Conformational analysis of antibody binding site using EDMA methods /

Euclidean distance matrix analysis (EDMA) methods are used to distinguish whether or not significant difference exists between conformational samples of antibody complementarity determining region (CDR) loops, isolated LI loop and LI in three-loop assembly (LI, L3 and H3) obtained from Monte Carlo simulation. After the significant difference is detected, the specific inter-Ca distance which contributes to the difference is identified using EDMA.The estimated and improved mean forms of the conformational samples of isolated LI loop and LI loop in three-loop assembly, CDR loops of antibody binding site, are described using EDMA and distance geometry (DGEOM). To the best of our knowledge, it is the first time the EDMA methods are used to analyze conformational samples of molecules obtained from Monte Carlo simulations. Therefore, validations of the EDMA methods using both positive control and negative control tests for the conformational samples of isolated LI loop and LI in three-loop assembly must be done. The EDMA-I bootstrap null hypothesis tests showed false positive results for the comparison of six samples of the isolated LI loop and true positive results for comparison of conformational samples of isolated LI loop and LI in three-loop assembly. The bootstrap confidence interval tests revealed true negative results for comparisons of six samples of the isolated LI loop, and false negative results for the conformational comparisons between isolated LI loop and LI in three-loop assembly. Different conformational sample sizes are further explored by combining the samples of isolated LI loop to increase the sample size, or by clustering the sample using self-organizing map (SOM) to narrow the conformational distribution of the samples being comparedmolecular conformations. However, there is no improvement made for both bootstrap null hypothesis and confidence interval tests. These results show that more work is required before EDMA methods can be used reliably as a method for comparison of samples obtained by Monte Carlo simulations.

Improving the use of the nursing process: the impact of charting methodology developed from King's conceptual framework on the use of the nursing process

The purpose of this study was to assess the effects of changing a nursing documentation system, developed from King's Conceptual Framework, on the use of the nursing process. The null hypothesis was that there would be no significant increase in the reflection of the use of the nursing process on the nursing care plan or nurses' notes, as a result of using a nursing documentation system developed using King's Conceptual Framework (1981). The design involved the development of a questionnaire that was used to review health records pre and post implementation of a documentation system developed based on King's Conceptual Framework and Theory of Goal Attainment (1981). A Record Completeness Score was obtained from some of the questions. The null hypothesis was rejected. The results of the study have implications for nursing administration and the evaluation of nursing practice. If the use of a documentation system developed from a conceptual framework increases the reflection of the nursing process on the patient's health record, nursing will have the means to measure patient outcomes/goal attainment. All health care organizations and levels of government are focusing on methods to monitor and control the health-care dollar. In order for nursing to clearly determine the costs associated with nursing care, measurement of patient outcomes/goal attainment will need to be possible. In order to measure patient outcomes/goals attainment nurses will need to be able to collect data on their practice. It will be critical that nursing have a documentation system in place which facilitates the reflection of the nursing process within a theoretical framework.

Introduced taxa in disturbed ecosystems

In the literature, introduced taxa are assumed to be present, more abundant, and occupy greater physical space in portions of ecosystems disturbed by human activity. This study tested this principle in two sites, Short Hills provincial Park ("SHU) and Backus Woods ("B~l"). spatial distribution of introduced taxa of vegetation, isopods, and earthworms was determined with the runs test along 300m transects encompassing gradients of anthropogenic disturbance severity. The hypothesis was that introduced taxa would be aggregated along these transects; the null hypothesis was that they would not be aggregated. The null hypothesis was rejected for the introduced taxa as a unit, and vegetation and earthworms individually. Introduced taxa were aggregated along 53.33% (N~30) and 57.14% (N~21) of the transects in SH and BW (respectively). Introduced vegetation (90.00%, N~10 and 100.00%, N~7) and earthworms (50.00%, N~10 and 50.00%, N~8) were also significantly aggregated within the sites. Introduced isopods, however, were not significantly aggregated at either place (20. 00%, N-=10 and 16. 67%, ~J~6). This study demonstrated that introduced taxa are aggregated within ecosystems disturbed by human activity. However, since introduced isopods were not significantly aggregated it was also shown that taxa respond differently.

