Immune system's role in viral encephalitis.

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation.

Integration of olfactory information in a spatial representation enabling accurate arm choice in the radial arm maze

The aim of the present study was to determine whether and how rats can use local olfactory cues for spatial orientation. Rats were trained in an eight-arm radial maze under different conditions as defined by the presence or absence of supplementary olfactory cues marking each arm, the availability of distant visuospatial information, and the illumination of the maze (light or darkness). The different visual conditions were designed to dissociate among the effects of light per se and those of visuospatial cues, on the use of olfactory cues for accurate arm choice. Different procedures with modifications of the arrangement of olfactory cues were used to determine if rats formed a representation of the spatial configuration of the olfactory cues and if they could rely on such a representation for accurate arm choice in the radial maze. The present study demonstrated that the use of olfactory cues to direct arm choice in the radial arm maze was critically dependent on the illumination conditions and implied two different modes of processing of olfactory information according to the presence or the absence of light. Olfactory cues were used in an explicit manner and enabled accurate arm choice only in the absence of light. Rats, however, had an implicit memory of the location of the olfactory cues and formed a representation of the spatial position of these cues, whatever the lighting conditions. They did not memorize the spatial configuration of the olfactory cues per se but needed these cues to be linked to the external spatial frame of reference.

Systems Genetics of Metabolism: The Use of the BXD Murine Reference Panel for Multiscalar Integration of Traits.

Metabolic homeostasis is achieved by complex molecular and cellular networks that differ significantly among individuals and are difficult to model with genetically engineered lines of mice optimized to study single gene function. Here, we systematically acquired metabolic phenotypes by using the EUMODIC EMPReSS protocols across a large panel of isogenic but diverse strains of mice (BXD type) to study the genetic control of metabolism. We generated and analyzed 140 classical phenotypes and deposited these in an open-access web service for systems genetics (www.genenetwork.org). Heritability, influence of sex, and genetic modifiers of traits were examined singly and jointly by using quantitative-trait locus (QTL) and expression QTL-mapping methods. Traits and networks were linked to loci encompassing both known variants and novel candidate genes, including alkaline phosphatase (ALPL), here linked to hypophosphatasia. The assembled and curated phenotypes provide key resources and exemplars that can be used to dissect complex metabolic traits and disorders.

Integration and Implementation of Accounting Information Systems in Global Companies Case: The UPM-Kymmene Group

Tämän tutkielman tavoitteena on perehtyä globaalin yrityksen laskentatoimen tietojärjestelmien yhtenäistämiseen ja käyttöönottoon esimerkkinä UPM-Kymmene konsernin projekti. Tutkielmassa sovelletaan hermeneuttista tutkimusotetta. Teoreettisesti aihetta tarkastellaan globalisoitumisen ja laskentatoimen tietojärjestelmille asetettavien vaatimusten pohjalta, sekä järjestelmän muutosprosessin eri vaiheissa huomioon otettavien muuttujien perusteella. Yhtenäisen laskentatoimen tietojärjestelmän tuomat edut globaalille yritykselle ovat ilmeisiä. Ennen yhtenäisen projektin kehittelyä on olennaista tutkia lähtökohdat projektin onnistumiselle ja suunnitella projektin eri vaiheet huolella. Tutkielmassa havaitaan myös, että globaalissa yrityksessä tulee huomioida eri yrityskulttuurit sekä tulosyksiköiden erilaiset toimintatavat. Johtopäätöksenä todetaan, että sekä yritysjohdon että tulosyksiköiden sitoutuneisuus projektiin ja yhtenäiset tavoitteet ovat oleellisia projektin onnistumisen kannalta.

Synaptic Integration of Adult-Born Hippocampal Neurons Is Locally Controlled by Astrocytes.

Adult neurogenesis is regulated by the neurogenic niche, through mechanisms that remain poorly defined. Here, we investigated whether niche-constituting astrocytes influence the maturation of adult-born hippocampal neurons using two independent transgenic approaches to block vesicular release from astrocytes. In these models, adult-born neurons but not mature neurons showed reduced glutamatergic synaptic input and dendritic spine density that was accompanied with lower functional integration and cell survival. By taking advantage of the mosaic expression of transgenes in astrocytes, we found that spine density was reduced exclusively in segments intersecting blocked astrocytes, revealing an extrinsic, local control of spine formation. Defects in NMDA receptor (NMDAR)-mediated synaptic transmission and dendrite maturation were partially restored by exogenous D-serine, whose extracellular level was decreased in transgenic models. Together, these results reveal a critical role for adult astrocytes in local dendritic spine maturation, which is necessary for the NMDAR-dependent functional integration of newborn neurons.

