Identification of two novel human neuronal ceroid lipofuscinosis genes

The neuronal ceroid lipofuscinoses (NCLs) are a group of mostly autosomal recessively inherited neurodegenerative disorders. The aim of this thesis was to characterize the molecular genetic bases of these, previously genetically undetermined, NCL forms. Congenital NCL is the most aggressive form of NCLs. Previously, a mutation in the cathepsin D (CTSD) gene was shown to cause congenital NCL in sheep. Based on the close resemblance of the phenotypes between congenital NCLs in sheep and human, CTSD was considered as a potential candidate gene in humans as well. When screened for mutations by sequencing, a homozygous nucleotide duplication creating a premature stop codon was identified in CTSD in one family with congenital NCL. While in vitro the overexpressed truncated mutant protein was stable although inactive, the absence of CTSD staining in brain tissue samples of patients indicated degradation of the mutant CTSD in vivo. A lack of CTSD staining was detected also in another, unrelated family with congenital NCL. These results imply that CTSD deficiency underlies congenital NCL. While initially Turkish vLINCL was considered a distinct genetic entity (CLN7), mutations in the CLN8 gene were later reported to account for the disease in a subset of Turkish patients with vLINCL. To further dissect the genetic basis of the disease, all known NCL genes were screened for homozygosity by haplotype analysis of microsatellite markers and/or sequenced in 13 mainly consanguineous, Turkish vLINCL families. Two novel, family-specific homozygous mutations were identified in the CLN6 gene. In the remaining families, all known NCL loci were excluded. To identify novel gene(s) underlying vLINCL, a genomewide single nucleotide polymorphism scan, homozygosity mapping, and positional candidate gene sequencing were performed in ten of these families. On chromosome 4q28.1-q28.2, a novel major facilitator superfamily domain containing 8 (MFSD8) gene with six family-specific homozygous mutations in vLINCL patients was identified. MFSD8 transcript was shown to be ubiquitously expressed with a complex pattern of alternative splicing. Our results suggest that MFSD8 is a novel lysosomal integral membrane protein which, as a member of the major facilitator superfamily, is predicted to function as a transporter. Identification of MFSD8 emphasizes the genetic heterogeneity of Turkish vLINCL. In families where no MFSD8 mutations were detected, additional NCL-causing genes remain to be identified. The identification of CTSD and MFSD8 increases the number of known human NCL-causing genes to eight, and is an important step towards the complete understanding of the genetic spectrum underlying NCLs. In addition, it is a starting point for dissecting the molecular mechanisms behind the associated NCLs and contributes to the challenging task of understanding the molecular pathology underlying the group of NCL disorders.

A model Integrating the Facilities Management Process with the Building End User’s Business Process (ProFacil)

The ProFacil model is a generic process model defined as a framework model showing the links between the facilities management process and the building end user’s business process. The purpose of using the model is to support more detailed process modelling. The model has been developed using the IDEF0 modelling method. The ProFacil model describes business activities from the generalized point of view as management-, support-, and core processes and their relations. The model defines basic activities in the provision of a facility. Examples of these activities are “operate facilities”, “provide new facilities”, “provide re-build facilities”, “provide maintained facilities” and “perform dispose of facilities”. These are all generic activities providing a basis for a further specialisation of company specific FM activities and their tasks. A facilitator can establish a specialized process model using the ProFacil model and interacting with company experts to describe their company’s specific processes. These modelling seminars or interviews will be done in an informal way, supported by the high-level process model as a common reference.

Kotitalouden opetustilat osana kehittyvää oppimisympäristöä : asumistoiminnot ja opetussuunnitelma muutoksen määrittäjinä

Home Economics Classrooms as Part of Developing the Environment Housing Activities and Curriculums Defining Change --- The aim of the research project was to develop home economics classrooms to be flexible and versatile learning environments where household activities might be practiced according to the curriculum in different social networking situations. The research is based on the socio-cultural approach, where the functionality of the learning environment is studied specifically from an interactive learning viewpoint. The social framework is a natural starting point in home economics teaching because of the group work in classrooms. The social nature of learning thus becomes a significant part of the learning process. The study considers learning as experience based, holistic and context bound. The learning environment, i.e. home economics classrooms and the material tools there, plays a significant role in developing students skills to manage everyday life. --- The first research task was to analyze the historical development of household activities. The second research task was to develop and test criteria for functional home economics classrooms in planning both the learning environment and the students activities during lessons. The third research task was to evaluate how different professionals (commissioners, planners and teachers) use the criteria as a tool. The research consists of three parts. The first contains a historical analysis of how social changes have created tension between traditional household classrooms and new activities in homes. The historical analysis is based on housing research, regulations and instructions. For this purpose a new theoretical concept, the tension arch, was introduced. This helped in recognizing and solving problems in students activities and in developing innovations. The functionality criteria for home economics classrooms were developed based on this concept. These include technical (health, safety and technical factors), functional (ergonomic, ecological, aesthetic and economic factors) and behavioural (cooperation and interaction skills and communication technologies) criteria. --- The second part discusses how the criteria were used in renovating school buildings. Empirical data was collected from two separate schools where the activities during lessons were recorded both before and after classrooms were renovated. An analysis of both environments based on video recordings was conducted. The previously created criteria were made use of, and problematic points in functionality looked for particularly from a social interactive viewpoint. The results show that the criteria were used as a planning tool. The criteria facilitated layout and equipment solutions that support both curriculum and learning in home economics classrooms taking into consideration cooperation and interaction in the classroom. With the help of the criteria the home economics classrooms changed from closed and complicated space into integrated and open spaces where the flexibility and versatility of the learning environment was emphasized. The teacher became a facilitator and counselor instead a classroom controller. --- The third part analyses the discussions in planning meetings. These were recorded and an analysis was conducted of how the criteria and research results were used in the planning process of new home economics classrooms. The planning process was multivoiced, i.e. actors from different interest groups took part. All the previously created criteria (technical, functional and behavioural) emerged in the discussions and some of them were used as planning tools. Planning meetings turned into planning studios where boundaries between organizations were ignored and the physical learning environments were developed together with experts. The planning studios resulted in multivoiced planning which showed characteristics of collaborative and participating planning as well as producing common knowledge and shared expertise. --- KEY WORDS: physical learning environment, socio-cultural approach, tension arch, boundary crossing, collaborative planning.