Modified Vaccinia Virus Ankara Exerts Potent Immune Modulatory Activities in a Murine Model

Background

Modified vaccinia virus Ankara (MVA), a highly attenuated strain of vaccinia virus, has been used as vaccine delivery vector in preclinical and clinical studies against infectious diseases and malignancies. Here, we investigated whether an MVA which does not encode any antigen (Ag) could be exploited as adjuvant per se.

Methodology/Principal Findings

We showed that dendritic cells infected in vitro with non-recombinant (nr) MVA expressed maturation and activation markers and were able to efficiently present exogenously pulsed Ag to T cells. In contrast to the dominant T helper (Th) 1 biased responses elicited against Ags produced by recombinant MVA vectors, the use of nrMVA as adjuvant for the co-administered soluble Ags resulted in a long lasting mixed Th1/Th2 responses.

Conclusions/Significance

These findings open new ways to potentiate and modulate the immune responses to vaccine Ags depending on whether they are co-administered with MVA or encoded by recombinant viruses.     

The Brazilian legal framework on the scientific use of animals

Brazil has an exceptionally dynamic research sector in Latin America in health, biotechnology, and pharmacology, backed by defined government policies on science and technology and a health research agenda focusing on important neglected diseases: malaria, leishmaniasis, Chagas disease, turberculosis, leprosy, and dengue. The Brazilian health research policy promotes partnerships and networks among scientists in academic institutions in both wealthy industrialized and disease-endemic countries, and in these efforts the government's guidelines for animal use in biomedical research are considered fundamental to guarantee both animal welfare and the quality of research. Given international discussions of animal experimentation regulations and guidelines, in this article we describe current Brazilian legislation governing the use of animals in scientific investigations. We conclude that, despite advances in the implementation of the 3Rs (reduction, refinement, replacement), the new regulatory framework does not sufficiently incorporate ethical considerations, lacking explicit reference to the 3Rs as well as measures for their full application. The more humane use of animals in research will depend on the approach adopted by Brazil's National Council for the Control of Animal Experimentation to promote the 3Rs and to improve internal regulations as well as data collection and analysis in research institutions. In Brazil as elsewhere, one of the greatest challenges to policymakers is to harmonize the myriad and intertwined legal provisions without hindering biomedical research.     

Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy

Nodal and Activin belong to the TGF-β superfamily and are important regulators of embryonic stem cell fate. Here we investigated whether Nodal and Activin regulate self-renewal of pancreatic cancer stem cells. Nodal and Activin were hardly detectable in more differentiated pancreatic cancer cells, while cancer stem cells and stroma-derived pancreatic stellate cells markedly overexpressed Nodal and Activin, but not TGF-β. Knockdown or pharmacological inhibition of the Nodal/Activin receptor Alk4/7 in cancer stem cells virtually abrogated their self-renewal capacity and in vivo tumorigenicity, and reversed the resistance of orthotopically engrafted cancer stem cells to gemcitabine. However, engrafted primary human pancreatic cancer tissue with a substantial stroma showed no response due to limited drug delivery. The addition of a stroma-targeting hedgehog pathway inhibitor enhanced delivery of the Nodal/Activin inhibitor and translated into long-term, progression-free survival. Therefore, inhibition of the Alk4/7 pathway, if combined with hedgehog pathway inhibition and gemcitabine, provides a therapeutic strategy for targeting cancer stem cells.     

Saturated fat intake and alcohol consumption modulate the association between the APOE polymorphism and risk of future coronary heart disease: a nested case-control study in the Spanish EPIC cohort

The association is still not clear between the common APOE polymorphism and coronary heart disease (CHD) risk, nor its modulation by diet. Thus, our aim was to study the association between the APOE genotypes and incident CHD and how dietary fat and alcohol consumption modify these effects. We performed a nested case-control study in the Spanish European Prospective Investigation into Cancer and Nutrition cohort. Healthy men and women (41?440, 30-69 years) were followed up over a 10-year period, with the incident CHD cases being identified. We analyzed 534 incident CHD cases and 1123 controls. APOE, dietary intake and plasma lipids were determined at baseline. The APOE polymorphism was significantly associated with low-density lipoprotein cholesterol (LDL-C), and gene-alcohol interactions in determining LDL-C were detected. In the whole population, the E2 allele was significantly associated with a lower CHD risk than E3/E3 subjects [odds ratio (OR), 0.58; 95% confidence interval (CI), 0.38-0.89]. The E4 allele did not reach statistical significance vs. E3/E3 (OR, 1.17; 95% CI, 0.88-1.58). However, saturated fat intake modified the effect of the APOE polymorphism in determining CHD risk. When saturated fat intake was low (<10% of energy), no statistically significant association between the APOE polymorphism and CHD risk was observed (P=.682). However, with higher intake (≥10%), the polymorphism was significant (P=.005), and the differences between E2 and E4 carriers were magnified (OR for E4 vs. E2, 3.33; 95% CI, 1.61-6.90). Alcohol consumption also modified the effect of the APOE on CHD risk.In conclusion, in this Mediterranean population, the E2 allele is associated with lower CHD risk, and this association is modulated by saturated fat and alcohol consumption.     

