Cardiovascular comorbidity in rheumatoid arthritis

This thesis is based on four different studies, all focusing on co-morbidities in rheumatoid arthritis. Diabetes mellitus is assessed as a risk factor for rheumatoid arthritis, the temporal relationship between ischemic heart disease and rheumatoid arthritis, and the extent of coronary stenosis in rheumatoid arthritis, is studied. The rationale for this is that patients with rheumatoid arthritis suffer an increased risk of ischemic heart disease that cannot be explained by traditional risk factors for cardiovascular disease but is hypothesized to be related to rheumatoid arthritis specific factors, that patients with rheumatoid arthritis have been reported to have a more severe atherosclerosis and that autoimmunity seem to aggregate. First, we studied diabetes mellitus and its relationship to rheumatoid arthritis using a population-based case-control study of rheumatoid arthritis. 1,419 patients with newly diagnosed rheumatoid arthritis and 1,674 age-, sex-, and residential area- matched controls were compared with respect to having diabetes mellitus prior to study inclusion. After validating self-reported information, 20 cases and 5 controls were classified as having type 1 diabetes mellitus and 42 cases and 46 controls as having type 2 diabetes mellitus. This study demonstrated that having type 1 diabetes mellitus conferred a seven-fold increased risk of developing a specific subset of rheumatoid arthritis defined by the presence of anti-citrullinated protein antibodies. This association depended to some extent on a genetic variant known to be involved in the pathogenesis of both type 1 diabetes and rheumatoid arthritis. We then studied the temporal relationship between ischemic heart disease and rheumatoid arthritis in two population-based cohorts of patients with rheumatoid arthritis and age-, sex-, and residential area-matched controls from the general population. The occurrence of ischemic heart disease before first symptom of rheumatoid arthritis (controls were given the same date as their matched case) in two population-based cohorts of rheumatoid arthritis (ncohort 1= 8,454, ncohort2=2,025) was compared to the occurrence of ischemic heart disease among controls (ncohort 1=42,267, ncohort2=2,760) and revealed that having a history of ischemic heart disease before onset of first symptom of rheumatoid arthritis was as common among cases as controls; approximately 6% of cases and 6% of controls in cohort 1 had experienced an ischemic heart disease before first symptom of rheumatoid arthritis. After excluding those who had had any ischemic heart disease at diagnosis of rheumatoid arthritis, we followed cohort 1 over time and found that there indeed was an increased risk of ischemic heart disease in patients with rheumatoid arthritis (n=7,469) compared with the general population (n=37,024) and that this increased risk was apparent and manifest already within a few years following rheumatoid arthritis diagnosis. Among individuals included in cohort 1 who underwent angiography with indication acute coronary syndrome (nrheumatoid arthritis=168, ncomparators=534) we found that although the development of ischemic heart disease was much more rapid in patients with rheumatoid arthritis, the extent of coronary stenosis was not related to rheumatoid arthritis. In summary, these results indicate that type 1 diabetes mellitus increases the risk of developing a specific type of rheumatoid arthritis defined by a specific auto-antibody, that the risk of ischemic heart disease in rheumatoid arthritis goes from not being elevated to 60% increased compared to the general population within a few years following diagnosis of rheumatoid arthritis, and that the extent of coronary stenosis in rheumatoid arthritis with acute coronary syndromes is very similar to that in controls with the same clinical symptoms of acute coronary syndrome. The rapid increase in risk of ischemic heart disease could be related to factors associated with rheumatoid arthritis

Diversity and transcription of proteases involved in the maturation of hydrogenases in Nostoc punctiforme ATCC 29133 and Nostoc sp. strain PCC 7120

