An Integrated Mitochondrial ROS Production and Scavenging Model: Implications for Heart Failure

It has been observed experimentally that cells from failing hearts exhibit elevated levels of reactive oxygen species (ROS) upon increases in energetic workload. One proposed mechanism for this behavior is mitochondrial Ca²⁺ mismanagement that leads to depletion of ROS scavengers. Here, we present a computational model to test this hypothesis. Previously published models of ROS production and scavenging were combined and reparameterized to describe ROS regulation in the cellular environment. Extramitochondrial Ca²⁺ pulses were applied to simulate frequency-dependent changes in cytosolic Ca²⁺. Model results show that decreased mitochondrial Ca²⁺uptake due to mitochondrial Ca²⁺ uniporter inhibition (simulating Ru360) or elevated cytosolic Na⁺, as in heart failure, leads to a decreased supply of NADH and NADPH upon increasing cellular workload. Oxidation of NADPH leads to oxidation of glutathione (GSH) and increased mitochondrial ROS levels, validating the Ca²⁺ mismanagement hypothesis. The model goes on to predict that the ratio of steady-state [H₂O₂]_m during 3Hz pacing to [H₂O₂]_m at rest is highly sensitive to the size of the GSH pool. The largest relative increase in [H₂O₂]_m in response to pacing is shown to occur when the total GSH and GSSG is close to 1 mM, whereas pool sizes below 0.9 mM result in high resting H₂O₂ levels, a quantitative prediction only possible with a computational model.     

Design,synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.     

Nectar bacteria,but not yeast,weaken a plant–pollinator mutualism

Mutualistic interactions are often subject to exploitation by species that are not directly involved in the mutualism. Understanding which organisms act as such ‘third-party’ species and how they do so is a major challenge in the current study of mutualistic interactions. Here, we show that even species that appear ecologically similar can have contrasting effects as third-party species. We experimentally compared the effects of nectar-inhabiting bacteria and yeasts on the strength of a mutualism between a hummingbird-pollinated shrub, Mimulus aurantiacus, and its pollinators. We found that the common bacterium Gluconobacter sp., but not the common yeast Metschnikowia reukaufii, reduced pollination success, seed set and nectar consumption by pollinators, thereby weakening the plant–pollinator mutualism. We also found that the bacteria reduced nectar pH and total sugar concentration more greatly than the yeasts did and that the bacteria decreased glucose concentration and increased fructose concentration whereas the yeasts affected neither. These distinct changes to nectar chemistry may underlie the microbes'' contrasting effects on the mutualism. Our results suggest that it is necessary to understand the determinants of microbial species composition in nectar and their differential modification of floral rewards to explain the mutual benefits that plants and pollinators gain from each other.     

Does aging affect the immune status? A comparative analysis in 300 healthy volunteers from France,Austria and Spain

Background

As the European population is getting older, there is growing need in scientific data on how to achieve healthy and successful aging. A decline in immune function with age is unanimously supported by many epidemiological and clinical observations, with a decrease in T-cell mediated function encompassing a large part of this alteration. In the EU-funded VITAGE project, the effects of aging on biomarkers of immune status are being studied in three European countries. According to strict inclusion/exclusion criteria, a cohort of 300 healthy male non-smoking 20–75 years old volunteers were enrolled in France (n?=?99), Spain (n?=?100) and Austria (n?=?101). In each country, the volunteers were classified as a function of age (one age group per decade). Biomarkers of immune status were determined including delayed-type hypersensitivity tests, measurement of lymphocyte surface markers, and serum determinations of interleukin-2, complement fractions and immunoglobulins.

Results

There were moderate differences in the biomarkers of immune status of the VITAGE study volunteers among the three European centres. The percentage of Natural Killer (NK) cells was 156% and 142% higher in Spain as compared to France and Austria, respectively (p?<?0.0001), and this increase was observed at any age group above 30 years. Comparison between age-groups showed that in Spain, but not in France or Austria, older individuals had significantly a lower B lymphocyte distribution and conversely, a higher NK cell distribution. Moreover, the CD4/CD8 ratio was positively correlated with age in Austrian subjects (p?<?0.0001).

Conclusion

Our results provide evidence of an increased NK cell distribution in the elderly, especially in the Spanish population. NK cell status may predict morbidity and mortality in the elderly, emphasizing the importance of innate as well as adaptive immunity in ensuring healthy longevity and cancer resistance, possibly in link with the Mediterranean diet.

     

Interactive effects of pests increase seed yield

Loss in seed yield and therefore decrease in plant fitness due to simultaneous attacks by multiple herbivores is not necessarily additive, as demonstrated in evolutionary studies on wild plants. However, it is not clear how this transfers to crop plants that grow in very different conditions compared to wild plants. Nevertheless, loss in crop seed yield caused by any single pest is most often studied in isolation although crop plants are attacked by many pests that can cause substantial yield losses. This is especially important for crops able to compensate and even overcompensate for the damage. We investigated the interactive impacts on crop yield of four insect pests attacking different plant parts at different times during the cropping season. In 15 oilseed rape fields in Sweden, we estimated the damage caused by seed and stem weevils, pollen beetles, and pod midges. Pest pressure varied drastically among fields with very low correlation among pests, allowing us to explore interactive impacts on yield from attacks by multiple species. The plant damage caused by each pest species individually had, as expected, either no, or a negative impact on seed yield and the strongest negative effect was caused by pollen beetles. However, seed yield increased when plant damage caused by both seed and stem weevils was high, presumably due to the joint plant compensatory reaction to insect attack leading to overcompensation. Hence, attacks by several pests can change the impact on yield of individual pest species. Economic thresholds based on single species, on which pest management decisions currently rely, may therefore result in economically suboptimal choices being made and unnecessary excessive use of insecticides.     