Cats under cover: Habitat models indicate a high dependency on woodlands by Atlantic Forest felids

Four Neotropical small and medium felids—the ocelot, jaguarundi, margay, and southern tiger cat—have overlapping geographic distributions in the endangered Atlantic Forest. Local studies show that these felids avoid areas with high human impact, but the three smaller ones use human‐modified areas more frequently than do ocelots. To understand how landscape changes affect the habitat distribution of these four felids in the Atlantic Forest of Argentina, we used maximum entropy models to analyze the effect of environmental and anthropogenic factors. We estimated niche breadth and overlap among these felids. The conversion of the native forest to land uses without trees was the most important variable that determined the habitat distribution of the four species. For all four species, the optimal habitat covered about 1/3 of the study area and corresponds mainly to the native forest areas. Nearly 50% of these areas had some level of protection. The niche width was higher for the small felids than for ocelots. Niche overlap was high for all species pairs, but higher among the small felids and lower for each of these with the ocelot. The four felids were negatively affected by native forest loss, with ocelots being more sensitive than the smaller felids. The conversion of unprotected forest areas to other types of land uses would imply a greater habitat loss for these felids. The protection of current remnants of Atlantic Forest in Argentina is important for the long‐term conservation of the four felids. Abstract in Spanish is available with online material.     

Phylogenetic evidence from freshwater crayfishes that cave adaptation is not an evolutionary dead‐end

Caves are perceived as isolated, extreme habitats with a uniquely specialized biota, which long ago led to the idea that caves are “evolutionary dead‐ends.” This implies that cave‐adapted taxa may be doomed for extinction before they can diversify or transition to a more stable state. However, this hypothesis has not been explicitly tested in a phylogenetic framework with multiple independently evolved cave‐dwelling groups. Here, we use the freshwater crayfish, a group with dozens of cave‐dwelling species in multiple lineages, as a system to test this hypothesis. We consider historical patterns of lineage diversification and habitat transition as well as current patterns of geographic range size. We find that while cave‐dwelling lineages have small relative range sizes and rarely transition back to the surface, they exhibit remarkably similar diversification patterns to those of other habitat types and appear to be able to maintain a diversity of lineages through time. This suggests that cave adaptation is not a “dead‐end” for freshwater crayfish, which has positive implications for our understanding of biodiversity and conservation in cave habitats.     

Polymorphisms of 20 regulatory proteins between Mycobacterium tuberculosis and Mycobacterium bovis

Mycobacterium tuberculosis and Mycobacterium bovis are responsible for tuberculosis in humans and animals, respectively. Both species are closely related and belong to the Mycobacterium tuberculosis complex (MTC). M. tuberculosis is the most ancient species from which M. bovis and other members of the MTC evolved. The genome of M. bovis is over >99.95% identical to that of M. tuberculosis but with seven deletions ranging in size from 1 to 12.7 kb. In addition, 1200 single nucleotide mutations in coding regions distinguish M. bovis from M. tuberculosis. In the present study, we assessed 75 M. tuberculosis genomes and 23 M. bovis genomes to identify non‐synonymous mutations in 202 coding sequences of regulatory genes between both species. We identified species‐specific variants in 20 regulatory proteins and confirmed differential expression of hypoxia‐related genes between M. bovis and M. tuberculosis.     

Optimisation of biocide dose as a function of residual biocide in a heat exchanger pilot plant effluent

Biofouling is one of the most serious problems facing numerous industrial processes. In the case of a heat exchanger unit, biological deposits adhering to the inside surface of its tubes reduce heat transfer and, thus, the thermal performance of the cycle. Control of this phenomenon is proving fundamental for both land and marine equipment to operate in optimum working conditions. Hence, it is necessary to apply antifouling methods capable of keeping surfaces free of any kind of biofouling. This paper reports on the behaviour resulting from use of the flow inversion method vs that obtained by using various chemical treatments. The study compares the effectiveness of certain chemical treatments (Na hypochlorite, peracetic acid and a compound formed by Na bromide + Na hypochlorite) for removing a biofouling film that has already formed on the inside surfaces of tubes in a heat exchanger pilot plant. The paper also addresses the issue of optimising the concentration of biocide dose as a function of the residual biocide in order minimise the environmental impact caused by effluent from industrial plants. The results indicate that it is possible to eliminate a biofilm formed on the inside surfaces of tubes by the use of intermittent doses of chemical treatments at low concentrations and over long application times. Furthermore, once the stabilisation phase is reached 6 d after starting the treatment, it is possible to maintain the conditions achieved using only 20% of the initial dosage.