Primary structure and expression studies of the dihydrofolate reductase gene (DFRI) of Saccharomyces cerevisiae

The nucleotide sequence of a genomic DNA fragment thought previously to contain the dihydrofolate reductase gene (DFR1) of Saccharomyces cerevisiae by genetic criteria was determined. This DNA fragment of 1784' basepairs contains a large open reading frame from position 800 to 1432, which encodes a enzyme with a predicted molecular weight of 24,229.8 Daltons. Analysis of the amino acid sequence of this protein revealed that the yeast polypep·tide contained 211 amino acids, compared to the 186 residues commonly found in the polypeptides of other eukaryotes. The difference in size of the gene product can be attributed mainly to an insert in the yeast gene. Within this region, several consensus sequences required for processing of yeast nuclear and class II mitochondrial introns were identified, but appear not sufficient for the RNA splicing. The primary structure of the yeast DHFR protein has considerable sequence homology with analogous polypeptides from other organisms, especially in the consensus residues involved in cofactor and/or inhibitor binding. Analysis of the nucleotide sequence also revealed the presence of a number of canonical sequences identified in yeast as having some function in the regulation of gene expression. These include UAS elements (TGACTC) required for tIle amino acid general control response, and "TATA H boxes as well as several consensus sequences thought to be required for transcriptional termination and polyadenylation. Analysis of the codon usage of the yeast DFRl coding region revealed a codon bias index of 0.0083. this valve very close to zero suggestes 3 that the gene is expressed at a relatively low level under normal physiological conditions. The information concerning the organization of the DFRl were used to construct a variety of fusions of its 5' regulatory region with the coding region of the lacZ gene of E. coli. Some of such fused genes encoded a fusion product that expressed in E.coli and/or in yeast under the control of the 5' regulatory elements of the DFR1. Further studies with these fusion constructions revealed that the beta-galactosidase activity encoded on multicopy plasmids was stimulated transiently by prior exposure of yeast host cells to UV light. This suggests that the yeast PFRl gene is indu.ced by UV light and nlay in1ply a novel function of DHFR protein in the cellular responses to DNA damage. Another novel f~ature of yeast DHFR was revealed during preliminary studies of a diploid strain containing a heterozygous DFRl null allele. The strain was constructed by insertion of a URA3 gene within the coding region of DFR1. Sporulation of this diploid revealed that meiotic products segregated 2:0 for uracil prototrophy when spore clones were germinated on medium supplemented with 5-formyltetrahydrofolate (folinic acid). This finding suggests that, in addition to its catalytic activity, the DFRl gene product nlay play some role in the anabolisln of folinic acid. Alternatively, this result may indicate that Ura+ haploid segregants were inviable and suggest that the enzyme has an essential cellular function in this species.

Frequency-dependent selection at the amylase locus in Drosophila melanogaster

A. strain of Drosophila melanog-aster deficient in null amylase activity (Amylase ) was isolated from a wild null population of flies. The survivorship of Amylase homozygous flies is very low when the principal dietary carbohydrate source is starch. However, the survivorship of the null Amylase genotype is comparable to the wild type when the dietary starch is replaced by glucose. In addition, the null viability of the amylase-producing and Amylase strains is comparable v and very lm<] f on a medium with no carbohydrates . Furthermore, amylase-producing genotypes were shovm to excrete enzymatically active amylase protein into the food medium. The excreted amylase causes the external breakdown of dietary starch to sugar. These results led to the following null prediction: the viability of the A.mvlase genotype (fed on a starch rich diet) might increase in the presence of individuals which were amylase-producing. It was shown experimentally that such an increase in viability did in fact occur and that this increase v\Tas proportional to the number of mnylase..::producing fli.es present. These results provide a unique example of a non-"competi ti ve inter-genotype interaction, and one where the underlying physio~ logical and biochemical mechanism has been fully understood.

Grant of Permission for lease of military lands from Sir Robert Prescott to Thomas Clark, 1798-1801.