Maturation and Functional Integration of New Granule Cells into the Adult Hippocampus.

The adult hippocampus generates functional dentate granule cells (GCs) that release glutamate onto target cells in the hilus and cornus ammonis (CA)3 region, and receive glutamatergic and γ-aminobutyric acid (GABA)ergic inputs that tightly control their spiking activity. The slow and sequential development of their excitatory and inhibitory inputs makes them particularly relevant for information processing. Although they are still immature, new neurons are recruited by afferent activity and display increased excitability, enhanced activity-dependent plasticity of their input and output connections, and a high rate of synaptogenesis. Once fully mature, new GCs show all the hallmarks of neurons generated during development. In this review, we focus on how developing neurons remodel the adult dentate gyrus and discuss key aspects that illustrate the potential of neurogenesis as a mechanism for circuit plasticity and function.

Institutional legacies, employment and professional integration of non EU/EEA doctors in France

Internationally, policies for attracting highly-skilled migrants have become the guidelines mainly used by the Organisation for Economic Co-operation and Development (OECD) countries. Governments are implementing specific procedures to capture and facilitate their mobility. However, all professions are not equal when it comes to welcoming highly-skilled migrants. The medical profession, as a protective market, is one of these. Taking the case of non-EU/EEA doctors in France, this paper shows that the medical profession defined as the closed labour market, remains the most controversial in terms of professional integration of migrants, protectionist barriers to migrant competition and challenge of medical shortage. Based on the path-dependency approach, this paper argues that non-EU/EEA doctors' issues in France derive from a complex historical process of interaction between standards settled in the past, particularly the historical power of medical corporatism, the unexpected long-term effects of French hospital reforms of 1958, and budgetary pressures. Theoretically, this paper shows two significant findings. Firstly, the French medical system has undergone a series of transformations unthinkable in the strict sense of a path-dependence approach: an opening of the medical profession to foreign physicians in the context of the Europeanisation of public policy, acceptance of non-EU/EEA doctors in a context of medical shortage and budgetary pressures. Secondly, there is no change of the overall paradigm: significantly, the recruitment policies of non-EU/EEA doctors continue to highlight the imprint of the past and reveal a significant persistence of prejudices. Non-EU/EEA doctors are not considered legitimate doctors even if they have the qualifications of physicians which are legitimate in their country and which can be recognised in other receiving countries.

Academics as parents--parents as academics : a study of the integration of intellectual and child-care labours /

Discussions concerning the challenges of combining work and family are certainly not new, and still actively continue. There is, however, a silence in the related literature regarding a comprehensive description of integrating specifically university academic ~. work and family responsibilities. This silence is especially evident for men who are parents as well as academics. With the participation of 4 key informants, this qualitative research study gave voice to men and women who participate in the academic labour of a Canadian university as professors, and as graduate students, along with the parenting labour of at least 1 child under the age of7. Methodology was developed to reveal in-depth perspectives regarding the work practices employed by 4 key informants as they combined intellectual and child-care responsibilities. Multiple data collection methods included journal reflections, day time observation sessions, a focus group, and a final evaluation questionnaire. Using research findings, together with information extrapolated from Three Models of the Family (Eichler, 1997), this study also took steps toward developing a Proposed "Three Models of the University," to offer explanation for the work practices of the key informants as academics/parents, and also for future consideration in university policy formation.

Partnership for arts integration : exploring the experiences of teachers and artists working with integrated arts programs

This research acknowledges the difficulties experienced by teachers presenting integrated arts curricula. Instructional support is offered by arts organizations that provide arts partnerships with local schools boards. The study focuses on the experiences of 8 teachers from a Catholic school board in southern Ontario who participated in integrated arts programs offered by The Royal Conservatory of Music's Learning Through the Arts™ (LTTATM) program and a local art gallery's Art Based Integrated Learning (ABIL) program and examines their responses to the programs and their perception of personal and professional development through this association. Additionally, questions were posed to the . "aftisfs"from-tneSe]Jfograrrrs;-and"they liiscus·sed·how"participating in-collaboration with teachers in the development of in-school programs enabled them to experience personal and professional development as well. Seven themes emerged from the data. These themes included: teachers' feelings of a lack of preparedness to teach the arts; the value of the arts and arts partnerships in schools; the role of the artists in the education of teachers; professional development for both teachers and artists; the development of collegiality; perceptions of student engagement; and the benefits and obstacles of integrating the arts into the curriculum. This document highlights the benefits to both teachers and artists of arts partnerships between schools and outside arts organizations.