Screening for Unruptured Intracranial Aneurysms in Autosomal Dominant Polycystic Kidney Disease: A Survey of 420 Nephrologists

BackgroundDespite a high prevalence of intracranial aneurysm (ICA) in autosomal dominant polycystic kidney disease (ADPKD), rupture events are rare. The current recommendations for ICA screening are based on expert opinions and studies with low levels of evidence.ObjectivesThe aim of our study was to describe the attitudes of practicing nephrologists in Europe towards screening for ICA using magnetic resonance angiography (MRA).MethodsWe conducted a web-based survey among 1315 European French-speaking nephrologists and nephrology residents. An anonymous, electronic questionnaire including 24 independent questions related to ICA screening modalities, indications and participant profiles was sent by email between September and December 2014. Four hundred and twenty nephrologists (mostly from France) participated, including 31 nephrology residents; the response rate was 32%.ResultsSystematic screening for ICA was advocated by 28% of the nephrologists. A family history of ICA rupture, sudden death, stroke and migraine were consensual indications for screening (> 90% of the panel). In other clinical situations largely not covered by the recommendations (pregnancy, nephrectomy, kidney transplantation, cardiac or hepatic surgery, uncontrolled hypertension, lack of familial ADPKD history, at-risk activity, tobacco use), the attitudes towards screening were highly divergent. ICA screening was influenced by nephrologists experience with ADPKD and by their practice setting. The majority of participants (57%) would not repeat a normal ICA screening. Only a few participants (22%) knew that non-contrast MRA was the reference diagnostic tool for ICA screening, whereas most participants thought that contrast enhancement was necessary to screen for ICA. The results from the nephrology residents were analyzed separately and yielded similar results.ConclusionThis practice survey revealed that most nephrologists follow the current recommendations for the initial screening of ICAs. However, more than a quarter of the panel was in favor of systematic ICA screening, most nephrologists did not know that contrast medium was not necessary to screen for ICA using MRA, and many areas of uncertainty remain.     

Density-dependent reproduction causes winter crashes in a common vole population

Common voles in western France exhibit three-year population cycles with winter crashes after large outbreaks. During the winter of 2011–2012, we monitored survival, reproduction, recruitment and population growth rate of common voles at different densities (from low to outbreak densities) in natura to better understand density dependence of demographic parameters. Between October and April, the number of animals decreased irrespective of initial density. However, the decline was more pronounced when October density was higher (loss of ≈54 % of individuals at low density and 95 % at high density). Using capture-mark-recapture models with Pradel's temporal symmetry approach, we found a negative effect of density on recruitment and reproduction. In contrast, density had a slightly positive effect on survival indicating that mortality did not drive the steeper declines in animal numbers at high density. We discuss these results in a population cycle framework, and suggest that crashes after outbreaks could reflect negative effects of density dependence on reproduction rather than changes in mortality rates.     

Structural and functional responses of invertebrate communities to climate change and flow regulation in alpine catchments

Understanding and predicting how biological communities respond to climate change is critical for assessing biodiversity vulnerability and guiding conservation efforts. Glacier‐ and snow‐fed rivers are one of the most sensitive ecosystems to climate change, and can provide early warning of wider‐scale changes. These rivers are frequently used for hydropower production but there is minimal understanding of how biological communities are influenced by climate change in a context of flow regulation. This study sheds light on this issue by disentangling structural (water temperature preference, taxonomic composition, alpha, beta and gamma diversities) and functional (functional traits, diversity, richness, evenness, dispersion and redundancy) effects of climate change in interaction with flow regulation in the Alps. For this, we compared environmental and aquatic invertebrate data collected in the 1970s and 2010s in regulated and unregulated alpine catchments. We hypothesized a replacement of cold‐adapted species by warming‐tolerant ones, high temporal and spatial turnover in taxa and trait composition, along with reduced taxonomic and functional diversities in consequence of climate change. We expected communities in regulated rivers to respond more drastically due to additive or synergistic effects between flow regulation and climate change. We found divergent structural but convergent functional responses between free‐flowing and regulated catchments. Although cold‐adapted taxa decreased in both of them, greater colonization and spread of thermophilic species was found in the free‐flowing one, resulting in higher spatial and temporal turnover. Since the 1970s, taxonomic diversity increased in the free flowing but decreased in the regulated catchment due to biotic homogenization. Colonization by taxa with new functional strategies (i.e. multivoltine taxa with small body size, resistance forms, aerial dispersion and reproduction by clutches) increased functional diversity but decreased functional redundancy through time. These functional changes could jeopardize the ability of aquatic communities facing intensification of ongoing climate change or new anthropogenic disturbances.