Transcript (original spelling and grammar retained): By His Excellency Robert Prescott Esquire, Captain General and Governor in Chief in and over His Majestys Provinces of Upper and Lower Canada, General and Commander in Chief of all His Majesty’s forces in the Provinces of Upper and Lower Canada, Nova Scotia, New Brunswick and their several Dependencies and in the Island of Newfoundland &ca. &ca. &ca. I do hereby authorise and permit Thomas Clark of Queenstown in the County of Lincoln in the Province of Upper Canada merchant to take possession of all that Lot, piece and parcel of Land (being part of the land reserved by his Majesty for Military purposes) situate, lying and being at Queenstown in the Township of Newark, in the Home District in the said Province of Upper Canada, bounded and abutted as follows, that is to say beginning at the Distance of two Chains and ninety links from the South East End of his Majesty’s Store House, the said distance being measured along the Bank up Stream, thence South thirty nine degrees and an half West one Chain and fifty links thence south fifty degrees and an half East one Chain and thirty links thence North thirty nine degrees and an half East to the Edge of the Bank and from thence along the Bank to the place of beginning, containing thirty one perches and one hundred and twenty five square links and to occupy and hold the said Lot, piece and parcel of Land during pleasure subject nevertheless to the provisoes and Conditions herein after contained, that is to say. First on condition that it shall and may be lawful to and for His Majesty his Heirs and Successors and to and for the Commander in Chief of His Majesty Forces for the time being and to and for the Officer commanding his Majesty’s Forces in Upper Canada for the time being and to and for either of them to determine and make void this present permission to occupy during pleasure the said Lot, Piece or Parcel of Land above described at any time hereafter whenever he or they shall see fit so to do without any compensation or indemnification to the said Thomas Clark or any other Person or Persons whosoever for any Loss Injury or Damage which he the said Thomas Clark or any other Person or Persons whosoever may thereby sustain. Secondly on this further Condition that it shall and may be lawful to and for His Majesty his Heirs and Successors and to and for his and their Officers, Soldiers and Servants at any time hereafter by order of the Commander in Chief of His Majesty’s Forces for the time being or by order of the Officer commanding his Majesty’s forces in Upper Canada for the time being or by order of the Officer of His Majesty’s Corps of Royal Engineers commanding in the said Province of Upper Canada for the time being to enter upon the said Lot Piece and parcel of Land which the said Thomas Clark is hereby permitted to occupy during pleasure or upon any part thereof and to take down and from the said Lot piece and parcel of Land or from any part thereof to remove any dwelling House Store or other Buildings on the said Lot, piece or Parcel of Land or any part thereof erected and to remove any goods or Chattels on the said Lot piece and parcel of Land or on any part thereof or on any such dwelling House Store or other building found or being and that His Majesty his Heirs and Successors or any other Person or Persons whosoever shall not be liable or responsible to the said Thomas Clark or to any other Person or Persons whosoever for any Loss, Injury or Damage which he or they shall or may in such case sustain. Thirdly on this further Condition that the said Thomas Clark shall not erect on the said Lot Piece or Parcel of Land which the said Thomas Clark is hereby permitted to occupy during pleasure or upon any part thereof at any time or times hereafter any dwelling House store or other Building whatsoever of Stone or brick or of any other materials wood only exccepted and that if any dwelling House or Store or other building of Stone or brick or of any other materials except wood shall at any time be erected on the said Lot, piece or parcel of Land or upon any part thereof, then and in such case, this present permission and every Clause and Article thereof shall from thenceforth cease and determine and be absolutely and entirely null and void. And lastly on this further Condition that the said Thomas Clark or any other Person whosoever shall not assign this permission to occupy the said Lot, Piece or Parcel of Land above described to any Person of Persons whosoever, and if any such assignment shall be made by the said Thomas Clark or by any other Person in his right, or on his behalf, that then and in such case such assignment and this permission to occupy during pleasure the said Lot piece and parcel of Land above described, and every Clause and Article thereof shall from thenceforth cease and determine and be absolutely and entirely null and void. Given under my hand at the Castle of St. Lewis in the City of Quebec in the Province of Lower Canada this Ninth day of July in the year of our Lord one thousand seven hundred and ninety eight and in the thirty eighth year of His Majesty’s Reign. [Signed here by Robert Prescott] By Order of the Commander in Chief [Signed here by James Green (Illegible signature)] I the said Thomas Clark above named do hereby accept the above written Permission to occupy during pleasure the said Lot piece and parcel of Land above described upon and subject to the several Provisioes and Conditions above written and each and every of them severally and respectively. In witness whereof I have hereunto set my hand the Sixteenth day of August in the year of our Lord one thousand seven hundred and ninety eight and in the thirty eighth year of His Majesty’s Reign. [Signed here by Thomas Clark] Signed in the presence of [Illegible signature – looks like J. M Donell Lt. Col.] [Illegible – looks like 2d. Battn R. C. Sm?] [Signed here by C. Anderson] Whereas Inconveniences did arise from the peculiar situation of the Ground contiguous to the above described Lot of Land and the occupation thereof, if estimated by the above Limits would prove highly disadvantageous to Mr. Thomas Clark be it known that in consideration thereof we do permit the above Lot to extend one half Chain more in length up stream so as to comprehend the space allowed for the Road between Lots Two + Three, and we do hereby appropriate the said additional space wholly to the use of the said Thomas Clark. In witness whereof we have hereunto subscribed this Thirteenth Day of October in the Year of our Lord one thousand Eight Hundred and one. [Signed here by J. M’Donell Lt. Col] 2d. Battn. R. C. [in?] Com of Fort George + Dependencies Robt. Pilkington Captain Royal Engineers