Development of techniques for testing the effect of the E1 region on adenovirus integration /

Adenoviral vectors are currently the most widely used gene therapeutic vectors, but their inability to integrate into host chromosomal DNA shortened their transgene expression and limited their use in clinical trials. In this project, we initially planned to develop a technique to test the effect of the early region 1 (E1) on adenovirus integration by comparing the integration efficiencies between an E1-deleted adenoviral vector (SubE1) and an Elcontaining vector (SubE3). However, we did not harvest any SubE3 virus, even if we repeated the transfection and successfully rescued the SubE1 virus (2/4 transfections generated viruses) and positive control virus (6/6). The failure of rescuing SubE3 could be caused by the instability of the genomic plasmid pFG173, as it had frequent intemal deletions when we were purifying It. Therefore, we developed techniques to test the effect of E1 on homologous recombination (HR) since literature suggested that adenovirus integration is initiated by HR. We attempted to silence the E1 in 293 cells by transfecting E1A/B-specific small interfering RNA (siRNA). However, no silenced phenotype was observed, even if we varied the concentrations of E1A/B siRNA (from 30 nM to 270 nM) and checked the silencing effects at different time points (48, 72, 96 h). One possible explanation would be that the E1A/B siRNA sequences are not potent enough to Induce the silenced phenotype. For evaluating HR efficiencies, an HR assay system based on bacterial transfonmatJon was designed. We constmcted two plasmids ( designated as pUC19-dl1 and pUC19-dl2) containing different defective lacZa cassettes (forming white colonies after transformation) that can generate a functional lacZa cassette (forming blue colonies) through HR after transfecting into 293 cells. The HR efficiencies would be expressed as the percentages of the blue colonies among all the colonies. Unfortunately, after transfonnation of plasmid isolated from 293 cells, no colony was found, even at a transformation efficiency of 1.8x10^ colonies/pg pUC19, suggesting the sensitivity of this system was low. To enhance the sensitivity, PCR was used. We designed a set of primers that can only amplify the recombinant plasmid fomied through HR. Therefore, the HR efficiencies among different treatments can be evaluated by the amplification results, and this system could be used to test the effect of E1 region on adenovirus integration. In addition, to our knowledge there was no previous studies using PCR/ Realtime PCR to evaluate HR efficiency, so this system also provides a PCR-based method to carry out the HR assays.

Development of packaging cell lines for rescuing BAV2 viral vectors

The construction of adenovirus vectors for cloning and foreign gene expression requires packaging cell lines that can complement missing viral functions caused by sequence deletions and/or replacement with foreign DNA sequences. In this study, packaging cell lines were designed to provide in trans the missing bovine adenovirus functions, so that recombinant viruses could be generated. Fetal bovine kidney and lUng cells, acquired at the trimester term from a pregnant cow, were tranfected with both digested wild type BAV2 genomic DNA and pCMV-EI. The plasmid pCMV-EI was specifically constructed to express El of BAV2 under the control of the cytomegalovirus enhancer/promoter (CMV). Selection for "true" transformants by continuous passaging showed no success in isolating immortalised cells, since the cells underwent crisis resulting in complete cell death. Moreover, selection for G418 resistance, using the same cells, also did not result in the isolation of an immortalised cell line and the same culture-collapse event was observed. The lack of success in establishing an immortalised cell line from fetal tissue prompted us to transfect a pre-established cell line. We began by transfecting MDBK (Mardin-Dardy bovine kidney) cells with pCMV-El-neo, which contain the bacterial selectable marker neo gene. A series of MDBK-derived cell lines, that constitutively express bovine adenoviral (BAV) early region 1 (El), were then isolated. Cells selected for resistance to the drug G418 were isolated collectively for full characterisation to assess their suitability as packaging cell lines. Individual colonies were isolated by limiting dilution and further tested for El expression and efficiency of DNA uptake. Two cell lines, L-23 and L-24, out of 48 generated foci tested positive for £1 expression using Northern Blot analysis. DNA uptake studies, using both lipofectamine and calcium phosphate methods, were performed to compare these cells, their parental MDBK cells, 8 and the unrelated human 293 cells as a benchmark. The results revealed that the new MDBKderived clones were no more efficient than MDBK cells in the transient expression of transfected DNA and that they were inferior to 293 cells, when using lacZ as the reporter gene. In view of the inherently poor transfection efficiency of MDBK cells and their derivatives, a number of other bovine cells were investigated for their potential as packaging cells. The cell line CCL40 was chosen for its high efficiency in DNA uptake and subsequently transfected with the plasmid vector pCMV El-neo. By selection with the drug G418, two cell lines were isolated, ProCell 1 and ProCell 2. These cell lines were tested for El expression, permissivity to BAV2 and DNA uptake efficiency, revealing a DNA uptake efficiency of 37 % , comparable to that of CCL40. Attempts to rescue BAV2 mutants carrying the lacZ gene in place of £1 or £3 were carried out by co-transfecting wild type viral DNA with either the plasmid pdlElE-Z (which contains BAV2 sequences from 0% to 40.4% with the lacZ gene in place of the £1 region from 1.1% to 8.25%) or with the plasmid pdlE3-5-Z (which contains BAV2 sequences from 64.8% to 100% with the lacZ gene in place of the E3 region from 75.8% to 81.4%). These cotransfections did not result in the generation of a viral mutant. The lack of mutant generation was thought to be caused by the relative inefficiency ofDNA uptake. Consequently, cosBAV2, a cosmid vector carrying the BAV2 genome, was modified to carry the neo reporter gene in place of the £3 region from 75.8% to 81.4%. The use of a single cosmid vector earring the whole genome would eliminate the need for homologous recombination in order to generate a viral vector. Unfortunately, the transfection of cosBAV2- neo also did not result in the generation of a viral mutant. This may have been caused by the size of the £3 deletion, where excess sequences that are essential to the virus' survival might have been deleted. As an extension to this study, the spontaneous E3 deletion, accidently discovered in our viral stock, could be used as site of foreign gene insertion.

