Vaccines against toxoplasma gondii : challenges and opportunities

Development of vaccines against Toxoplasma gondii infection in humans is of high priority, given the high burden of disease in some areas of the world like South America, and the lack of effective drugs with few adverse effects. Rodent models have been used in research on vaccines against T. gondii over the past decades. However, regardless of the vaccine construct, the vaccines have not been able to induce protective immunity when the organism is challenged with T. gondii, either directly or via a vector. Only a few live, attenuated T. gondii strains used for immunization have been able to confer protective immunity, which is measured by a lack of tissue cysts after challenge. Furthermore, challenge with low virulence strains, especially strains with genotype II, will probably be insufficient to provide protection against the more virulent T. gondii strains, such as those with genotypes I or II, or those genotypes from South America not belonging to genotype I, II or III. Future studies should use animal models besides rodents, and challenges should be performed with at least one genotype II T. gondii and one of the more virulent genotypes. Endpoints like maternal-foetal transmission and prevention of eye disease are important in addition to the traditional endpoint of survival or reduction in numbers of brain cysts after challenge

On the nature of defects in liquid-phase exfoliated graphene

Liquid-phase exfoliation is one of the most promising routes for large-scale production of multilayer graphene dispersions. These dispersions, which may be used in coatings, composites, or paints, are believed to contain disorder-free graphene multilayers. Here, we address the nature of defects in such samples obtained by liquid-phase exfoliation of graphite powder in N-methyl-2-pyrrolidone. Our Raman spectroscopy data challenge the assumption that these multilayers are free of bulk defects, revealing that defect localization strongly depends on the sonication time. For short ultrasound times, defects are located mainly at the layer edges but they turn out to build up in the bulk for ultrasonic times above 2 h. This knowledge may help to devise better strategies to achieve high-quality graphene dispersions.submittedVersionFil: Bracamonte, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Física Enrique Gaviola; Argentina.Fil: Bracamonte, María Victoria. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Lacconi, Gabriela Inés. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Fisicoquímica; Argentina.Fil: Lacconi, Gabriela Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Fisicoquímica de Córdoba; Argentina.Fil: Urreta, Silvia Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Física Enrique Gaviola; Argentina.Fil: Urreta, Silvia Elena. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Fil: Foa Torres, Luis Eduardo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Física Enrique Gaviola; Argentina.Fil: Foa Torres, Luis Eduardo Francisco. Universidad Nacional de Córdoba. Facultad de Matemática, Astronomía y Física; Argentina.Física de los Materiales Condensado

Transient Ureteral Obstruction Prevents against Kidney Ischemia/Reperfusion Injury via Hypoxia-Inducible Factor (HIF)-2α Activation

Although the protective effect of transient ureteral obstruction (UO) prior to ischemia on subsequent renal ischemia/reperfusion (I/R) injury has been documented, the underlying molecular mechanism remains to be understood. We showed in the current study that 24 h of UO led to renal tubular hypoxia in the ipsilateral kidney in mice, with the accumulation of hypoxia-inducible factor (HIF)-2α, which lasted for a week after the release of UO. To address the functions of HIF-2α in UO-mediated protection of renal IRI, we utilized the Mx-Cre/loxP recombination system to knock out target genes. Inactivation of HIF-2α, but not HIF-1α blunted the renal protective effects of UO, as demonstrated by much higher serum creatinine level and severer histological damage. UO failed to prevent postischemic neutrophil infiltration and apoptosis induction in HIF-2α knockout mice, which also diminished the postobstructive up-regulation of the protective molecule, heat shock protein (HSP)-27. The renal protective effects of UO were associated with the improvement of the postischemic recovery of intra-renal microvascular blood flow, which was also dependent on the activation of HIF-2α. Our results demonstrated that UO protected the kidney via activation of HIF-2α, which reduced tubular damages via preservation of adequate renal microvascular perfusion after ischemia. Thus, preconditional HIF-2α activation might serve as a novel therapeutic strategy for the treatment of ischemic acute renal failure

