Experimental and numerical simulations of oblique extreme wave conditions in front of a breakwater's trunk and round head

ABSTARCT: Climate change studies already reported sea level rise as an accepted scenario, which induces changes in nearshore wave conditions. A large range of new experiences including water level, run-up, overtopping, hydrodynamic data for different wave steepnesses and directions was performed in the Leibniz Universität Hannover (LUH) wave basin for a rubble mound breakwater with a slope of 1(V):2(H). This work presents, focusing on oblique extreme wave conditions, numerical simulations of the hydrodynamics in that experiment using OpenFOAM®. Results of the wave generation boundary conditions and their propagation, namely elevation of the water level free-surface and velocity data at specific locations are compared and discussed with data from experimental measurements acquired by acoustic wave gauges and acoustic doppler velocimeter (ADV) / Vectrino equipment. Although an exact match between numerical and laboratory values was not reached, an appropriate incident wave angle and a reasonable amplitude of velocities and water depths was achieved and the same happened to the statistics of those values

Tear Fluid SIgA as a Noninvasive Biomarker of Mucosal Immunity and Common Cold Risk

PURPOSE: Research has not convincingly demonstrated the utility of saliva secretory immunoglobulin-A (SIgA) as a biomarker of upper respiratory tract infection (URTI) risk, and disagreement exists about the influence of heavy exercise ("open-window theory") and dehydration on saliva SIgA. Prompted by the search for viable alternatives, we compared the utility of tear and saliva SIgA to predict URTI prospectively (study 1) and assessed the influence of exercise (study 2) and dehydration (study 3) using a repeated-measures crossover design. METHODS: In study 1, 40 subjects were recruited during the common-cold season. Subjects provided tear and saliva samples weekly and recorded upper respiratory symptoms (URS) daily for 3 wk. Real-time PCR confirmed common-cold pathogens in 9 of 11 subjects reporting URS (82%). Predictive utility of tear and saliva SIgA was explored by comparing healthy samples with those collected during the week before URS. In study 2, 13 subjects performed a 2-h run at 65% V O2peak. In study 3, 13 subjects performed exercise heat stress to 3% body mass loss followed by overnight fluid restriction. RESULTS: Tear SIgA concentration and secretion rate were 48% and 51% lower, respectively, during URTI and 34% and 46% lower the week before URS (P 30%. Tear SIgA secretion rate >5.5 mug.min(-1) or no decrease of >30% predicted subjects free of URS in >80% of cases. Tear SIgA concentration decreased after exercise (-57%, P < 0.05) in line with the "open-window theory" but was unaffected by dehydration. Saliva flow rate decreased and saliva SIgA concentration increased after exercise and during dehydration (P < 0.05). CONCLUSIONS: Tear SIgA has utility as a noninvasive biomarker of mucosal immunity and common-cold risk

Paleogenomic Evidence for Multi-generational Mixing between Neolithic Farmers and Mesolithic Hunter-Gatherers in the Lower Danube Basin

The transition from hunting and gathering to farming involved profound cultural and technological changes. In Western and Central Europe, these changes occurred rapidly and synchronously after the arrival of early farmers of Anatolian origin [1-3], who largely replaced the local Mesolithic hunter-gatherers [1, 4-6]. Further east, in the Baltic region, the transition was gradual, with little or no genetic input from incoming farmers [7]. Here we use ancient DNA to investigate the relationship between hunter-gatherers and farmers in the Lower Danube basin, a geographically intermediate area that is characterized by a rapid Neolithic transition but also by the presence of archaeological evidence that points to cultural exchange, and thus possible admixture, between hunter-gatherers and farmers. We recovered four human paleogenomes (1.1× to 4.1× coverage) from Romania spanning a time transect between 8.8 thousand years ago (kya) and 5.4 kya and supplemented them with two Mesolithic genomes (1.7× and 5.3×) from Spain to provide further context on the genetic background of Mesolithic Europe. Our results show major Western hunter-gatherer (WHG) ancestry in a Romanian Eneolithic sample with a minor, but sizeable, contribution from Anatolian farmers, suggesting multiple admixture events between hunter-gatherers and farmers. Dietary stable-isotope analysis of this sample suggests a mixed terrestrial/aquatic diet. Our results provide support for complex interactions among hunter-gatherers and farmers in the Danube basin, demonstrating that in some regions, demic and cultural diffusion were not mutually exclusive, but merely the ends of a continuum for the process of Neolithization.This research was supported by a European Research Council (ERC) Starting Grant (ERC-2010-StG 263441) to R.P. G.G.-F. was also supported by MSC Individual Fellowship (NeoGenHeritage, grant no. 655478). E.R.J. was supported by a Herchel Smith Research Fellowship. M.H. and A.M. were supported by ERC consolidator grants 310763 GeneFlow and 647797 LocalAdaptation, respectively. V.S. was supported by the Gates Cambridge Trust. The work of C.L. was undertaken through the Partnerships in Priority Areas Program PN II, developed with the support of MEN-UEFISCDI (project no. PN-II-PTPCCA-2013-4-2302). A.G.-D. is supported by the research project BIOGEOS (CGL2014-57209-P) of the Spanish MINECO. The research of P.A., M.D.G., and L.D. on Los Canes is currently supported by the project CoChange (HAR2014-51830-P) of the Spanish State Plan for R+D+i (MINECO)

Nitroheterocyclic drugs cure experimental <i>Trypanosoma cruzi</i> infections more effectively in the chronic stage than in the acute stage

The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies

The Trypanosoma cruzi vitamin C dependent peroxidase confers protection against oxidative stress but is not a determinant of virulence.

BACKGROUND: The neglected parasitic infection Chagas disease is rapidly becoming a globalised public health issue due to migration. There are only two anti-parasitic drugs available to treat this disease, benznidazole and nifurtimox. Thus it is important to identify and validate new drug targets in Trypanosoma cruzi, the causative agent. T. cruzi expresses an ER-localised ascorbate-dependent peroxidase (TcAPx). This parasite-specific enzyme has attracted interest from the perspective of targeted chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: To assess the importance of TcAPx in protecting T. cruzi from oxidative stress and to determine if it is essential for virulence, we generated null mutants by targeted gene disruption. Loss of activity was associated with increased sensitivity to exogenous hydrogen peroxide, but had no effect on susceptibility to the front-line Chagas disease drug benznidazole. This suggests that increased oxidative stress in the ER does not play a significant role in its mechanism of action. Homozygous knockouts could proceed through the entire life-cycle in vitro, although they exhibited a significant decrease in their ability to infect mammalian cells. To investigate virulence, we exploited a highly sensitive bioluminescence imaging system which allows parasites to be monitored in real-time in the chronic stage of murine infections. This showed that depletion of enzyme activity had no effect on T. cruzi replication, dissemination or tissue tropism in vivo. CONCLUSIONS/SIGNIFICANCE: TcAPx is not essential for parasite viability within the mammalian host, does not have a significant role in establishment or maintenance of chronic infections, and should therefore not be considered a priority for drug design