Certificate of Acceptance and Initiation to Canadian Order Chosen Friends - Thomas Cowan

A certificate of initiation and acceptance to the Canadian Order Chosen Friends, Thomas Cowan. The certificate reads "This certifies that evidence has been received that Thomas Cowan has been accepted and initiated by the Council name below, and has thus become a member of the Canadian Order of Chosen Friends, and entitled to all the rights and privileges of membership and a benefit of not exceeding one thousand dollars from the relief fund of said order, which shall in case of death be paid to Annie Cowan his wife in the manner and subject to the conditions set forth in the laws governing said relief fund and in the application for membership. This certificate to be in force and binding when accepted in writing by the said member, with the acceptance attested by the Councilor and Recorder and the seal of the Subordinate Council affixed, so long as said member shall comply with the requirements of the Constitution, Laws and Regulations now in force or hereafter adopted for the government of the Order: otherwise, and also in the case of granting of a new certificate, to be null and void. In witness whereof, we have hereunto attached our signatures, and affixed the seal of the Grand Council of the Canadian Order of Chosen Friends. Dated the Twenty Seventh day of July, A.D. 1891." The front and back of the certificate are available for viewing.

UNDERSTANDING THE RELATIONSHIP BETWEEN ONCOLYTIC AD5 DELETED E1b55KDA LYTIC INFECTION AND P53 IN MAMMALIAN CELLS

Adenoviruses are the most commonly used in the development of oncolytic therapy. Oncolytic adenoviruses are genetically modified to selectivity replicate in and kill tumor cells. The p53 molecule is a tumor suppressor protein that responds to viral infection through the activation of apoptosis, which is inhibited by adenovirus E1B55kDa protein leading to progressive viral lytic cycle. The non-specificity of replication has limited the use of wild type adenovirus in cancer therapy. This issue was resolved by using an E1b deleted Ad that can only replicate in cells with a deficiency in the p53 protein, a common feature of most cancer cells. Although demonstrating a moderate success rate, E1b55kDa deleted Ad has not been approved as a standard therapy for all cancer types. Several studies have revealed that E1b deleted Ad replication was independent of p53 status in the cell, as the virus replicated better in some p53 deficient cancers more than others. However, this mechanism has not been investigated deeply. Therefore, the objective of this study is to understand the relationship between p53 status, levels and functional activity, and oncolytic Ad5dlE1b55kDa replication efficiency. Firstly, five transient p53 expression vectors that contain different regulatory elements were engineered and then evaluated in H1299, HEK293 and HeLa cell lines. Data indicated that vector that contains the MARs and HPRE regulatory elements achieved the highest stability of p53 expression. Secondly, we used these vectors to examine the effect of various p53 expression levels on the replication efficiency of oncolytic Ad5dlE1b55kDa. We found that the level of p53 in the cell had an insignificant effect on the oncolytic viruses’ replication. However, the functional activity of p53 had a significant effect on its replication, as Ad5dlE1b55kDa was shown to have selective activity in H1299 cells (p53-null). In contrast, a decrease in viral replication was found in HeLa cells (p53-positive). Finally, the effect of p53’s functional activity on the replication efficiency of oncolytic Ad5dlE1b55kDa was examined. Viral growth was evaluated in H1299 cells expressing number of p53 mutants. P53-R175H mutant successfully rescued viral growth by allowing the virus to exert its mechanism of selectivity. The mechanism entailed deregulating the expression of specific genes, cell cycle and apoptosis, in the p53 pathway to promote its production leading to efficient oncolytic effect. These results confirmed that oncolytic Ad5dlE1b55kDa sensitivity is mutation-type specific. Therefore, before it is applied clinically as cancer therapy for p53 deficient tumors, the type of p53 mutation must be determined for efficient antitumor effect.

