Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain.

The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP(L)) is required for proliferation and effector T-cell development. However, the role of c-FLIP(L) in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP(L) transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4(+) T cells and may result from impaired thymic selection. At the molecular level, c-FLIP(L) overexpression inhibits the zeta chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP(L) as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.

Optimization strategies for fast detection of positive selection on phylogenetic trees.

MOTIVATION: The detection of positive selection is widely used to study gene and genome evolution, but its application remains limited by the high computational cost of existing implementations. We present a series of computational optimizations for more efficient estimation of the likelihood function on large-scale phylogenetic problems. We illustrate our approach using the branch-site model of codon evolution. RESULTS: We introduce novel optimization techniques that substantially outperform both CodeML from the PAML package and our previously optimized sequential version SlimCodeML. These techniques can also be applied to other likelihood-based phylogeny software. Our implementation scales well for large numbers of codons and/or species. It can therefore analyse substantially larger datasets than CodeML. We evaluated FastCodeML on different platforms and measured average sequential speedups of FastCodeML (single-threaded) versus CodeML of up to 5.8, average speedups of FastCodeML (multi-threaded) versus CodeML on a single node (shared memory) of up to 36.9 for 12 CPU cores, and average speedups of the distributed FastCodeML versus CodeML of up to 170.9 on eight nodes (96 CPU cores in total).Availability and implementation: ftp://ftp.vital-it.ch/tools/FastCodeML/. CONTACT: selectome@unil.ch or nicolas.salamin@unil.ch.

Predictors of mortality from pump failure and sudden cardiac death in patients with systolic heart failure and left ventricular dyssynchrony: results of the CARE-HF trial.

BACKGROUND: Determining a specific death cause may facilitate individualized therapy in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) decreased mortality in the Cardiac Resynchronization in Heart Failure trial by reducing pump failure and sudden cardiac death (SCD). This study analyzes predictors of specific causes of death. METHODS AND RESULTS: Univariate and multivariate analyses used 8 baseline and 3-month post-randomization variables to predict pump failure and SCD (categorized as "definite," "probable," and "possible"). Of 255 deaths, 197 were cardiovascular. There were 71 SCDs with a risk reduction by CRT of 0.47 (95% confidence interval 0.29-0.76; P = .002) with similar reductions in SCD classified as definite, probable, and possible. Univariate SCD predictors were 3-month HF status (mitral regurgitation [MR] severity, plasma brain natriuretic peptide [BNP], end-diastolic volume, and systolic blood pressure), whereas randomization to CRT decreased risk. Multivariate SCD predictors were randomization to CRT 0.56 (0.53-0.96, P = .035) and 3-month MR severity 1.82 (1.77-2.60, P = .0012). Univariate pump failure death predictors related to baseline HF state (quality of life score, interventricular mechanical delay, end-diastolic volume, plasma BNP, MR severity, and systolic pressure), whereas randomization to CRT and nonischemic cardiomyopathy decreased risk; multivariate predictors of pump failure death were baseline plasma BNP and systolic pressure and randomization to CRT. CONCLUSION: CRT decreased SCD in patients with systolic HF and ventricular dyssynchrony. SCD risk was increased with increased severity of MR (including the 3-month value for MR as a time-dependent covariate) and reduced by randomization to CRT. HF death was increased related to the level of systolic blood pressure, log BNP, and randomization to CRT. These results emphasize the importance and interdependence of HF severity to mortality from pump failure and SCD.

The contribution of a pollinating seed predator to selection on Silene latifolia females.

Interactions, antagonistic or mutualistic, can exert selection on plant traits. We explored the role of Hadena bicruris, a pollinating seed predator, as a selective agent on its host, the dioecious plant Silene latifolia. We exposed females from artificial-selection lines (many, small flowers (SF) vs. few, large flowers (LF)) to this moth. Infestation did not differ significantly between lines, but the odds of attacked fruits aborting were higher in SF females. We partitioned selection between that caused by moth attack and that resulting from all other factors. In both lines, selection via moth attack for fewer, smaller flowers contrasted with selection via other factors for more flowers. In LF females, selection via the two components was strongest and selection via moth attack also favoured increased fruit abortion. This suggests that the moths act as more of a selective force on flower size and number via their predating than their pollinating role.

Eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia have similar clinical, endoscopic and histological findings.

BACKGROUND: Some patients with a phenotypic appearance of eosinophilic oesophagitis (EoE) respond histologically to PPI, and are described as having PPI-responsive oesophageal eosinophilia (PPI-REE). It is unclear if PPI-REE is a GERD-related phenomenon, a subtype of EoE, or a completely unique entity. AIM: To compare demographic, clinical and histological features of EoE and PPI-REE. METHODS: Two databases were reviewed from the Walter Reed and Swiss EoE databases. Patients were stratified into two groups, EoE and PPI-REE, based on recent EoE consensus guidelines. Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least a 6-week course of treatment. RESULTS: One hundred and three patients were identified (63 EoE and 40 PPI-REE; mean age 40.2 years, 75% male and 89% Caucasian). The two cohorts had similar dysphagia (97% vs. 100%, P = 0.520), food impaction (43% vs. 35%, P = 0.536), and heartburn (33% vs. 32%, P = 1.000) and a similar duration of symptoms (6.0 years vs. 5.8 years, P = 0.850). Endoscopic features were also similar between EoE and PPI-REE; rings (68% vs. 68%, P = 1.000), furrows (70% vs. 70%, P = 1.000), plaques (19% vs. 10%, P = 0.272), strictures (49% vs. 30%, P = 0.066). EoE and PPI-REE were similar in the number of proximal (39 eos/hpf vs. 38 eos/hpf, P = 0.919) and distal eosinophils (50 vs. 43 eos/hpf, P = 0.285). CONCLUSIONS: EoE and PPI-responsive oesophageal eosinophilia are similar in clinical, histological and endoscopic features and therefore are indistinguishable without a PPI trial. Further studies are needed to determine why a subset of patients with oesophageal eosinophilia respond to PPI.

Inbreeding and selection on sex ratio in the bark beetle Xylosandrus germanus.

ABSTRACT: BACKGROUND: Local Mate Competition (LMC) theory predicts a female should produce a more female-biased sex ratio if her sons compete with each other for mates. Because it provides quantitative predictions that can be experimentally tested, LMC is a textbook example of the predictive power of evolutionary theory. A limitation of many earlier studies in the field is that the population structure and mating system of the studied species are often estimated only indirectly. Here we use microsatellites to characterize the levels of inbreeding of the bark beetle Xylosandrus germanus, a species where the level of LMC is expected to be high. RESULTS: For three populations studied, genetic variation for our genetic markers was very low, indicative of an extremely high level of inbreeding (FIS = 0.88). There was also strong linkage disequilibrium between microsatellite loci and a very strong genetic differentiation between populations. The data suggest that matings among non-siblings are very rare (3%), although sex ratios from X. germanus in both the field and the laboratory have suggested more matings between non-sibs, and so less intense LMC. CONCLUSIONS: Our results confirm that caution is needed when inferring mating systems from sex ratio data, especially when a lack of biological detail means the use of overly simple forms of the model of interest.

The evolution of trans-generational altruism: kin selection meets niche construction.

A cornerstone result of sociobiology states that limited dispersal can induce kin competition to offset the kin selected benefits of altruism. Several mechanisms have been proposed to circumvent this dilemma but all assume that actors and recipients of altruism interact during the same time period. Here, this assumption is relaxed and a model is developed where individuals express an altruistic act, which results in posthumously helping relatives living in the future. The analysis of this model suggests that kin selected benefits can then feedback on the evolution of the trait in a way that promotes altruistic helping at high rates under limited dispersal. The decoupling of kin competition and kin selected benefits results from the fact that by helping relatives living in the future, an actor is helping individuals that are not in direct competition with itself. A direct consequence is that behaviours which actors gain by reducing the common good of present and future generations can be opposed by kin selection. The present model integrates niche-constructing traits with kin selection theory and delineates demographic and ecological conditions under which altruism can be selected for; and conditions where the 'tragedy of the commons' can be reduced.

