Alternative splicing of human peroxisome proliferator-activated receptor delta (PPARdelta):effects on translation efficiency and trans-activation ability

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptor delta (PPARδ) is a member of the nuclear receptor superfamily. Numerous studies have aimed at unravelling the physiological role of PPARδ as a transcriptional regulator whereas the regulation of PPARδ gene expression has been less studied.</p> <p>Results</p> <p>The principal transcription start site in the human PPARδ gene identified here is positioned upstream of exon 1, although four alternative 5'-ends related to downstream exons were identified. The demonstration of multiple 5'-UTR splice variants of PPARδ mRNA, with an impact on translation efficiency, suggests a translational regulation of human PPARδ expression. Five untranslated exons identified in this study contribute to the variability among the 5'-UTRs of human PPARδ mRNAs. Moreover, <it>in vitro </it>studies of a 3'-splice transcript encoding a truncated variant of PPARδ (designated PPARδ2) show that this isoform constitutes a potential dominant negative form of the receptor.</p> <p>Conclusion</p> <p>We propose that alternative splicing of human PPARδ constitutes an intrinsic role for the regulation of PPARδ expression and thus activity, and highlight the significance of alternative splicing of this nuclear receptor in physiology and disease.</p

The price on farmland : influencing factors

The price of farmland has risen sharply in the last 20 years. This has led to discussions about what creates the value of farmland. The aim in this study was to try and find what factors are affecting the price on farmland. The area that is studied is the counties around Mälardalen during the period 2005 to 2009. The method chosen to achieve the objective is the hedonic price model. The variables are chosen after a preliminary study where a literature search has been made and a number of interviews with people in the industry. The interviews revealed the existence of three different purposes for the purchase of agricultural properties, production, interest or accommodation. Depending on the buyers objective different variables will have different effects on the price. Therefore, three models were produced, one for each purpose. To obtain information about the purchases that had occurred in the region, during the selected time period, data was collected from NaiSvefas program RealEstate and Lantmäteriets Fastighetssök. Based on the data collected the buyers where contacted and short telephone interviews were conducted. This was done to find out the purpose for which the purchase had been made, and also to collect information for some of the potential explanatory variables. The data for the groups consisted of 54 observations in the production group, 35 of them in the interest group and 27 observations in the accommodation group. The process of generating the hedonic pricing model was as follows. First, a regression analysis with all the potential explanatory variables was made. When analyzing the results a problem with multicollinearity was discovered. To get rid of this problem the non-significant variables and those that had a high correlation between them where gradually removed. This was done manually to ensure that important variables for the study were not removed. It can be established that regardless of what purpose the purchase has been made it will require different types of variables to get a high degree of explanation. It requires production variables as well as urbanization and economic variables. The variables that are interesting to study also differ between the groups. The coefficient of determination for the final model in the production group was 55.8% with seven significant variables of a total of nine. The significant variables were average price of grain, the normal harvest in the area, interest rate, the average income in the municipality, the population density in the municipality, if the purchaser exercises the option to hunt and the distance to the nearest road. The coefficient of determination for the final model of the interest group was 70.2% with five significant variables of a total of nine. The significant variables were the time variable, normal harvest for the area, population density in the municipality, number of sales in the municipality as well as travel time to Stockholm. The coefficient of determination for the final model in the accommodation group was 72,6%, with seven significant variables out of eight. The significant variables were, interest rate, the time variable, population density in the municipality, whether it was sold by a broker, travel time to nearest town, if the purchaser exercises the option to hunt and if the land is leased

Toupet versus Dor as a procedure to prevent reflux after cardiomyotomy for achalasia: Results of a randomised clinical trial