The Influence of the Media on Shaping Perceptions of Leadership in Sport: A Within and Between Groups Design

An experimental design that included both between-group and within-group designs was used to assess media influence on perceptions of sport leadership. Participants were recruited and randomly assigned to three groups, where each group completed two separate survey sessions regarding leader personality traits and behaviours. During the second survey session, experimental Groups 1 and 2 watched a video on a separate, respective sport leader prior to filling out the survey. There were a total of 104 participants (N = 104) for the first session, and 99 (N = 99) participants completed the second session. One-way ANOVA, factorial repeated measures ANOVA, and ANCOVA were used for data analysis. Results indicate a significant change in Group 2’s results after watching the video clip, thus rejecting the null hypotheses. Results and implications are discussed, highlighting their relationships to sport and media related theories and sport management practice.

Exact Tests for Contemporaneous Correlation of Disturbances in Seemingly Unrelated Regressions.

This paper proposes finite-sample procedures for testing the SURE specification in multi-equation regression models, i.e. whether the disturbances in different equations are contemporaneously uncorrelated or not. We apply the technique of Monte Carlo (MC) tests [Dwass (1957), Barnard (1963)] to obtain exact tests based on standard LR and LM zero correlation tests. We also suggest a MC quasi-LR (QLR) test based on feasible generalized least squares (FGLS). We show that the latter statistics are pivotal under the null, which provides the justification for applying MC tests. Furthermore, we extend the exact independence test proposed by Harvey and Phillips (1982) to the multi-equation framework. Specifically, we introduce several induced tests based on a set of simultaneous Harvey/Phillips-type tests and suggest a simulation-based solution to the associated combination problem. The properties of the proposed tests are studied in a Monte Carlo experiment which shows that standard asymptotic tests exhibit important size distortions, while MC tests achieve complete size control and display good power. Moreover, MC-QLR tests performed best in terms of power, a result of interest from the point of view of simulation-based tests. The power of the MC induced tests improves appreciably in comparison to standard Bonferroni tests and, in certain cases, outperforms the likelihood-based MC tests. The tests are applied to data used by Fischer (1993) to analyze the macroeconomic determinants of growth.

Simulation-Based Finite-Sample Tests for Heteroskedasticity and ARCH Effects.

A wide range of tests for heteroskedasticity have been proposed in the econometric and statistics literature. Although a few exact homoskedasticity tests are available, the commonly employed procedures are quite generally based on asymptotic approximations which may not provide good size control in finite samples. There has been a number of recent studies that seek to improve the reliability of common heteroskedasticity tests using Edgeworth, Bartlett, jackknife and bootstrap methods. Yet the latter remain approximate. In this paper, we describe a solution to the problem of controlling the size of homoskedasticity tests in linear regression contexts. We study procedures based on the standard test statistics [e.g., the Goldfeld-Quandt, Glejser, Bartlett, Cochran, Hartley, Breusch-Pagan-Godfrey, White and Szroeter criteria] as well as tests for autoregressive conditional heteroskedasticity (ARCH-type models). We also suggest several extensions of the existing procedures (sup-type of combined test statistics) to allow for unknown breakpoints in the error variance. We exploit the technique of Monte Carlo tests to obtain provably exact p-values, for both the standard and the new tests suggested. We show that the MC test procedure conveniently solves the intractable null distribution problem, in particular those raised by the sup-type and combined test statistics as well as (when relevant) unidentified nuisance parameter problems under the null hypothesis. The method proposed works in exactly the same way with both Gaussian and non-Gaussian disturbance distributions [such as heavy-tailed or stable distributions]. The performance of the procedures is examined by simulation. The Monte Carlo experiments conducted focus on : (1) ARCH, GARCH, and ARCH-in-mean alternatives; (2) the case where the variance increases monotonically with : (i) one exogenous variable, and (ii) the mean of the dependent variable; (3) grouped heteroskedasticity; (4) breaks in variance at unknown points. We find that the proposed tests achieve perfect size control and have good power.