The incidence and selection of multiple mating in plants.

Mating with more than one pollen donor, or polyandry, is common in land plants. In flowering plants, polyandry occurs when the pollen from different potential sires is distributed among the fruits of a single individual, or when pollen from more than one donor is deposited on the same stigma. Because polyandry typically leads to multiple paternity among or within fruits, it can be indirectly inferred on the basis of paternity analysis using molecular markers. A review of the literature indicates that polyandry is probably ubiquitous in plants except those that habitually self-fertilize, or that disperse their pollen in pollen packages, such as polyads or pollinia. Multiple mating may increase plants' female component by alleviating pollen limitation or by promoting competition among pollen grains from different potential sires. Accordingly, a number of traits have evolved that should promote polyandry at the flower level from the female's point of view, e.g. the prolongation of stigma receptivity or increases in stigma size. However, many floral traits, such as attractiveness, the physical manipulation of pollinators and pollen-dispensing mechanisms that lead to polyandrous pollination, have probably evolved in response to selection to promote male siring success in general, so that polyandry might often best be seen as a by-product of selection to enhance outcross siring success. In this sense, polyandry in plants is similar to geitonogamy (selfing caused by pollen transfer among flowers of the same plant), because both polyandry and geitonogamy probably result from selection to promote outcross siring success, although geitonogamy is almost always deleterious while polyandry in plants will seldom be so.

Pulmonary embolism severity index and troponin testing for the selection of low-risk patients with acute symptomatic pulmonary embolism.

Summary Background: The combination of the Pulmonary Embolism Severity Index (PESI) and troponin testing could help physicians identify appropriate patients with acute pulmonary embolism (PE) for early hospital discharge. Methods: This prospective cohort study included a total of 567 patients from a single center registry with objectively confirmed acute symptomatic PE. On the basis of the PESI, each patient was classified into 1 of 5 classes (I to V). At the time of hospital admission, patients had troponin I (cTnI) levels measured. The endpoint of the study was all-cause mortality within 30 days after diagnosis. We calculated the mortality rates in 4 patient groups: group 1: PESI class I-II plus cTnI <0.1 ng mL(-1); group 2: PESI classes III-V plus cTnI <0.1 ng mL(-1); group 3: PESI classes I-II plus cTnI >/= 0.1 ng mL(-1); and group 4: PESI classes III-V plus cTnI >/= 0.1 ng mL(-1). Results: The study cohort had a 30-day mortality of 10% (95% confidence interval [CI], 7.6 to 12.5%). Mortality rates in the 4 groups were 1.3%, 14.2%, 0% and 15.4%, respectively. Compared to non-elevated cTnl, the low-risk PESI had a higher negative predictive value (NPV) (98.9% vs 90.8%) and negative likelihood ratio (NLR) (0.1 vs 0.9) for predicting mortality. The addition of non-elevated cTnI to low-risk PESI did not improve the NPV or the NLR compared to either test alone. Conclusions: Compared to cTnl testing, PESI classification more accurately identified patients with PE who are at low risk of all-cause death within 30-days of presentation.

Evolution of the epithelial sodium channel and the sodium pump as limiting factors of aldosterone action on sodium transport.