<p>Abstract</p> <p>Background</p> <p>The last step in the maturation process of the large subunit of [NiFe]-hydrogenases is a proteolytic cleavage of the C-terminal by a hydrogenase specific protease. Contrary to other accessory proteins these hydrogenase proteases are believed to be specific whereby one type of hydrogenases specific protease only cleaves one type of hydrogenase. In cyanobacteria this is achieved by the gene product of either <it>hupW </it>or <it>hoxW</it>, specific for the uptake or the bidirectional hydrogenase respectively. The filamentous cyanobacteria <it>Nostoc punctiforme </it>ATCC 29133 and <it>Nostoc </it>sp strain PCC 7120 may contain a single uptake hydrogenase or both an uptake and a bidirectional hydrogenase respectively.</p> <p>Results</p> <p>In order to examine these proteases in cyanobacteria, transcriptional analyses were performed of <it>hupW </it>in <it>Nostoc punctiforme </it>ATCC 29133 and <it>hupW </it>and <it>hoxW </it>in <it>Nostoc </it>sp. strain PCC 7120. These studies revealed numerous transcriptional start points together with putative binding sites for NtcA (<it>hupW</it>) and LexA (<it>hoxW</it>). In order to investigate the diversity and specificity among hydrogeanse specific proteases we constructed a phylogenetic tree which revealed several subgroups that showed a striking resemblance to the subgroups previously described for [NiFe]-hydrogenases. Additionally the proteases specificity was also addressed by amino acid sequence analysis and protein-protein docking experiments with 3D-models derived from bioinformatic studies. These studies revealed a so called "HOXBOX"; an amino acid sequence specific for protease of Hox-type which might be involved in docking with the large subunit of the hydrogenase.</p> <p>Conclusion</p> <p>Our findings suggest that the hydrogenase specific proteases are under similar regulatory control as the hydrogenases they cleave. The result from the phylogenetic study also indicates that the hydrogenase and the protease have co-evolved since ancient time and suggests that at least one major horizontal gene transfer has occurred. This co-evolution could be the result of a close interaction between the protease and the large subunit of the [NiFe]-hydrogenases, a theory supported by protein-protein docking experiments performed with 3D-models. Finally we present data that may explain the specificity seen among hydrogenase specific proteases, the so called "HOXBOX"; an amino acid sequence specific for proteases of Hox-type. This opens the door for more detailed studies of the specificity found among hydrogenase specific proteases and the structural properties behind it.</p

Transcription of the extended hyp-operon in Nostoc sp. strain PCC 7120

<p>Abstract</p> <p>Background</p> <p>The maturation of hydrogenases into active enzymes is a complex process and e.g. a correctly assembled active site requires the involvement of at least seven proteins, encoded by <it>hypABCDEF </it>and a hydrogenase specific protease, encoded either by <it>hupW </it>or <it>hoxW</it>. The N₂-fixing cyanobacterium <it>Nostoc </it>sp. strain PCC 7120 may contain both an uptake and a bidirectional hydrogenase. The present study addresses the presence and expression of <it>hyp</it>-genes in <it>Nostoc </it>sp. strain PCC 7120.</p> <p>Results</p> <p>RT-PCRs demonstrated that the six <it>hyp</it>-genes together with one ORF may be transcribed as a single operon. Transcriptional start points (TSPs) were identified 280 bp upstream from <it>hypF </it>and 445 bp upstream of <it>hypC</it>, respectively, demonstrating the existence of several transcripts. In addition, five upstream ORFs located in between <it>hupSL</it>, encoding the small and large subunits of the uptake hydrogenase, and the <it>hyp</it>-operon, and two downstream ORFs from the <it>hyp</it>-genes were shown to be part of the same transcript unit. A third TSP was identified 45 bp upstream of asr0689, the first of five ORFs in this operon. The ORFs are annotated as encoding unknown proteins, with the exception of alr0692 which is identified as a NifU-like protein. Orthologues of the four ORFs asr0689-alr0692, with a highly conserved genomic arrangement positioned between <it>hupSL</it>, and the <it>hyp </it>genes are found in several other N₂-fixing cyanobacteria, but are absent in non N₂-fixing cyanobacteria with only the bidirectional hydrogenase. Short conserved sequences were found in six intergenic regions of the extended <it>hyp</it>-operon, appearing between 11 and 79 times in the genome.</p> <p>Conclusion</p> <p>This study demonstrated that five ORFs upstream of the <it>hyp</it>-gene cluster are co-transcribed with the <it>hyp</it>-genes, and identified three TSPs in the extended <it>hyp</it>-gene cluster in <it>Nostoc </it>sp. strain PCC 7120. This may indicate a function related to the assembly of a functional uptake hydrogenase, hypothetically in the assembly of the small subunit of the enzyme.</p