Testing for a Unit Root in Panels with Dynamic Factors

This paper studies testing for a unit root for large n and T panels in which the cross-sectional units are correlated. To model this cross-sectional correlation, we assume that the data is generated by an unknown number of unobservable common factors. We propose unit root tests in this environment and derive their (Gaussian) asymptotic distribution under the null hypothesis of a unit root and local alternatives. We show that these tests have significant asymptotic power when the model has no incidental trends. However, when there are incidental trends in the model and it is necessary to remove heterogeneous deterministic components, we show that these tests have no power against the same local alternatives. Through Monte Carlo simulations, we provide evidence on the finite sample properties of these new tests.

Méthodes d’inférence exactes pour un modèle de régression avec erreurs AR(2) gaussiennes

Ce texte propose des méthodes d’inférence exactes (tests et régions de confiance) sur des modèles de régression linéaires avec erreurs autocorrélées suivant un processus autorégressif d’ordre deux [AR(2)], qui peut être non stationnaire. L’approche proposée est une généralisation de celle décrite dans Dufour (1990) pour un modèle de régression avec erreurs AR(1) et comporte trois étapes. Premièrement, on construit une région de confiance exacte pour le vecteur des coefficients du processus autorégressif (φ). Cette région est obtenue par inversion de tests d’indépendance des erreurs sur une forme transformée du modèle contre des alternatives de dépendance aux délais un et deux. Deuxièmement, en exploitant la dualité entre tests et régions de confiance (inversion de tests), on détermine une région de confiance conjointe pour le vecteur φ et un vecteur d’intérêt M de combinaisons linéaires des coefficients de régression du modèle. Troisièmement, par une méthode de projection, on obtient des intervalles de confiance «marginaux» ainsi que des tests à bornes exacts pour les composantes de M. Ces méthodes sont appliquées à des modèles du stock de monnaie (M2) et du niveau des prix (indice implicite du PNB) américains

Methods to Estimate Dynamic Stochastic General Equilibrium Models

This paper employs the one-sector Real Business Cycle model as a testing ground for four different procedures to estimate Dynamic Stochastic General Equilibrium (DSGE) models. The procedures are: 1 ) Maximum Likelihood, with and without measurement errors and incorporating Bayesian priors, 2) Generalized Method of Moments, 3) Simulated Method of Moments, and 4) Indirect Inference. Monte Carlo analysis indicates that all procedures deliver reasonably good estimates under the null hypothesis. However, there are substantial differences in statistical and computational efficiency in the small samples currently available to estimate DSGE models. GMM and SMM appear to be more robust to misspecification than the alternative procedures. The implications of the stochastic singularity of DSGE models for each estimation method are fully discussed.

Monte Carlo Tests with Nuisance Parameters: A General Approach to Finite-Sample Inference and Nonstandard Asymptotics

The technique of Monte Carlo (MC) tests [Dwass (1957), Barnard (1963)] provides an attractive method of building exact tests from statistics whose finite sample distribution is intractable but can be simulated (provided it does not involve nuisance parameters). We extend this method in two ways: first, by allowing for MC tests based on exchangeable possibly discrete test statistics; second, by generalizing the method to statistics whose null distributions involve nuisance parameters (maximized MC tests, MMC). Simplified asymptotically justified versions of the MMC method are also proposed and it is shown that they provide a simple way of improving standard asymptotics and dealing with nonstandard asymptotics (e.g., unit root asymptotics). Parametric bootstrap tests may be interpreted as a simplified version of the MMC method (without the general validity properties of the latter).