle cells (PASMCs) of resistance arteries. The resulting membrane depolarization increases opening of voltage-gated calcium channels, raising cytosolic Ca2+ and initiating HPV. There are presently nine families of Kv channels known and pharmacological inhibitors lack the specificity to distinguish those involved in control of resting membrane potential (Em) or HPV. However, the Kv channels involved in Em and HPV have characteristic electrophysiological and pharmacological properties which suggest their molecular identity. They are slowly inactivating, delayed rectifier currents, inhibited by 4-aminopyridine (4-AP) but insensitive to charybdotoxin. Candidate Kv channels with these traits (Kv1.5 and Kv2.1) were studied. Antibodies were used to immunolocalize and functionally characterize the contribution of Kv1. 5 and Kv2.1 to PASMC electrophysiology and vascular tone. Immunoblotting confirmed the presence of Kv1.1, 1.2, 1.3, 1.5, 1.6, and 2.1, but not Kv1.4, in PASMCs. Intracellular administration of anti-Kv2.1 inhibited whole cell K+ current (IK) and depolarized Em. Anti-Kv2.1 also elevated resting tension and diminished 4-AP-induced vasoconstriction in membrane-permeabilized pulmonary artery rings. Anti-Kv1.5 inhibited IK and selectively reduced the rise in [Ca2+]i and constriction caused by hypoxia and 4-AP. However, anti-Kv1.5 neither caused depolarization nor elevated basal pulmonary artery tone. This study demonstrates that antibodies can be used to dissect the whole cell K+ currents in mammalian cells. We conclude that Kv2. 1 is an important determinant of resting Em in PASMCs from resistance arteries. Both Kv2.1 and Kv1.5 contribute to the initiation of HPV.