Characterization of the hupSL promoter activity in Nostoc punctiforme ATCC 29133

<p>Abstract</p> <p>Background</p> <p>In cyanobacteria three enzymes are directly involved in the hydrogen metabolism; a nitrogenase that produces molecular hydrogen, H₂, as a by-product of nitrogen fixation, an uptake hydrogenase that recaptures H₂and oxidize it, and a bidirectional hydrogenase that can both oxidize and produce H₂.<it>Nostoc punctiforme </it>ATCC 29133 is a filamentous dinitrogen fixing cyanobacterium containing a nitrogenase and an uptake hydrogenase but no bidirectional hydrogenase. Generally, little is known about the transcriptional regulation of the cyanobacterial uptake hydrogenases. In this study gel shift assays showed that NtcA has a specific affinity to a region of the <it>hupSL </it>promoter containing a predicted NtcA binding site. The predicted NtcA binding site is centred at 258.5 bp upstream the transcription start point (tsp). To further investigate the <it>hupSL </it>promoter, truncated versions of the <it>hupSL </it>promoter were fused to either <it>gfp </it>or <it>luxAB</it>, encoding the reporter proteins Green Fluorescent Protein and Luciferase, respectively.</p> <p>Results</p> <p>Interestingly, all <it>hupsSL </it>promoter deletion constructs showed heterocyst specific expression. Unexpectedly the shortest promoter fragment, a fragment covering 57 bp upstream and 258 bp downstream the tsp, exhibited the highest promoter activity. Deletion of the NtcA binding site neither affected the expression to any larger extent nor the heterocyst specificity.</p> <p>Conclusion</p> <p>Obtained data suggest that the <it>hupSL </it>promoter in <it>N. punctiforme </it>is not strictly dependent on the upstream NtcA cis element and that the shortest promoter fragment (-57 to tsp) is enough for a high and heterocyst specific expression of <it>hupSL</it>. This is highly interesting because it indicates that the information that determines heterocyst specific gene expression might be confined to this short sequence or in the downstream untranslated leader sequence.</p

Topological dynamics of micelles formed by geometrically varied surfactants

The molecular architecture of sugar-based surfactants strongly affects their self-assembled structure, i.e., the type of micelles they form, which in turn controls both the dynamics and rheological properties of the system. Here, we report the segmental and mesoscopic structure and dynamics of a series of C16 maltosides with differences in the anomeric configuration and degree of tail unsaturation. Neutron spin-echo measurements showed that the segmental dynamics can be modeled as a one-dimensional array of segments where the dynamics increase with inefficient monomer packing. The network dynamics as characterized by dynamic light scattering show different relaxation modes that can be associated with the micelle structure. Hindered dynamics are observed for arrested networks of worm-like micelles, connected to their shear-thinning rheology, while nonentangled diffusing rods relate to Newtonian rheological behavior. While the design of novel surfactants with controlled properties poses a challenge for synthetic chemistry, we demonstrate how simple variations in the monomer structure can significantly influence the behavior of surfactantsThe authors thank the Swedish Research Council Formas (Grant 2015-666) for funding J.L. The research was performed with financial support from the Vinnova─Swedish Governmental Agency for Innovation Systems within the NextBioForm Competence Centre. The authors also thank the Institut Laue-Langevin, France, for the awarded beamtime (Proposal No. 9-10-1652). NSE data is openly available at doi: 10.5291/ILL-DATA.9-10-1652S

One-year follow-up after the time management group intervention let’s get organized