Measuring curriculum integration in the junior grades: the design of an instrument

This study \Alas initiated in response to the Junior Division Review (1985) publ ished by the Ministry of Education for the Province of Ontario. Curriculum integration is an element used within the educational paradigm designed by the Ontario Ministry of Education. It is a term frequent1y verbal ized b>' educators in this province, but because of 1 imi ted resource support regarding this methodology, it was open to broad interpretation resulting in an extreme v ar i at i on i nit simp 1 eme n tat i on • I n de ed, the Min i s try intimated that it was not occurring to any significant degree across the province. The objective of this thes is was· to define integration in the junior classroom and de-:.ign a meas.ur·ement in-:.tr-ument which would in turn high 1 i gh t indicators of curriculum integration. The :.tudy made a prel iminary, field-based survey of educa tiona 1 professionals in order to generate a relevant description of integrated curr-iculum programm i ng as def i ned in the j un i or classroom. The description was a compilation of views expressed by a random selection of teachers, consultants, supervisory officers and principals. The survey revea 1 ed a much more comprehens i ve vi et·<,l of the attributes of integrated programming than tradition would dictate and resulted in a functional definition tha t was broader than past prac t ices. Based on the information generated by this survey, an instrument ou t 1 in i ng program cr iter i a of was devised. an integrated junior cla~·sroom Th i s measuremen t i nstrumen t , designed for all levels of educators, was named uThe Han~.son I nstrumen t for the Measuremen t of Program Integrat ion in the Jun i or Cl assroom". It refl ected five categories intrinsic to the me thodol ogy of integration: Teacher Behaviour, Student Behaviour, Classroom Layout, Cl as~·r oom Environment and Progr amm i ng. Each category and the items therein were successfully tested in val idi ty and rel iabi 1 i ty checKs. Interestingly, the individual class was found to be the major variable programming in in the measuremen t the j un i or d i vis i on • of The integrated instrument demonstrated potential not onl)' a~· an initial measure of the degree of integrated curriculum, but as a guide to strategies to implement such a methodology.

Partial characterization of the cloned dihydrofolate reductase gene of Saccharomyces cerevisiae