AbstractBackgroundThe optimal anti-reflux procedure after Heller cardiomyotomy for oesophageal achalasia remains unclear. The most commonly used procedure is the anterior partial fundoplication according to Dor, although during recent years the posterior counterpart (Toupet) has become popular.MethodsPatients with newly diagnosed achalasia and referred for cardiomyotomy were randomised to receive either an anterior or partial posterior fundoplication following a classical cardiomyotomy. The effect of surgery was assessed during the first postoperative year by Eckardt scores, EORTC QLQ-OES18 scores and HRQL questionnaires. Timed barium oesophagogram (TBO) and ambulatory 24-h pH monitoring were performed to determine oesophageal emptying and the degree of reflux control, respectively.ResultsForty-two patients were randomised into Dor (n = 20) and Toupet (n = 22) groups. Eckardt scores improved dramatically with both procedures, but the EORTC QLQ-OES18 (functional scales) scores revealed significantly better relative improvements in the Toupet group compared to the Dor repair (P = 0.044). Corresponding advantages in favour of Toupet were observed postoperatively in the percentage of oesophageal emptying at TBO (P = 0.011 in height and P = 0.018 in area), an effect not observed in the Dor group. There were no other significant differences recorded between the study groups concerning HRQL evaluations and objective assessment of gastro-oesophageal acid reflux.ConclusionsA partial posterior fundoplication after cardiomyotomy seems to achieve more improvement in oesophageal emptying and EORTC QLQ-OES18 functional scale scores than the anterior fundoplication. Otherwise no differences between the two anti-reflux repairs were noted.Trial registration numberClinicalTrials.gov Identifier: NCT01933373

Radial distribution of dilated intercellular spaces of the esophageal squamous epithelium in patients with reflux disease exhibiting discrete endoscopic lesions

Introduction: Dilatation of intercellular spaces of the esophageal squamous epithelium has been suggested as a marker of early acid reflux-induced damage. This change is a potentially useful addition to histomorphological changes that represent so called minimal endoscopic lesions. We have assessed dilatation of intercellular spaces with regard to: (1) interobserver variability, and (2) whether the incidence of this varies between 'red streaks' and the adjacent normal looking squamous epithelium. Methods: Esophageal biopsies from 44 patients with chronic gastro-esophageal reflux (GERD) were evaluated. At endoscopy, these patients had one or more red streaks on the tops of the mucosal folds in the distal esophagus. Biopsies were taken from the red streaks and from the normal-appearing mucosa 1 cm lateral to the red streaks. Biopsies were assessed in a blinded fashion by two independent pathologists (MV & RF). Criteria for assessing intercellular space dilatation were evaluated and agreed on prior to the study. Results: Good interobserver agreement was recorded (kappa = 0.82 at the streaks and 0.77 for the control tissues) for absence/presence of intercellular space dilatation. Red streak and control biopsies differed significantly (p = 0.0001), with respect to presence of dilated intercellular spaces, with 90.5 % of the former demonstrating this as present compared to 56.1% in the controls. Conclusion: This study supports the concept that esophageal mucosal minimal changes due to reflux is localised and that dilatation of intercellular spaces is an early sign of reflux-induced epithelial damage. The low interobserver variability in the assessment of intercellular space dilatation suggests that this may be a useful variable for assessment of early signs of acid-reflux induced damage to the squamous epithelium of the esophagus by use of light microscopy. Copyrigh

Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus

BACKGROUND: An increased risk of pregnancy complications is seen in women with systemic lupus erythematosus (SLE), but the specific immunopathological drivers are still unclear. Hallmarks of SLE are granulocyte activation, type I interferon (IFN) overproduction, and autoantibodies. Here we examined whether low-density granulocytes (LDG) and granulocyte activation increase during pregnancy, and related the results to IFNα protein levels, autoantibody profile, and gestational age at birth. METHODS: Repeated blood samples were collected during pregnancy in trimesters one, two, and three from 69 women with SLE and 27 healthy pregnant women (HC). Nineteen of the SLE women were also sampled late postpartum. LDG proportions and granulocyte activation (CD62L shedding) were measured by flow cytometry. Plasma IFNα protein concentrations were quantified by single molecule array (Simoa) immune assay. Clinical data were obtained from medical records. RESULTS: Women with SLE had higher LDG proportions and increased IFNα protein levels compared to HC throughout pregnancy, but neither LDG fractions nor IFNα levels differed during pregnancy compared to postpartum in SLE. Granulocyte activation status was higher in SLE relative to HC pregnancies, and it was increased during pregnancy compared to after pregnancy in SLE. Higher LDG proportions in SLE were associated with antiphospholipid positivity but not to IFNα protein levels. Finally, higher LDG proportions in trimester three correlated independently with lower gestational age at birth in SLE. CONCLUSION: Our results suggest that SLE pregnancy results in increased peripheral granulocyte priming, and that higher LDG proportions late in pregnancy are related to shorter pregnancy duration but not to IFNα blood levels in SLE

Allele-specific regulation of MTTP expression influences the risk of ischemic heart disease

Peer reviewe

The C-Type Lectin of the Aggrecan G3 Domain Activates Complement

Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint

Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBackground: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS). Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed. Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells. Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring. Clinical implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices. Keywords: 22q11.2 deletion syndrome; DiGeorge syndrome; T lymphopenia; TREC; long-term outcome; newborn screening; severe combined immunodeficiency.University of Gothenburg Regional research grant Region Halland Swedish Research Council European Commission Queen Silvia Jubilee Foundation Swedish Primary Immunodeficiency Organization Sparbanken Foundation Varberg Frimurare Barnhusdirektionen Foundation Gothenburg Medical Society Medical Faculty at Umea University Cancer Research Foundation in Northern Sweden Swedish government county councils, the ALF-agreement Umea University Vasterbottens County Counci

Dag Solstads krigstrilogi : krigshistorien som politisk og litterært prosjekt

En studie av Dag Solstads krigstrilogi med særlig vekt på forholdet mellom det litterære og politisk prosjektet. Oppgaven inneholder en gjennomgang og analyse av resepsjonen av krigstrilogien, i verkets samtid og i ettertid. Analysen av verket belyser forholdet mellom det politiske og litterære prosjektet, sett i lys av realismeestetikken, resepsjonen og forfatterens uttalte intensjon

Sandwich to Single Skin Laminate : A study of tapered transitions subjected to shear load

Any geometrical change and material transition renders a weak point accumulating stress concentrations in structural members. This research focuses on the transition between a sandwich panel and a single skin laminate, a setup commonly seen in yachts today. The need for different material layouts over a yacht’s complete structure leaves theses transitions inevitable. While the sandwich provides a strong and stiff, yet lightweight solution, the single skin is far more compliant and stronger when subjected to localised loads. The project included applying both finite element modelling and practical testing of the studied transition. Combining a computer based evaluation method with physical testing shortened production time and helped to focus the research on problematic areas of the design. Part of the project was also to highlight differences with these methods, their shortcomings and benefits, as well as how they can be used together as an effective way of research. The studied setups combined of three tapers including one to one, three to one, four and a half to one ratios and two different core thickness of the sandwich panel. Theses where partly modelled and tested in four point bending in a series of three load cases. Ranging from a shear load dominated to a much more mixed loading case including bending moment, the shear strength of the core could be seen as a reoccurring weak point of the structure. Results from modelling support earlier research on the benefits of a longer taper, lowering the stress concentrations at the tip of the transition, thus lowering the risk of further delamination. The practical testing indicated how the compression of the taper increased the shear strength of the core, making the taper far stronger than anticipated, leaving the uncompressed core material as the weakest point and the majority of times the source of failure. Successful in locating the critical element in the construction new difficulties with theconstruction could also be detected. The influence of the asymmetric laminate used, could be shown to affect the stress distributions but leaves more to be researched on how the laminates and core work together over the taper. The results and conclusions show that more work on this subject is needed, the complexity of the problem still needs tackled by decreasing the numbers of variables to reach a more general how tapers behave depending on the materials in use