BACKGROUND: Time management skills are essential to maintain occupations in everyday life. People with neurodevelopmental or mental disorders often experience persistent difficulties with managing time and organizing daily life, consequently, there is a need to establish interventions with sustainable results. AIM: The aim was to perform a one-year post-intervention follow-up after the intervention Let’s Get Organized (LGO-S) for people with neurodevelopmental or mental disorders. METHODS: The study is a one-year follow-up of a single group pre-test–post-test design. Thirtyeight persons with difficulties in time management due to neurodevelopmental or mental disorders participated. Instruments to collect data were Assessment of Time Management Skills; Weekly Calendar Planning Activity and the Satisfaction with Daily Occupations instrument. Wilcoxons’s signed-rank test was used to compare data over time. RESULTS: There were no significant differences in the participants’ outcomes between post-intervention and one-year follow-up in time management skills and regulation of emotions, satisfaction with daily occupations, and global satisfaction. A significant improvement could be seen in the subscale organization and planning at the one-year follow-up compared to post-intervention. CONCLUSIONS: Improvements in time management skills, organization, and planning, regulation of emotions, and satisfaction with daily occupations after the LGO-S can be maintained in the long term.The Centre for Clinical Research Dalarna, Falun, the Faculty of Medicine and Health, Orebro University, the Regional Research Council in the Uppsala-Orebro Region, and the Research Committee in Region Orebro County.https://www.tandfonline.com/toc/iocc20pm2022Centre for Augmentative and Alternative Communication (CAAC

Transcript analysis of the extended hyp-operon in the cyanobacteria Nostoc sp. strain PCC 7120 and Nostoc punctiforme ATCC 29133

<p>Abstract</p> <p>Background</p> <p>Cyanobacteria harbor two [NiFe]-type hydrogenases consisting of a large and a small subunit, the Hup- and Hox-hydrogenase, respectively. Insertion of ligands and correct folding of nickel-iron hydrogenases require assistance of accessory maturation proteins (encoded by the <it>hyp</it>-genes). The intergenic region between the structural genes encoding the uptake hydrogenase (<it>hupSL</it>) and the accessory maturation proteins (<it>hyp </it>genes) in the cyanobacteria <it>Nostoc </it>PCC 7120 and <it>N. punctiforme </it>were analysed using molecular methods.</p> <p>Findings</p> <p>The five ORFs, located in between the uptake hydrogenase structural genes and the <it>hyp</it>-genes, can form a transcript with the <it>hyp</it>-genes. An identical genomic localization of these ORFs are found in other filamentous, N₂-fixing cyanobacterial strains. In <it>N. punctiforme </it>and <it>Nostoc </it>PCC 7120 the ORFs upstream of the <it>hyp</it>-genes showed similar transcript level profiles as <it>hupS </it>(hydrogenase structural gene), <it>nifD </it>(nitrogenase structural gene), <it>hypC </it>and <it>hypF </it>(accessory hydrogenase maturation genes) after nitrogen depletion. <it>In silico </it>analyzes showed that these ORFs in <it>N. punctiform</it>e harbor the same conserved regions as their homologues in <it>Nostoc </it>PCC 7120 and that they, like their homologues in <it>Nostoc </it>PCC 7120, can be transcribed together with the <it>hyp</it>-genes forming a larger extended <it>hyp-</it>operon. DNA binding studies showed interactions of the transcriptional regulators CalA and CalB to the promoter regions of the extended <it>hyp</it>-operon in <it>N. punctiforme </it>and <it>Nostoc </it>PCC 7120.</p> <p>Conclusions</p> <p>The five ORFs upstream of the <it>hyp</it>-genes in several filamentous N₂-fixing cyanobacteria have an identical genomic localization, in between the genes encoding the uptake hydrogenase and the maturation protein genes. In <it>N. punctiforme </it>and <it>Nostoc </it>PCC 7120 they are transcribed as one operon and may form transcripts together with the <it>hyp</it>-genes. The expression pattern of the five ORFs within the extended <it>hyp</it>-operon in both <it>Nostoc punctiforme </it>and <it>Nostoc </it>PCC 7120 is similar to the expression patterns of <it>hupS</it>, <it>nifD</it>, <it>hypF </it>and <it>hypC</it>. CalA, a known transcription factor, interacts with the promoter region between <it>hupSL </it>and the five ORFs in the extended <it>hyp</it>-operon in both <it>Nostoc </it>strains.</p

Folk først - Eksempler på bedre livskvalitet, overvannshåndtering og biologisk mangfold i byrom. En studieturrapport om blå-grønn infrastruktur fra Upton, Sheffield og London.

