Interactions between enteroviruses and the host : implications for type 1 diabetes

Type 1 diabetes (T1D) is a disease that results after a selective destruction of the insulin-producing β-cells in the pancreas. The lack of β-cells renders T1D patients completely unable to synthesize and secrete insulin, which leads to a life-long need of exogenous insulin for survival. The cause for this selective destruction is still debated, but both genetic and environmental factors have been shown to regulate susceptibility and development of T1D. Together with my colleagues, I have studied different aspects of the observed link between enterovirus (EV) infections, especially those by Coxsackievirus serotype B (CVB) and the development of T1D. CVB infections may accelerate diabetes development in diabetes-prone mice. This acceleration can however be abrogated by activated iNKT cells. By studying how stimulated or non-stimulated iNKT cells differently regulated macrophages after a CVB4 infection, we have suggested a mechanism for this suppression. We showed that iNKT cells activated in the presence of CVB4 induced suppressive functions in isletresident macrophages, which then inhibited diabetes development in diabetes-prone mice. Recently, two multi-center studies suggested CVB1 infections to be diabetogenic, causing human β-cell autoimmunity and T1D development. The identification of a specific virus strain suggests a possibility to use a vaccine, in order to reduce diabetes development. We therefore developed a prototype CVB1 vaccine and tested the functions and safety profile in two different animal models. We showed that the vaccine was well tolerated and protected mice from CVB1 infection. Furthermore, we also observed that the vaccine was safe in an autoimmune setting where we showed no acceleration of diabetes development or triggered autoimmunity in vaccinated mice prone to develop autoimmune diabetes. Despite the findings that CVB1 may be diabetogenic, an inverse correlation between the incidence of T1D and the number of recorded EV infections have been observed. This counterintuitive observation may be explained by the poliovirus hypothesis, stating that a low herd immunity due to a low frequency of virus infections in the population, may make children that lack maternally transferred antibodies more susceptible to diabetogenic infections. Hence, we tested if maternally transferred antibodies transferred could protect offspring from a diabetogenic CVB3 infection in a mouse model for virus-induced diabetes. Our results support a role for the poliovirus hypothesis in explaining the observed inverse correlation between T1D incidence and prevalence of EVs. The primary site of replication for CVBs is in intestinal epithelial cells (IECs), but what regulates the viral spread to other targeted organs is not known. IFN-λs may regulate permissiveness to the infection. We therefore investigated how intestinal epithelial cells respond to IFN-λ stimulation and found that they could upregulate specific antiviral proteins. This suggested that IECs could be used in a model to study if IFN-λs can regulate IEC permissiveness to CVBs

Individuell avlastning eller kollektiv utveckling? Erfarenheter från ett fortbildningsprogram för lärare vid InfoKomps skolor

Studien redovisar och diskuterar erfarenheter från en fortbildningssatsning för personal vid utbildningsföretaget Information & Kompetens i Sverige AB, och vad satsningen betytt för enskilda individer och för den organisatoriska utvecklingen i respektive skola. Samtliga anställda deltog i en kurs anordnad av Södertörns högskola som handlade om fördjupade perspektiv på lärares yrkeskunskaper. Kursens syfte var att deltagarna bättre skulle förstå och utveckla den del av läraryrket som formas i den praktiska verksamheten. Kursen genomfördes under fyra timmar var annan vecka under hela 2006. Varje kurstillfälle inleddes med en föreläsning och följdes av gruppdiskussioner kring deltagarnas egna berättelser och dilemman dokumenterade i essäform. Kursen har på ett individuellt plan haft mycket olika betydelse för enskilda lärare, bland annat beroende på förkunskaper, förståelse av kompetens i läraryrket och stressrelaterad belastning i allmänhet. Kursens värde ligger snarare på ett kollektivt plan. Lärare har synliggjort sina erfarenheter för varandra på ett sätt som annars inte sker, lärt känna varandra som personer och skapat en större trygghet i lärarlagen. Genom de skrivna berättelserna skapades gemensamma erfarenheter och så tydliga bilder av var och ens agerande man kan komma utan att vara i samma situation samtidigt. Slutsatsen är därför att kursen har lagt en god grund för ett fortsatt lärande av och med varandra i lärargrupperna, ett lärande som är speciellt viktigt för att utveckla skolorna som helhet. I rapporten relateras resultaten till andra satsningar på att utveckla skolan och dess personal, och till forskningen på området. Bland annat diskuteras betydelsen av att personalen synliggör sina erfarenheter för varandra och vad det betyder om det sociala stödet lärare emellan är ett stöd för avlastning eller ett stöd för utveckling.Schools; school development; training; learning; human development