Despite large changes in salt intake, the mammalian kidney is able to maintain the extracellular sodium concentration and osmolarity within very narrow margins, thereby controlling blood volume and blood pressure. In the aldosterone-sensitive distal nephron (ASDN), aldosterone tightly controls the activities of epithelial sodium channel (ENaC) and Na,K-ATPase, the two limiting factors in establishing transepithelial sodium transport. It has been proposed that the ENaC/degenerin gene family is restricted to Metazoans, whereas the α- and β-subunits of Na,K-ATPase have homologous genes in prokaryotes. This raises the question of the emergence of osmolarity control. By exploring recent genomic data of diverse organisms, we found that: 1) ENaC/degenerin exists in all of the Metazoans screened, including nonbilaterians and, by extension, was already present in ancestors of Metazoa; 2) ENaC/degenerin is also present in Naegleria gruberi, an eukaryotic microbe, consistent with either a vertical inheritance from the last common ancestor of Eukaryotes or a lateral transfer between Naegleria and Metazoan ancestors; and 3) The Na,K-ATPase β-subunit is restricted to Holozoa, the taxon that includes animals and their closest single-cell relatives. Since the β-subunit of Na,K-ATPase plays a key role in targeting the α-subunit to the plasma membrane and has an additional function in the formation of cell junctions, we propose that the emergence of Na,K-ATPase, together with ENaC/degenerin, is linked to the development of multicellularity in the Metazoan kingdom. The establishment of multicellularity and the associated extracellular compartment ("internal milieu") precedes the emergence of other key elements of the aldosterone signaling pathway.

How to Improve the Use of Proton Pump Inhibitors

Introduction: Proton pump inhibitors (PPI) are one of the most prescribed medications in the world with proven efficacy. However, several studies showed that their use often doesn't respect indications, leading to over-consumption, thus exposing patients to drug interactions and adverse events (for example pneumonias). Interruption of PPIs can induce a rebound phenomenon. This generates costs for health systems.Methods: This is a prospective interventional study performed in two hospitals: La Chaux-de-Fonds (CDF, cases) and Neucha^tel (NE, control) during two six-month periods, comparing use of PPIs before and after intervention. We elaborated recommendations (PPI doses and treatment duration) based on recent medical literature that we summarized on A6 cards and gave out to all prescribing doctors in the hospital of CDF and held a 30-minute information session for the departments of surgery, medicine and anesthesiology in March 2010. Doctors were asked to apply our recommendations as often as possible, leaving space for their own assessment. No information was given to the doctors of the control hospital. The number of PPI tablets that the pharmacy sent to each careunit in both hospitals was counted and adjusted to the number of patientdays from April to September 2009 (before intervention) and April to September 2010 (after intervention). The number of other antacids that were used in both hospitals was counted during the same periods. General practitioners (GP) in the region around CDF received an explanation letter to avoid re-introduction, after discharge from the hospital, of PPI treatment stopped during the stay. The number of gastro-duodenal ulcers and upper digestive hemorrhages was counted from April to December 2009 and the same period in 2010 in both hospitals.Results: In 2010, in the hospital of CDF, the use of PPIs per 100 patient-days decreased by 36% in the surgical and medical departments compared to 2009. In the control hospital the use of PPIs per 100 patient-days increased by 10% in the surgical department and decreased by 5% in the medical department during the same periods. The decrease from 2009 to 2010 of PPI utilization in CDF comparing to NE is statistically significant: p<0.0001. Use of other antacids didn't change, ulcers or digestive hemorrhages decreased slightly from 2009 to 2010 in both hospitals. Conclusions: The study showed that with a very low-cost intervention, it is possible to decrease considerably the use of PPIs in a hospital, without taking any risk for gastro-intestinal complications.

Adaptive changes in a radial maze task: Efficient selection of baited arms with reduced foraging in senescent hooded rats

Qualitative differences in strategy selection during foraging in a partially baited maze were assessed in young and old rats. The baited and non-baited arms were at a fixed position in space and marked by a specific olfactory cue. The senescent rats did more re-entries during the first four-trial block but were more rapid than the young rats in selecting the reinforced arms during the first visits. Dissociation between the olfactory spatial cue reference by rotating the maze revealed that only few old subjects relied on olfactory cues to select the baited arms and the remainder relied mainly on the visuo-spatial cues.