Maria Hägglund

The Obesity Gene, FTO, Is of Ancient Origin, Up-Regulated during Food Deprivation and Expressed in Neurons of Feeding-Related Nuclei of the Brain

Gene variants of the FTO (fatso) gene have recently been strongly associated with body mass index and obesity. The FTO gene is well conserved and found in a single copy in vertebrate species including fish and chicken, suggesting that the ancestor of this gene was present 450 million years ago. Surprisingly, the FTO gene is present in two species of algae but not in any other invertebrate species. This could indicate that this gene has undergone a horizontal gene transfer. Quantitative real-time PCR showed that the gene is expressed in many peripheral and central rat tissues. Detailed in situ hybridization analysis in the mouse brain showed abundant expression in feeding-related nuclei of the brainstem and hypothalamus, such as the nucleus of the solitary tract, area postrema, and arcuate, paraventricular, and supraoptic nuclei as well as in the bed nucleus of the stria terminalis. Colabeling showed that the FTO gene is predominantly expressed in neurons, whereas it was virtually not found in astrocytes or glia cells. The FTO was significantly up-regulated (41%) in the hypothalamus of rats after 48-h food deprivation. We also found a strong negative correlation of the FTO expression level with the expression of orexigenic galanin-like peptide, which is mainly synthesized in the arcuate nucleus. These results are consistent with the hypothesis that FTO could participate in the central control of energy homeostasis.

The solute carrier (SLC) complement of the human genome: Phylogenetic classification reveals four major families

Solute carriers (SLCs) is the largest group of transporters, embracing transporters for inorganic ions, amino acids, neurotransmitters, sugars, purines and fatty acids among other substrates. We mined the finished assembly of the human genome using Hidden Markov Models (HMMs) obtaining a total of 384 unique SLC sequences. Detailed clustering and phylogenetic analysis of the entire SLC family showed that 15 of the families place into four large phylogenetic clusters with the largest containing eight SLC families, suggesting that many of the distinct families of SLCs have a common evolutionary origin. This study represents the first overall genomic roadmap of the SLCs providing large sequence sets and clarifies the phylogenetic relationships among the families of the second largest group of membrane proteins.

Health informatics and the delivery of care to older people.

In the light of an aging society, effective delivery of healthcare will be more dependent on different technological solutions supporting the decentralization of healthcare, higher patient involvement and increased societal demands. The aim of this article is therefore, to describe the role of health informatics in the care of elderly people and to give an overview of the state of the art in this field. Based on a review of the existing scientific literature, 29 review articles from the last 15 years and 119 original articles from the last 5 years were selected and further analysed. Results show that review articles cover the fields of information technology in the home environment, integrated health information systems, public health systems, consumer health informatics and non-technology oriented topics such as nutrition, physical behaviour, medication and the aging process in general. Articles presenting original data can be divided into 5 major clusters: information systems and decision support, consumer health informatics, emerging technologies, home telehealth, and informatics methods. Results show that health informatics in elderly care is an expanding field of interest but we still do lack knowledge about the elderly persons needs of technology and how it should best be designed. Surprisingly, few studies cover gender differences related to technology use. Further cross-disciplinary research is needed that relates informatics and technology to different stages of the aging process and that evaluates the effects of technical solutions.

Identification of SLC38A7 (SNAT7) Protein as a Glutamine Transporter Expressed in Neurons

The SLC38 family of transporters has in total 11 members in humans and they encode amino acid transporters called sodium-coupled amino acid transporters (SNAT). To date, five SNATs have been characterized and functionally subdivided into systems A (SLC38A1, SLC38A2, and SLC38A4) and N (SLC38A3 and SLC38A5) showing the highest transport for glutamine and alanine. Here we present identification of a novel glutamine transporter encoded by the Slc38a7 gene, which we propose should be named SNAT7. This transporter has l-glutamine as the preferred substrate but also transports other amino acids with polar side chains, as well as l-histidine and l-alanine. The expression pattern and substrate profile for SLC38A7 shows highest similarity to the known system N transporters. Therefore, we propose that SLC38A7 is a novel member of this system. We used in situ hybridization and immunohistochemistry with a custom-made antibody to show that SLC38A7 is expressed in all neurons, but not in astrocytes, in the mouse brain. SLC38A7 is unique in being the first system N transporter expressed in GABAergic and also other neurons. The preferred substrate and axonal localization of SLC38A7 close to the synaptic cleft indicates that SLC38A7 could have an important function for the reuptake and recycling of glutamate.

Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects

About 25% of all solute carriers (SLCs) are likely to transport amino acids as their primary substrate. One of the major phylogenetic clusters of amino acid transporters from the SLC family is the β-family, which is part of the PFAM APC clan. The β-family includes three SLC families, SLC32, SLC36 and SLC38 with one, four and eleven members in humans, respectively. The most well characterized genes within these families are the vesicular inhibitory amino acid transporter (VIAAT, SLC32A1), PAT1 (SLC36A1), PAT2 (SLC36A2), PAT4 (SLC36A4), SNAT1 (SLC38A1), SNAT2 (SLC38A2), SNAT3 (SLC38A3), and SNAT4 (SLC38A4). Here we review the structural characteristics and functional role of these transporters. We also mined the complete protein sequence datasets for nine different genomes to clarify the evolutionary history of the β-family of transporters. We show that all three main branches of the this family are found as far back as green algae suggesting that genes from these families existed in the early eukaryote before the split of animals and plants and that they are present in most animal species. We also address the potential of further drug development within this field highlighting the important role of these transporters in neurotransmission and transport of amino acids as nutrients.

-160C/A polymorphism in the E-cadherin gene promoter and risk of hereditary, familial and sporadic prostate cancer.