Prosjektleder Isabel Seifert-DähnnHvem lager vi byene for? SPARE-prosjektet søker å finne løsninger for en urban byutvikling som gjennom å spille på lag med naturen tilrettelegger for trygge, gode opplevelser for innbyggerne i et klima med økt risiko for ekstrem nedbør, og som støtter opp om et økt biologisk mangfold i byrommet. I England har byene Upton, Sheffield og London forsøkt å oppnå dette, og rapporten bygger på deres erfaringer. Med tekst og bilder formidler rapporten erfaringer fra prosjektgruppens studietur høsten 2023. Et hovedfunn er at en god byutvikling må skje sammen med byens befolkning. Folk først - er en forutsetning for et flerfunksjonelt byrom.Norges forskningsrådpublishedVersio

The Cyanobacterial Uptake Hydrogenase : Regulation, Maturation and Function

With accellerating global warming and pollution problems a change of energy regime is necessary. Solar energy offers a clean and unlimited energy source of enormous potential. Due to it’s intermittenet nature solar energy must be stored - ideally in the chemical bond of a carrier molecule. Hydrogen gas, H2, an energy carrier with water as only emission when used in a fuel cell, is considered to be the choise for the future. In this context cyanobacteria show promising potential as future H2 factories since they can produce H2 from solar energy and water. The main enzymes directly involved in cyanobacterial hydrogen metabolism are nitrogenases and hydrogenases. Cyanobacterial hydrogenases are either uptake hydrogenases or bidirectional hydrogenases and their maturation requires assistance of six maturation proteins and two hydrogenase specific proteases. In this thesis the transcriptional regulation, maturation and function of the cyanobacterial uptake hydrogenases were investigated in the filamentous, heterocyst forming strains Nostoc punctiforme ATCC 29133 and Nostoc sp. strain PCC 7120. Five genes, encoding proteins putatively involved in the maturation of the uptake hydrogenase were identified upstream the known maturation genes. Two transcription factors, CalA and CalB, were found interacting with the stretch of DNA forming the upstream regions of the uptake hydrogenase structural genes and the novel maturation genes. The expression of the uptake hydrogenase were  heterocysts specific and the specificity mapped to a short promoter region starting -57 bp upstream the transcription start point. In addition, the function of the uptake hydrogenase was inserted in a metabolic context. Among the proteases, a conserved region was discovered possibly involved in determining the hydrogenase specificity. This thesis has given valuable information about the transcriptional regulation, maturation and function of the uptake hydrogenase in filamentous, heterocystous cyanobacteria and identified new targets for bioengineering of mutant strains with higher H2 production rates

The Cyanobacterial Uptake Hydrogenase : Regulation, Maturation and Function

With accellerating global warming and pollution problems a change of energy regime is necessary. Solar energy offers a clean and unlimited energy source of enormous potential. Due to it’s intermittenet nature solar energy must be stored - ideally in the chemical bond of a carrier molecule. Hydrogen gas, H2, an energy carrier with water as only emission when used in a fuel cell, is considered to be the choise for the future. In this context cyanobacteria show promising potential as future H2 factories since they can produce H2 from solar energy and water. The main enzymes directly involved in cyanobacterial hydrogen metabolism are nitrogenases and hydrogenases. Cyanobacterial hydrogenases are either uptake hydrogenases or bidirectional hydrogenases and their maturation requires assistance of six maturation proteins and two hydrogenase specific proteases. In this thesis the transcriptional regulation, maturation and function of the cyanobacterial uptake hydrogenases were investigated in the filamentous, heterocyst forming strains Nostoc punctiforme ATCC 29133 and Nostoc sp. strain PCC 7120. Five genes, encoding proteins putatively involved in the maturation of the uptake hydrogenase were identified upstream the known maturation genes. Two transcription factors, CalA and CalB, were found interacting with the stretch of DNA forming the upstream regions of the uptake hydrogenase structural genes and the novel maturation genes. The expression of the uptake hydrogenase were  heterocysts specific and the specificity mapped to a short promoter region starting -57 bp upstream the transcription start point. In addition, the function of the uptake hydrogenase was inserted in a metabolic context. Among the proteases, a conserved region was discovered possibly involved in determining the hydrogenase specificity. This thesis has given valuable information about the transcriptional regulation, maturation and function of the uptake hydrogenase in filamentous, heterocystous cyanobacteria and identified new targets for bioengineering of mutant strains with higher H2 production rates