The copper(II) binding properties of the cyclic peptide c(HGHK)

The new cyclic tetrapeptide c(HGHK) was synthesised in the solid phase and its complexes with copper(II) were studied in aqueous solution at various pH values by means of potentiometric and spectroscopic methods (UV, EPR, CD). Six mononuclear coordination species were clearly identified within the pH range 3-11. Spectroscopic data strongly suggest sequential formation of N, 2N, 3N and 4N equatorial donor sets around the copper(II) centre from the lowest to the highest pH, involving both imidazole nitrogens and amide nitrogens. A detailed comparison with the copper(II) binding properties of HGHG and Ac-HGHG ligands is also reported.     

Characterization of the human lineage-specific pericentric inversion that distinguishes human chromosome 1 from the homologous chromosomes of the great apes

The human and chimpanzee genomes are distinguishable in terms of ten gross karyotypic differences including nine pericentric inversions and a chromosomal fusion. Seven of these large pericentric inversions are chimpanzee-specific whereas two of them, involving human chromosomes 1 and 18, were fixed in the human lineage after the divergence of humans and chimpanzees. We have performed detailed molecular and computational characterization of the breakpoint regions of the human-specific inversion of chromosome 1. FISH analysis and sequence comparisons together revealed that the pericentromeric region of HSA 1 contains numerous segmental duplications that display a high degree of sequence similarity between both chromosomal arms. Detailed analysis of these regions has allowed us to refine the p-arm breakpoint region to a 154.2 kb interval at 1p11.2 and the q-arm breakpoint region to a 562.6 kb interval at 1q21.1. Both breakpoint regions contain human-specific segmental duplications arranged in inverted orientation. We therefore propose that the pericentric inversion of HSA 1 was mediated by intra-chromosomal non-homologous recombination between these highly homologous segmental duplications that had themselves arisen only recently in the human lineage by duplicative transposition.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .Justyna M. Szamalek and Violaine Goidts are contributed equally to the paper.     

Toxoplasma gondii: Serological recognition of reinfection

Using murine chronic toxoplasmosis as an experimental model, we examined the utility of immunoenzymatic methods in recognizing reinfection in chronically infected individuals. Primary infection with avirulent Toxoplasma gondii DX strain (genotype II) induced strong immunity protecting the mice from mortality after inoculation with LD(100) of virulent BK strain (genotype I) and triggered highly expressed antibody production, within one new isotype detected by comparative immunoblots. The parasites multiplying at the site of reinfection were of BK origin as found by RAPD-PCR. The results revealed that the immunoblot assay seems to be a useful and reliable method for the monitoring of specific antibody profile in chronically infected individuals. In our opinion ELISA combined with immunoblot could enable the recognition of reinfection cases in humans, but earlier our experimental data should be verified in clinical laboratory.     

Enterococcus in wound infections: virulence and antimicrobial resistance

Enterococci, a complex group of facultative pathogens have become increasingly isolated in various hospital settings. They are considerable frequently cultured from traumatic and surgical wounds. We investigated 57 strains of the species E. faecalis, E. faecium and E. casseliflavus isolated from infected wounds. Their ability to produce virulence factors and their sensitivity to antibiotics were evaluated using phenotypic and genotyping methods. In the phenotype studies, significant portion of the isolates produced biofilm (66.7%) and gelatinase (36.8%). Nearly 30% of the strains expressed hemolytic properties. Only a few produced DNAse (15.8%) and lipase (7.0%). The genes esp, gelE, cylA, cylB, cylM and agg were detected in most of the isolates (38.6-87.7%). All the isolated enterococci were susceptible to vancomycin and were characterized by their low resistance to antibiotics, except aminoglycosides (HLR).     

Regional Differences in AIDS and Non-AIDS Related Mortality in HIV-Positive Individuals across Europe and Argentina: The EuroSIDA Study

Background

Differences in access to care and treatment have been reported in Eastern Europe, a region with one of the fastest growing HIV epidemics, compared to the rest of Europe. This analysis aimed to establish whether there are regional differences in the mortality rate of HIV-positive individuals across Europe, and Argentina.

