Giant cell arteritis: immune and vascular aging as disease risk factors

Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.     

Molecular recognition of human eosinophil-derived neurotoxin (RNase 2) by placental ribonuclease inhibitor

Placental ribonuclease inhibitor (RI) binds diverse mammalian RNases with dissociation constants that are in the femtomolar range. Previous studies on the complexes of RI with RNase A and angiogenin revealed that RI utilises largely distinctive interactions to achieve high affinity for these two ligands. Here we report a 2.0 angstroms resolution crystal structure of RI in complex with a third ligand, eosinophil-derived neurotoxin (EDN), and a mutational analysis based on this structure. The RI-EDN interface is more extensive than those of the other two complexes and contains a considerably larger set of interactions. Few of the contacts present in the RI-angiogenin complex are replicated; the correspondence to the RI-RNase A complex is somewhat greater, but still modest. The energetic contributions of various interface regions differ strikingly from those in the earlier complexes. These findings provide insight into the structural basis for the unusual combination of high avidity and relaxed stringency that RI displays.     

Polypyrimidine tract binding protein blocks the 5' splice site-dependent assembly of U2AF and the prespliceosomal E complex

Polypyrimidine tract binding protein (PTB) represses some alternatively spliced exons by direct occlusion of splice sites. In repressing the splicing of the c-src N1 exon, we find that PTB acts by a different mechanism. PTB does not interfere with U1 snRNP binding to the N1 5' splice site. Instead, PTB prevents formation of the prespliceosomal early (E) complex across the intervening intron by preventing the assembly of the splicing factor U2AF on the 3' splice site of exon 4. When the unregulated 5' splice site of the upstream exon 3 is present, U2AF binding is restored and splicing between exons 3 and 4 proceeds in spite of the N1 exon bound PTB. Thus, rather than directly blocking the N1 splice sites, PTB prevents the 5' splice site-dependent assembly of U2AF into the E complex. This mechanism likely occurs in many other alternative exons.     

Arsenic removal from the aqueous system using plant biomass: a bioremedial approach

Metal species released into the environment by technological activities tend to persist indefinitely, circulating and eventually accumulating throughout the food chain, thus becoming a serious threat to the environment. Environment pollution by toxic metals occurs globally through military, industrial, and agricultural processes and waste disposal. Bioremediation processes are the target of recent research and are considered low-cost, ecofriendly methods to alleviate the current problems of water decontamination, particularly for remote and rural areas. The present piece of work reports the unexploited sorption properties of the powdered seed of the plant Moringa oleifera (SMOS) for the removal of Arsenic [As(III) and As(V)] from aqueous solutions. Sorption studies, using standard practices, result in the standardization of optimum conditions such as biomass dosages (2.0 g), metal concentrations (25 ppm), contact time (60 min) and volume of the test solutions (200 ml) at pH 7.5, for As(III) and pH 2.5 for As(V). Maximum sorption for As(III) and As(V) species is 60.21 and 85.6%, respectively. Protein/Amino acid-Arsenic interactions are found to play an important role in the biosorption process using plant biomass SMOS.     

Synthesis and SAR of novel oxazolidinones: discovery of ranbezolid

Novel oxazolidinones were synthesized containing a number of substituted five-membered heterocycles attached to the 'piperazinyl-phenyl-oxazolidinone' core of eperezolid. Further, the piperazine ring of the core was replaced by other diamino-heterocycles. These modifications led to several compounds with potent activity against a spectrum of resistant and susceptible gram-positive organisms, along with the identification of ranbezolid (RBx 7644) as a clinical candidate.     

Enhanced proteolysis leads to pre-mature cell death under the influence of elicitor like mycelial components from karnal bunt (tilletia indica) pathogen in wheat callus cultures

Calli raised from mature embryos of susceptible wheat cultivar WH 542 were used in the present study as in vitro bioassay system to study the influence of disease determinant(s) of Karnal bunt (Tilletia indica), a semi-biotrophic fungal pathogen of wheat. Influence of elicitor and conditioned medium (CM) prepared from fungal cultures of T. indica was investigated on induction of programmed cell death (PCD). Induction of PCD was observed as hypersensitive response (HR) in terms of browning at localized regions of callus cultures and induction of proteolytic enzyme(s). Elicitor treated calli showed higher induction of protease activity than untreated and CM-treated cultures, which showed not much change in the activity. It was further substantiated by gel protease assay and activation of caspase-3 like protein(s) in callus cultures that clearly suggested the presence of signaling molecule(s) in the fungal elicitor preparation rather than in conditioned medium. This study further demonstrated that only elicitor preparation possesses such molecule(s), which might be cell wall bound components, rather than secretory in nature as CM was unable to induce PCD in wheat callus cultivars.     

Effect of cholesterol and 7-beta hydroxycholesterol on glutathione status and nitric oxide production in murine peritoneal macrophages

Present study was conducted to observe the effect of cholesterol and oxidized cholesterol (7beta-hydroxycholesterol,7beta-OH) on the nitric oxide (NO) production and the redox ratio by lipopolysaccharide-stimulated macrophages. Dose-dependent decrease in NO levels was seen with both cholesterol and 7beta-OH at different incubation intervals (6,12,18,24 hr) and concentrations (2.5,5,7.5microg/ml). On comparison, a significant decrease in the NO was observed at 24 hr interval in 7beta-OH exposed cells with all respective concentrations of cholesterol. Incubation with 7beta-OH also resulted in significant increase in levels of oxidized glutathione (GSSG) and decrease in reduced glutathione (GSH), while cholesterol showed no effect on GSSG levels. Moreover, GSH levels were lowered only at highest concentration (7.5microg/ml), and at longer incubation intervals (18,24 hr) with cholesterol exposure. This altered the redox status in both cholesterol/7beta-OH treated macrophages. Increased redox ratio and decreased NO levels indicated increased oxidative stress and decreased vasodilation by 7beta-OH compared to cholesterol.     

Tuberculosis masquerading as malignancy: a multimodality approach to the correct diagnosis – a case report

BACKGROUND: Extrapulmonary tuberculosis is one of the great mimickers of medicine, and often masquerades as malignancy. As a result, patients may be referred to oncologists and surgeons for further evaluation and management, delaying the institution of appropriate anti-tuberculous drug therapy. CASE PRESENTATION: We present the case of a 21 year old man with tuberculous osteomyelitis, who was referred to the Bone and Soft Tissue Sarcoma Service at our institution with a provisional diagnosis of malignancy. Further investigation revealed extensive retroperitoneal abdominal and pelvic lymphadenopathy. The recognition of certain patterns on imaging, and finally the isolation of Mycobacterium tuberculosis from tissue samples obtained under image guidance, enabled the correct diagnosis to be made. CONCLUSION: This case highlights the importance of remaining cognisant of the protean manifestations of extrapulmonary tuberculosis, and illustrates the advantage of a clinically directed multi-modality imaging approach to diagnosis.     

De novo alanine synthesis by bacteroids of Mesorhizobium loti is not required for nitrogen transfer in the determinate nodules of Lotus corniculatus

Deletion of both alanine dehydrogenase genes (aldA) in Mesorhizobium loti resulted in the loss of AldA enzyme activity from cultured bacteria and bacteroids but had no effect on the symbiotic performance of Lotus corniculatus plants. Thus, neither indeterminate pea nodules nor determinate L. corniculatus nodules export alanine as the sole nitrogen secretion product.