The E‐cadherin (CDH1) gene has been associated with prostate carcinogenesis. The C/A polymorphism −160 base pairs relative to the transcription start site has been shown to decrease gene transcription. We analyzed the association between this polymorphism and the risk of sporadic, familial (2 close relatives) and hereditary (3 or more close relatives) prostate cancer. We combined data from 3 population‐based epidemiologic studies in Sweden encompassing altogether 1,036 prostate cancer cases and 669 controls that were genotyped for the short nucleotide polymorphism. Odds ratios with 95% confidence intervals were estimated through unconditional logistic regression. We found no significant association between the A‐allele and sporadic (OR = 1.0; 95% CI = 0.8–1.2) or familial (OR = 1.4; 95% CI = 0.9–2.2) prostate cancer. In contrast, risk of hereditary cancer was increased among heterozygote CA carriers (OR = 1.7; 95% CI = 1.0–2.7) and particularly among homozygote AA carriers (OR = 2.6; 95% CI = 1.4–4.9). Our data indicate that the −160 single nucleotide polymorphism in CDH1 is a low‐penetrant prostate cancer susceptibility gene that might explain a proportion of familial and notably hereditary prostate cancer.

Scenarios to capture work processes in shared homecare--from analysis to application.

BACKGROUND Shared homecare is increasingly common, and in order to develop ICT that support such complex cooperative and interdisciplinary work it is crucial to obtain an understanding of work processes at the clinical level before the development is initiated. It is also crucial, but difficult, to correctly transfer this insight to the development team. METHOD User-centered scenario building in interdisciplinary working groups is applied for capturing cooperative work routines, information demands, and other central preconditions in shared homecare. RESULTS Use of scenarios for analysis of cooperative work and as information carrier is described via a case from the multi-disciplinary OLD@HOME project. Both current and future work scenarios were elicited. To illustrate the process of transforming scenarios into more technical descriptions (use cases), and finally into an application, examples showing the transparency in resulting use cases and in the implemented system are provided. CONCLUSION In this case study, scenarios proved to be useful not only in initial system development phases but throughout the entire development process, improving accessibility and assessment of end user needs. For the development team, scenarios assisted in solving usability issues, and served as a basis for describing use cases and for further system development. More importantly, the shared care scenarios ensured the provision of different perspectives on common work processes, which are often neglected in conventional requirements specifications. This also improved understanding between different clinical groups and between clinicians and developers.

Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron-specific Slc38a8 (SNAT8) in CNS

Glutamine transporters are important for regulating levels of glutamate and GABA in the brain. To date, six members of the SLC38 family (SNATs) have been characterized and functionally subdivided them into System A (SNAT1, SNAT2 and SNAT4) and System N (SNAT3, SNAT5 and SNAT7). Here we present the first functional characterization of SLC38A8, one of the previous orphan transporters from the family, and we suggest that the encoded protein should be named SNAT8 to adhere with the SNAT nomenclature. We show that SLC38A8 has preference for transporting L-glutamine, L-alanine, L-arginine, L-histidine and L-aspartate using a Na+-dependent transport mechanism and that the functional characteristics of SNAT8 have highest similarity to the known System A transporters. We also provide a comprehensive central nervous system expression profile in mouse brain for the Slc38a8 gene and the SNAT8 protein. We show that Slc38a8 (SNAT8) is expressed in all neurons, both excitatory and inhibitory, in mouse brain using in situ hybridization and immunohistochemistry. Furthermore, proximity ligation assay shows highly similar subcellular expression of SNAT7 and SNAT8. In conclusion, the neuronal SLC38A8 has a broad amino acid transport profile and is the first identified neuronal System A transporter. This suggests a key role of SNAT8 in the glutamine/glutamate (GABA) cycle in the brain.

Modeling shared care plans using CONTsys and openEHR to support shared homecare of the elderly

This case report describes how two complementary standards, CONTsys (European Standard EN 13940-1 for continuity of care) and the reference model of openEHR, were applied in modeling a shared care plan for shared homecare based on requirements from the OLD@HOME project. Our study shows that these requirements are matched by CONTsys on a general level. However, certain attributes are not explicit in CONTsys, for example agents responsible for performing planned interventions, and support for monitoring outcome of interventions. We further studied how the care plan conceptual model can be implemented using the openEHR reference model. The study demonstrates the feasibility of developing shared care plans combining a standard concept model, for example CONTsys with an electronic health records (EHR) interoperability specification, that is the openEHR, while highlighting areas that need further exploration. It also explores the reusability of existing clinical archetypes as building blocks of care plans and the modeling of new shared care plan archetypes.

The Adhesion GPCR GPR125 is specifically expressed in the choroid plexus and is upregulated following brain injury.

BackgroundGPR125 belongs to the family of Adhesion G protein-coupled receptors (GPCRs). A single copy of GPR125 was found in many vertebrate genomes. We also identified a Drosophila sequence, DmCG15744, which shares a common ancestor with the entire Group III of Adhesion GPCRs, and also contains Ig, LRR and HBD domains which were observed in mammalian GPR125.ResultsWe found specific expression of GPR125 in cells of the choroid plexus using in situ hybridization and protein-specific antibodies and combined in situ/immunohistochemistry co-localization using cytokeratin, a marker specific for epithelial cells. Induction of inflammation by LPS did not change GPR125 expression. However, GPR125 expression was transiently increased (almost 2-fold) at 4 h after traumatic brain injury (TBI) followed by a decrease (approximately 4-fold) from 2 days onwards in the choroid plexus as well as increased expression (2-fold) in the hippocampus that was delayed until 1 day after injury.ConclusionThese findings suggest that GPR125 plays a functional role in choroidal and hippocampal response to injury.