Methods

13,310 individuals under follow-up were included in the analysis. Poisson regression investigated factors associated with the risk of death.

Findings

During 82,212 person years of follow-up (PYFU) 1,147 individuals died (mortality rate 14.0 per 1,000 PYFU (95% confidence interval [CI] 13.1–14.8). Significant differences between regions were seen in the rate of all-cause, AIDS and non-AIDS related mortality (global p<0.0001 for all three endpoints). Compared to South Europe, after adjusting for baseline demographics, laboratory measurements and treatment, a higher rate of AIDS related mortality was observed in East Europe (IRR 2.90, 95%CI 1.97–4.28, p<.0001), and a higher rate of non-AIDS related mortality in North Europe (IRR 1.51, 95%CI 1.24–1.82, p<.0001). The differences observed in North Europe decreased over calendar-time, in 2009–2011, the higher rate of non-AIDS related mortality was no longer significantly different to South Europe (IRR 1.07, 95%CI 0.66–1.75, p = 0.77). However, in 2009–2011, there remained a higher rate of AIDS-related mortality (IRR 2.41, 95%CI 1.11–5.25, p = 0.02) in East Europe compared to South Europe in adjusted analysis.

Interpretations

There are significant differences in the rate of all-cause mortality among HIV-positive individuals across different regions of Europe and Argentina. Individuals in Eastern Europe had an increased risk of mortality from AIDS related causes and individuals in North Europe had the highest rate of non-AIDS related mortality. These findings are important for understanding and reviewing HIV treatment strategies and policies across the European region.     

Characterisation and Validation of Insertions and Deletions in 173 Patient Exomes

Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated.We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing.     

The reduction of (ImH)[<Emphasis Type="Italic">trans</Emphasis>-Ru<Superscript>III</Superscript>Cl<Subscript>4</Subscript>(dmso)(Im)] under physiological conditions: preferential reaction of the reduced complex with human serum albumin

A systematic study of the reduction of (ImH)[trans-RuCl(4)(dmso)(Im)] (NAMI-A; dmso is dimethyl sulfoxide, Im is imidazole), a promising antimetastasing agent, by L: -ascorbic acid under physiological conditions is reported. Under blood plasma conditions (pH 7.4, 0.1-0.15 M NaCl , 37 degrees C) the rapid reduction of trans-[Ru(III)Cl(4)(dmso)(Im)](-) results in the formation of trans-[Ru(II)Cl(4)(dmso)(Im)](2-) within seconds, and is followed by successive dissociation of the chloride ligands, whereas neither dmso nor imidazole ligands are released during the reaction. Under our experimental conditions, the formation of the ascorbate dianion is the rate-determining step, and once it has formed it reacts rapidly with NAMI-A. Moreover, the NAMI-A complex is very unstable at physiological pH (7.4); therefore, the hydrolysis of NAMI-A cannot be excluded as a competing reaction. During hydrolysis, aquated derivatives via stepwise dissociation of chloride and dmso ligands are formed, and most of these species have a higher redox potential and are expected to be even more easily reduced by ascorbic acid. Thus, it is very likely that the reduced form of NAMI-A or the reduction products of its hydrolytic derivatives react with albumin. The reaction of reduced NAMI-A with human serum albumin leads to the formation of stable adducts, with a binding efficiency very similar to that of the parent complex, viz., 3.2 +/- 0.3 and 4.0 +/- 0.4 mol of Ru(II) and Ru(III) per mole of albumin, respectively, however with a significantly higher reactivity.     

Influence of phosphorohydrazone derivatives of benzopyrones on polymerization and viscosity of fibrin

The synthesis and antitumour and antibacterial activity of coumarin and chromone phosphorohydrazones have been reported. This study describes influence of phosphorohydrazones derivatives of coumarin and chromone on the polymerization and viscosity of fibrin. The fibrin polymerization assay was performed by the Shen and Lorand method and the clot viscosity was measured on the basis of Shen and Lorand and Marchi and coworkers methods. Among the eight compounds tested, one coumarin derivative and two chromone derivatives showed significant activity.