Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy.

The mitochondrial deoxyribonucleotide (dNTP) pool is separated from the cytosolic pool because the mitochondria inner membrane is impermeable to charged molecules. The mitochondrial pool is maintained by either import of cytosolic dNTPs through dedicated transporters or by salvaging deoxynucleosides within the mitochondria; apparently, enzymes of the de novo dNTP synthesis pathway are not present in the mitochondria. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on the mitochondrial salvage pathway enzymes, the deoxyribonucleosides kinases. Two of the four human deoxyribonucleoside kinases, deoxyguanosine kinase (dGK) and thymidine kinase-2 (TK2), are expressed in mitochondria. Human dGK efficiently phosphorylates deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates deoxythymidine, deoxycytidine and deoxyuridine. Here we identify two mutations in TK2, histidine 90 to asparagine and isoleucine 181 to asparagine, in four individuals who developed devastating myopathy and depletion of muscular mitochondrial DNA in infancy. In these individuals, the activity of TK2 in muscle mitochondria is reduced to 14-45% of the mean value in healthy control individuals. Mutations in TK2 represent a new etiology for mitochondrial DNA depletion, underscoring the importance of the mitochondrial dNTP pool in the pathogenesis of mitochondrial depletion.     

Genome-wide association study identifies multiple loci influencing human serum metabolite levels

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.     

Expression of alpha-cardiac myosin heavy chain in mammalian skeletal muscle.

We have investigated the reactivity of different human, rat and cat muscles to a monoclonal antibody directed against human alpha-cardiac myosin heavy chain. We have found that special fiber subpopulations of human masseter and extraocular muscles, as well as the bag fibers of human, rat and cat muscle spindles, were reactive to this antibody, indicating that these fibers expressed alpha-cardiac myosin heavy chain or a closely related isoform. This isomyosin was present in the spindle bag fibers at early fetal stages, whereas its expression in masseter and extraocular muscle fibers was not detected during the first 22 weeks of gestation. Our results add to the list of muscle proteins which are expressed in locations or at developmental stages other than those initially described, suggesting that a revision of the present nomenclature of the subgroups of myosin heavy chains might be considered in the future.     

Falsificationism Falsified

A conceptual analysis of falsificationism is performed, in which the central falsificationist thesis is divided into several components. Furthermore, an empirical study of falsification in science is reported, based on the 70 scientific contributions that were published as articles in Nature in 2000. Only one of these articles conformed to the falsificationist recipe for successful science, namely the falsification of a hypothesis that is more accessible to falsification than to verification. It is argued that falsificationism relies on an incorrect view of the nature of scientific inquiry and that it is, therefore, not a tenable research methodology.     

Skeletin immunoreactivity in peripheral nerves

Summary By use of monospecific antibodies against the cow heart intermediate filament protein, skeletin, an antigenic relationship between skeletin and neurofilament protein of peripheral nerves is demonstrated. Crossreactivity is also demonstrated in the filament-containing Schwann cells. The results are consistent with the existence of several subclasses of related intermediate-sized filament proteins.Acknowledgments. The skilful technical assistence of Mrs Elisabeth Rubing, Miss Inga Johansson, and Miss Marléne Lundström is gratefully acknowledged. This work was supported by grants from Lions Research Fund, the Swedish Medical Research Council (12X-3934) and the Faculty of Medicine, University of Umeå.     

Implementation Structure and Participation at Neighbourhood Level-A Multiple Case Study of Neighbourhood Development in Sweden

The last decades have seen the emergence of the settings approach in Health Promotion one example is the Healthy City initiative which was launched by European division of WHO in 1990. In 2003, four Swedish municipalities accordingly signed a contract on a Partnership for Sustainable Welfare Development. One of the objectives was to promote participation, influence, and health at a neighbourhood level by focusing on one housing area in each municipality. These housing areas constitute the setting of this study. The purpose is to examine the implementation structures in the municipalities, and how variations in the implementation structure affect differences in integration of community participation. A triangulation of methods was used in building up a case study database: semi-structured key informant interviews with 29 stakeholders in the municipalities; examination of solicited and unsolicited documents; and participatory observations which included repeated visits to the neighbourhoods. The results show that the greater the visibility of community participation policy is in the implementation structure the greater is the integration of community participation in the neighbourhood renewal work. Two explanatory factors have been identified. The first is that making the community participation policy visible in the implementation structure results in more appropriate strategies for mobilizing the community in the neighbourhood renewal work. The second is that the municipal governing of the neighbourhood renewal allows more space for community participation when the policy is visible in the implementation structure.     

Cluster analysis of dyad distributions in networks

Existing statistical models for network data that are easy to estimate and fit are based on the assumption of dyad independence or conditional dyad independence if the individuals are categorized into subgroups. We discuss how such models might be overparameterized and argue that there is a need for subgrouping methods to find appropriate models. We propose clustering of dyad distributions as such a method and illustrate it by analyzing how cooperative learning methods affect friendship data for school children.Work for this report was initiated while Frank and Komaska visited the Department of Statistics at the University of California, Riverside. Partial support was provided by the Swedish Council for Research in the Humanities and Social Sciences.     

The molecular composition of a photographic fixing bath

Zusammenfassung In Thiosulfatlösungen von mäßiger Stärke bildet Silber die zwei Ionen Ag(S₂O₃) ₂ ^3– und Ag(S₂O₃) ₃ ^5– , deren Komplexkonstanten bestimmt wurden.