Studies on ageing and the severity of radiographic joint damage in rheumatoid arthritis

IntroductionThe western population is ageing. It is unknown whether age at diagnosis affects the severity of Rheumatoid Arthritis (RA), we therefore performed the present study.Method1,875 RA-patients (7,219 radiographs) included in five European and North-American cohorts (Leiden-EAC, Wichita, Umeå, Groningen and Lund) were studied on associations between age at diagnosis and joint damage severity. In 698 Leiden RA-patients with 7-years follow-up it was explored if symptom duration, anti-citrullinated-peptide-antibodies (ACPA), swollen joint count (SJC) and C-reactive-protein (CRP) mediated the association of age with joint damage. Fifty-six other RA-patients of the EAC-cohort underwent baseline MRIs of wrist, MCP and MTP-joints; MRI-inflammation (RAMRIS-synovitis plus bone marrow edema) was also evaluated in mediation analyses. Linear regression and multivariate normal regression models were used.ResultsAnalysis on the five cohorts and the Leiden-EAC separately revealed 1.026-fold and 1.034-fold increase of radiographic joint damage per year increase in age (β=1.026, 1.034, both p<0.001); this effect was present at baseline and persisted over time. Age correlated stronger with baseline erosion-scores compared to joint space narrowing (JSN)-scores (r=0.38 versus 0.29). Symptom duration, ACPA, SJC and CRP did not mediate the association of age with joint damage severity. Age was significantly associated with the MRI-inflammation-score after adjusting for CRP and SJC (β=1.018, p=0.027). The association of age with joint damage (β=1.032, p=0.004) decreased after also including the MRI-inflammation-score (β=1.025, p=0.021), suggesting partial mediation.ConclusionRA-patients presenting at higher age have more severe joint damage; this might be partially explained by more severe MRI-detected inflammation at higher age.

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A mutation in the cytosolic O-acetylserine (thiol) lyase induces a genome-dependent early leaf death phenotype in <Emphasis Type="Italic">Arabidopsis</Emphasis>

Background  

Cysteine is a component in organic compounds including glutathione that have been implicated in the adaptation of plants to stresses. O-acetylserine (thiol) lyase (OAS-TL) catalyses the final step of cysteine biosynthesis. OAS-TL enzyme isoforms are localised in the cytoplasm, the plastids and mitochondria but the contribution of individual OAS-TL isoforms to plant sulphur metabolism has not yet been fully clarified.     

Biotechnological production and bioactivities of mollisin and two new, structurally related fungal naphthoquinone metabolites

The antibiotic and fungicidal deuteromycete Mollisia caesia Sacc. was cultivated on a large scale. Mollisin (1; = 8-(dichloroacetyl)-5-hydroxy-2,7-dimethylnaphthalene-1,4-dione) and two new tri- and tetrahalogenated metabolites, mollisin A (2) and mollisin B (3) were isolated from M. caesia. The formation of 2 and 3 indicates that the biosynthesis of these compounds starts from a C(16) polyketide (Scheme). Mollisin (1) shows strong fungicidal activities against Sclerophoma pityophila (Corda) v. H?hn and Heterobasidion annosum (Fr.) Bref., which is one of the most-destructive basidiomycetes in coniferous forests. The metabolites 1-3 possess interesting pharmacological activities in assays in search of anti-inflammatory and antiproliferative drugs.     

Design, synthesis and early structure-activity relationship of farnesyltransferase inhibitors which mimic both the peptidic and the prenylic substrate

Inhibition of the farnesylation of ras proteins has been identified as a promising target in tumor therapy. Only a few farnesyltransferase inhibitors are bisubstrate analogues displaying features of both substrates, the farnesylpyrophosphate and the C-terminal CAAX-tetrapeptide sequence of the ras protein. These known bisubstrate analogues consist of an AAX-tripeptide and a farnesyl residue connected through various linkers. We have developed a class of novel compounds that mimic a bisubstrate inhibitor structure and that differ from the known ones by lacking peptidic or farnesylic substructures. Long chain fatty acids and aryl-substituted carboxylic acids were used as farnesyl surrogates. These structures were linked to isoleucine amide, benzoic acid amide, N-substituted aminobenzenesulfonamides and N(alpha)-aryl-substituted methionine derivatives, respectively, which function as AA- or AAX-mimetics.     

Microbiaeratin, a new natural indole alkaloid from a Microbispora aerata strain, isolated from Livingston Island, Antarctica

A new sulphur-containing natural alkaloid named microbiaeratin (1a) was isolated, together with the known microbiaeratinin (2, bacillamide) from the culture filtrate of Microbispora aerata strain IMBAS-11A. The organism was isolated from penguin excrements collected on the Antarctic Livingston Island. The structure was elucidated by one- and two-dimensional NMR experiments and mass spectrometric investigations.     

Proton extrusion by leaf discs ofVicia faba L.: light- and ion-stimulated H(su+) release†

Previous electrophysiological and tracer kinetic studies indicated that the uptake of neutral amino acids took place by means of the proton cotransport mechanism in the leaf tissue of broad bean plants. The present investigations were designed to characterize the origin of the driving force for this process, and the proton pumping activity of leaf cells ofVicia. This activity is known to be revealed when peeled broad been leaf discs, floated on a bathing solution in the light or in darkness acidify the medium. White light caused the strongest acidification. The presence of K⁺ and Na⁺ in the external solution increased the H⁺ secretion significantly, whereas addition of Ca⁺⁺caused only an insignificant enhancement of proton extrusion. The inhibitors of photosynthetic electron transport DCMTJ (50 μM) and nitrofen (50 μM) eliminated the light-enhanced H⁺ release indicating the dependence on photosynthesis. The involvement of a proton pump was evidenced by the effects of the uneoupler CCCP, the SH reagent HgCl₂ and the ATPase inhibitor orthovanadate. The experimental results support the conclusion that H⁺ extrusion byVicia leaf cells is an active electrogenic process requiring metabolic energy. In the light this energy requirement is suppliedvia photosynthetic electron transport. Dedicated to Prof. Dr. F. Jacob on the occasion of his 60th birthday     

Functional surface proteomic profiling reveals the host heat-shock protein A8 as a mediator of Lichtheimia corymbifera recognition by murine alveolar macrophages

Mucormycosis is an emergent, fatal fungal infection of humans and warm-blooded animals caused by species of the order Mucorales. Immune cells of the innate immune system serve as the first line of defence against inhaled spores. Alveolar macrophages were challenged with the mucoralean fungus Lichtheimia corymbifera and subjected to biotinylation and streptavidin enrichment procedures followed by LC–MS/MS analyses. A total of 28 host proteins enriched for binding to macrophage–L. corymbifera interaction. Among those, the HSP70-family protein Hspa8 was found to be predominantly responsive to living and heat-killed spores of a virulent and an attenuated strain of L. corymbifera. Confocal scanning laser microscopy of infected macrophages revealed colocalization of Hspa8 with phagocytosed spores of L. corymbifera. The amount of detectable Hspa8 was dependent on the multiplicity of infection. Incubation of alveolar macrophages with an anti-Hspa8 antibody prior to infection reduced their capability to phagocytose spores of L. corymbifera. In contrast, anti-Hspa8 antibodies did not abrogate the phagocytosis of Aspergillus fumigatus conidia by macrophages. These results suggest an important contribution of the heat-shock family protein Hspa8 in the recognition of spores of the mucoralean fungus L. corymbifera by host alveolar macrophages and define a potential immunomodulatory therapeutic target.