The Demographic Database — History of Technical and Methodological Achievements

The Demographic Data Base (DDB) at the Centre for Demographic and Ageing Research (CEDAR) at Umeå University has since the 1970s been building longitudinal population databases and disseminating data for research. The databases were built to serve as national research infrastructures, useful for addressing an indefinite number of research questions within a broad range of scientific fields, and open to all academic researchers who wanted to use the data. A countless number of customized datasets have been prepared and distributed to researchers in Sweden and abroad and to date, the research has resulted in more than a thousand published scientific reports, books, and articles within a broad range of academic fields. This article will focus on the development of techniques and methods used to store and structure the data at DDB from the beginning in 1973 until today. This includes digitization methods, database design and methods for linkage. The different systems developed for implementing these methods are also described and to some extent, the hardware used

An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression

Classification of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T-ALL patients were characterized by genome-wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P <0.001) and mitotic age (P <0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2-1, and novel genes in T-ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP- subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL-TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP-), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T-ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.Peer reviewe

The Prognostic Importance of CD20(+) B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets

The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). The aim of this study was to investigate infiltration of B lymphocytes into CRC tumours, and their clinical relevance, prognostic value and relation to other immune cell subsets. We used multiplexed immunohistochemistry and multispectral imaging to assay the amount of infiltrating CD20(+) B lymphocytes along with infiltration of CD8(+) cytotoxic T cells, FOXP3(+) T regulatory cells, CD68(+) macrophages and CD66b(+) neutrophils, in 316 archival CRC tissue specimens. A higher density of infiltrating CD20(+) B lymphocytes was associated with tumours of the right colon (P = 0.025) and of lower stages (P = 0.009). Furthermore, patients whose tumours were highly infiltrated by CD20(+) B lymphocytes had a significantly improved disease-specific survival (HR = 0.45, 95% CI 0.28-0.73, P = 0.001), which remained significant in multivariable analysis. CD20(+) B lymphocytes were highly and positively associated with CD8(+) T lymphocytes (P <0.001), and part of the prognostic role was found to be a cooperative effect between these lymphocyte subsets. Our results support a favourable prognostic value of tumour-infiltrating CD20(+) B lymphocytes in CRC. Furthermore, a cooperative prognostic effect between CD20(+) B lymphocytes and CD8(+) T lymphocytes is suggested.Peer reviewe

Landscape Epidemiology of Tularemia Outbreaks in Sweden

Transmission sites of specific Francisella tularensis genotypes were highly localized during natural outbreaks of human tularemia

Systematic Development of Miniaturized (Bio)Processes using Process Systems Engineering (PSE) Methods and Tools

The focus of this work is on process systems engineering (PSE) methods and tools, and especially on how such PSE methods and tools can be used to accelerate and support systematic bioprocess development at a miniature scale. After a short presentation of the PSE methods and the bioprocess development drivers, three case studies are presented. In the first example it is demonstrated how experimental investigations of the bi-enzymatic production of lactobionic acid can be modeled with help of a new mechanistic mathematical model. The reaction was performed at lab scale and the prediction quality analyzed. In the second example a computational fluid dynamic (CFD) model is used to study mass transfer phenomena in a microreactor. In this example the model is not only used to predict the transient dynamics of the reactor system but also to extract material properties like the diffusion velocities of substrate and product, which is otherwise difficult to access. In the last example, a new approach to the design of microbioreactor layouts using topology optimization is presented and discussed. Finally, the PSE methods are carefully discussed with respect to the complexity of the presented approaches, the applicability with respect to practical considerations and the opportunity to analyze experimental results and transfer the knowledge between different scales

Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli1

International audienceBACKGROUND: A function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets. METHODS: Bioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber. RESULTS: miR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro. CONCLUSIONS: miR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature

Canonical Insertion-Deletion Markers for Rapid DNA Typing of Francisella tularensis

By combining analysis of indel markers with multiple-locus variable-number tandem repeat analysis, individual strains were identified