Macrocyclic β-Sheet Peptides That Inhibit the Aggregation of a Tau-Protein-Derived Hexapeptide

This paper describes studies of a series of macrocyclic β-sheet peptides 1 that inhibit the aggregation of a tau-protein-derived peptide. The macrocyclic β-sheet peptides comprise a pentapeptide "upper" strand, two δ-linked ornithine turn units, and a "lower" strand comprising two additional residues and the β-sheet peptidomimetic template "Hao". The tau-derived peptide Ac-VQIVYK-NH(2) (AcPHF6) aggregates in solution through β-sheet interactions to form straight and twisted filaments similar to those formed by tau protein in Alzheimer's neurofibrillary tangles. Macrocycles 1 containing the pentapeptide VQIVY in the "upper" strand delay and suppress the onset of aggregation of the AcPHF6 peptide. Inhibition is particularly pronounced in macrocycles 1a, 1d, and 1f, in which the two residues in the "lower" strand provide a pattern of hydrophobicity and hydrophilicity that matches that of the pentapeptide "upper" strand. Inhibition varies strongly with the concentration of these macrocycles, suggesting that it is cooperative. Macrocycle 1b containing the pentapeptide QIVYK shows little inhibition, suggesting the possibility of a preferred direction of growth of AcPHF6 β-sheets. On the basis of these studies, a model is proposed in which the AcPHF6 amyloid grows as a layered pair of β-sheets and in which growth is blocked by a pair of macrocycles that cap the growing paired hydrogen-bonding edges. This model provides a provocative and appealing target for future inhibitor design

Active removal of waste dye pollutants using Ta[sub]3N[sub]5/W[sub]18O[sub]49 nanocomposite fibres

A scalable solvothermal technique is reported for the synthesis of a photocatalytic composite material consisting of orthorhombic Ta3N5 nanoparticles and WOx≤3 nanowires. Through X-ray diffraction and X-ray photoelectron spectroscopy, the as-grown tungsten(VI) sub-oxide was identified as monoclinic W18O49. The composite material catalysed the degradation of Rhodamine B at over double the rate of the Ta3N5 nanoparticles alone under illumination by white light, and continued to exhibit superior catalytic properties following recycling of the catalysts. Moreover, strong molecular adsorption of the dye to the W18O49 component of the composite resulted in near-complete decolourisation of the solution prior to light exposure. The radical species involved within the photocatalytic mechanisms were also explored through use of scavenger reagents. Our research demonstrates the exciting potential of this novel photocatalyst for the degradation of organic contaminants, and to the authors’ knowledge the material has not been investigated previously. In addition, the simplicity of the synthesis process indicates that the material is a viable candidate for the scale-up and removal of dye pollutants on a wider scale

Targeting Huntington’s disease through histone deacetylases

Huntington’s disease (HD) is a debilitating neurodegenerative condition with significant burdens on both patient and healthcare costs. Despite extensive research, treatment options for patients with this condition remain limited. Aberrant post-translational modification (PTM) of proteins is emerging as an important element in the pathogenesis of HD. These PTMs include acetylation, phosphorylation, methylation, sumoylation and ubiquitination. Several families of proteins are involved with the regulation of these PTMs. In this review, I discuss the current evidence linking aberrant PTMs and/or aberrant regulation of the cellular machinery regulating these PTMs to HD pathogenesis. Finally, I discuss the evidence suggesting that pharmacologically targeting one of these protein families the histone deacetylases may be of potential therapeutic benefit in the treatment of HD

Why Functional Pre-Erythrocytic and Bloodstage Malaria Vaccines Fail: A Meta-Analysis of Fully Protective Immunizations and Novel Immunological Model

Background: Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants. Methodology/Principal Findings: We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally. Conclusions/Significance: We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications fo