The cloned dihydrofolate reductase gene of Saccharomyces cerevisiae (DFR 1) is expressed in Escherichia coli. Bacterial strain JF1754 transformed with plasmids containing DFR 1 is at least 5X more resistant to inhibition by the folate antagonist trimethoprim. Expression of yeast DFR 1 in E. coli suggests it is likely that the gene lacks intervening sequences. The 1.8 kbp DNA fragment encoding yeast dhfr activity probably has its own promotor, as the gene is expressed in both orientations in E. coli. Expression of the yeast dhfr gene cloned into M13 viral vectors allowed positive selection of DFR 1 - M13 bacterial transfectants in medium supplemented with trimethoprim. A series of nested deletions generated by nuclease Bal 31 digestion and by restriction endonuclease cleavage of plasmids containing DFR 1 physically mapped the gene to a 930 bp region between the Pst 1 and Sal 1 cut sites. This is consistent with the 21,000 molecular weight attributed to yeast dhfr in previous reports. From preliminary DNA sequence analysis of the dhfr DNA fragment the 3' terminus of DFR 1 was assigned to a position 27 nucleotides from the Eco Rl cut site on the Bam Hi - Eco Rl DNA segment. Several putative yeast transcription termination consensus sequences were identified 3' to the opal stop codon. DFR 1 is expressed in yeast and it confers resistance to the antifolate methotrexate when the gene is present in 2 - 10 copies per cell. Plasmid-dependent resistance to methotrexate is also observed in a rad 6 background although the effect is somewhat less than that conferred to wild-type or rad 18 cells. Integration of DFR 1 into the yeast genome showed an intermediate sensitivity to folate antagonists. This may suggest a gene dosage effect. No change in petite induction in these yeast strains was observed in transformed cells containing yeast dhfr plasmids. The sensitivity of rad 6 , rad 18 and wild-type cell populations to trimethoprim were unaffected by the presence of DFR 1 in transformants. Moreover, trimethoprim did not induce petites in any strain tested, which normally results if dhfr is inhibited by other antifolates such as methotrexate. This may suggest that the dhfr enzyme is not the only possible target of trimethoprim in yeast. rad 6 mutants showed a very low level of spontaneous petite formation. Methotrexate failed to induce respiratory deficient mutants in this strain which suggested that rad 6 might be an obligate grande. However, ethidium bromide induced petites to a level approximately 50% of that exhibited by wild-type and rad 18 strains.

School integration and the friendships of youth with developmental disabilities

- The present study was an investigation into the effect ofschool integration on the friendships ofyouth with developmental disabilities and their peers without disabilities. The youths, their parents, and their teachers provided insights into the youths' friendships. A qualitative paradigm was used in this research. The researcher guided the collection and analysis ofthe data with the phenomenologicallifeworld existentials of body, space, time, and human relation (Van Manen, 1990). Individual interviews were conducted with each youth, and group interviews were conducted with each triad (a youth, their parent(s), and their teacher) to discuss the youth's friendships and the supports necessary to facilitate the friendships. Through phenomenological analysis of the data, four thematic statements emerged: friendships are far from perfect, to have a friend you have to be a friend, parents as choreographers offriendship, and teachers as reluctant partners in friendship facilitation. Based on the results ofthis study, it was concluded that the development of friendships between youth with developmental disabilities and their peers without disabilities was happening in integrated school settings. However, it was also evident that the support ofteachers and parents alike were required to facilitate the development and maintenance ofsuch friendships. Recommendations for practice are discussed, including the need for active participation by the youth's parents in the facilitation offriendships, and the use ofa "circle offriends" to facilitate friendship development. Also discussed are the recommendations for further research, including the need for the youth's friends to be interviewed regarding their friendships with the youth with disabilities, and the need for researcher observation ofth~ friendships in action. Further research could also explore the role ofthe mother versus the father in facilitating friendships, and the role of recreation and leisure opportunities in the ,development offriendships.

The problem of national integration in plural societies : a case study of Pakistan, 1947-71 /|nMuhammed A. Quddus. -- 260 St. Catharines [Ont. : s. n.],

Pakistan had a plural society per excellence. Its people were divided geographically between two separate regions, spoke different languages, had different cultures and economic structures. Like other plural societies elsewhere, Pakistan also faced the problem of national integration. Cleavages along the lines of traditional attachments are fundamental to any plural society, as they were in Pakistan. But their political manifestation could have been kept within managable limits if the Central Government, overwhelmingly composed of the West Pakistanis, was seriously committed to the task. All that Pakistan needed to maintain her integrated existence was deliberate, calculated and conscious efforts on the part of the Central Government to give the Bengalis, the majority linguistic and geographic group in the country, a partnership in the state of Pakistan, an effective power in the decision-making process of the country, a reasonable share from the economic resources of the country, and to show respect to their hopes and aspirations. In addition, Pakistan needed a national platform to bring her divergent linguistic and geographic groups toge~her for some common, national purpos~s. Political parties were the only institutions which could have served this purpose. Pakistan miserably failed to sustain national political parties and failed to satisfy Bengalis' demands. This failure eventually resulted in the falling apart of the political system of Pakistan in 1971.