Robustness and epistasis in mutation-selection models

We investigate the fitness advantage associated with the robustness of a phenotype against deleterious mutations using deterministic mutation-selection models of quasispecies type equipped with a mesa shaped fitness landscape. We obtain analytic results for the robustness effect which become exact in the limit of infinite sequence length. Thereby, we are able to clarify a seeming contradiction between recent rigorous work and an earlier heuristic treatment based on a mapping to a Schr\"odinger equation. We exploit the quantum mechanical analogy to calculate a correction term for finite sequence lengths and verify our analytic results by numerical studies. In addition, we investigate the occurrence of an error threshold for a general class of epistatic landscape and show that diminishing epistasis is a necessary but not sufficient condition for error threshold behavior.Comment: 20 pages, 14 figure

Alginate hydrogels for in vivo bone regeneration : the immune competence of the animal model matters

Biomaterials with tunable biophysical properties hold great potential for tissue engineering. The adaptive immune system plays an important role in bone regeneration. Our goal is to investigate the regeneration potential of cell-laden alginate hydrogels depending on the immune status of the animal model. Specifically, the regeneration potential of rat mesenchymal stromal cell (MSC)-laden, void-forming alginate hydrogels, with a stiffness optimized for osteogenic differentiation, is studied in 5 mm critical-sized femoral defects, in both T-cell deficient athymic RNU nude rats and immunocompetent Sprague Dawley rats. Bone volume fraction, bone mineral density and tissue mineral density are higher for athymic RNU nude rats 6 weeks post-surgery. Additionally, these animals show a significantly higher number of total cells and cells with non-lymphocyte morphology at the defect site, while the number of cells with lymphocyte-like morphology is lower. Hydrogel degradation is slower and the remaining alginate fragments are surrounded by a thicker fibrous capsule. Ossification islands originating from alginate residues suggest that encapsulated MSCs differentiate into the osteogenic lineage and initiate the mineralization process. However, this effect is insufficient to fully bridge the bone defect in both animal models. Alginate hydrogels can be used to deliver MSCs and thereby recruit endogenous cells through paracrine signaling, but additional osteogenic stimuli are needed to regenerate critical-sized segmental femoral defects

Osmotic pressure modulates single cell cycle dynamics inducing reversible growth arrest and reactivation of human metastatic cells

Biophysical cues such as osmotic pressure modulate proliferation and growth arrest of bacteria, yeast cells and seeds. In tissues, osmotic regulation takes place through blood and lymphatic capillaries and, at a single cell level, water and osmoregulation play a critical role. However, the effect of osmotic pressure on single cell cycle dynamics remains poorly understood. Here, we investigate the effect of osmotic pressure on single cell cycle dynamics, nuclear growth, proliferation, migration and protein expression, by quantitative time-lapse imaging of single cells genetically modified with fluorescent ubiquitination-based cell cycle indicator 2 (FUCCI2). Single cell data reveals that under hyperosmotic stress, distinct cell subpopulations emerge with impaired nuclear growth, delayed or growth arrested cell cycle and reduced migration. This state is reversible for mild hyperosmotic stress, where cells return to regular cell cycle dynamics, proliferation and migration. Thus, osmotic pressure can modulate the reversible growth arrest and reactivation of human metastatic cells

Infrared Observations of the Candidate LBV 1806-20 & Nearby Cluster Stars

We report near-infrared photometry, spectroscopy, and speckle imaging of the hot, luminous star we identify as candidate LBV 1806-20. We also present photometry and spectroscopy of 3 nearby stars, which are members of the same star cluster containing LBV 1806-20 and SGR 1806-20. The spectroscopy and photometry show that LBV 1806-20 is similar in many respects to the luminous ``Pistol Star'', albeit with some important differences. They also provide estimates of the effective temperature and reddening of LBV 1806-20, and confirm distance estimates, leading to a best estimate for the luminosity of this star of $> 5 \times 10^6 L_{\odot}$. The nearby cluster stars have spectral types and inferred absolute magnitudes which confirm the distance (and thus luminosity) estimate for LBV 1806-20. If we drop kinematic measurements of the distance ($15.1 ^{+1.8}_{-1.3}$ kpc), we have a lower limit on the distance of $>9.5$ kpc, and on the luminosity of $>2 \times 10^6 L_{\odot}$, based on the cluster stars. If we drop both the kinematic and cluster star indicators for distance, an ammonia absorption feature sets yet another lower limit to the distance of $>5.7$ kpc, with a corresponding luminosity estimate of $>7 \times 10^5 L_{\odot}$ for the candidate LBV 1806-20. Furthermore, based on very high angular-resolution speckle images, we determine that LBV 1806-20 is not a cluster of stars, but is rather a single star or binary system. Simple arguments based on the Eddington luminosity lead to an estimate of the total mass of LBV 1806-20 (single or binary) exceeding $190 M_{\odot}$. We discuss the possible uncertainties in these results, and their implications for the star formation history of this cluster.Comment: 36 pages, including 8 figures (Figures 1 and 7 in JPG format due to space); Accepted for publication in Ap

In vivo microCT-based time-lapse morphometry reveals anatomical site-specific differences in bone (re)modeling serving as baseline parameters to detect early pathological events

The bone structure is very dynamic and continuously adapts its geometry to external stimuli by modeling and remodeling the mineralized tissue. In vivo microCT-based time-lapse morphometry is a powerful tool to study the temporal and spatial dynamics of bone (re)modeling. Here an advancement in the methodology to detect and quantify site-specific differences in bone (re)modeling of 12-week-old BALB/c nude mice is presented. We describe our method of quantifying new bone surface interface readouts and how these are influenced by bone curvature. This method is then used to compare bone surface (re)modeling in mice across different anatomical regions to demonstrate variations in the rate of change and spatial gradients thereof. Significant differences in bone (re)modeling baseline parameters between the metaphyseal and epiphyseal are shown, as well as cortical and trabecular bone of the distal femur and proximal tibia. These results are validated using conventional static in vivo microCT analysis. Finally, the insights from these new baseline values of physiological bone (re)modeling were used to evaluate pathological bone (re)modeling in a pilot breast cancer bone metastasis model. The method shows the potential to be suitable to detect early pathological events and track their spatio-temporal development in both cortical and trabecular bone. This advancement in (re)modeling surface analysis and defined baseline parameters according to distinct anatomical regions will be valuable to others investigating various disease models with site-distinct local alterations in bone (re)modeling.ER

Estimating the potential public health impact of seasonal malaria chemoprevention in African children

Seasonal malaria chemoprevention, previously known as intermittent preventive treatment in children, is highly effective in areas with a short malaria transmission season. Here we assess seasonality in malaria incidence data and define a predictor of seasonality based on rainfall. We then use spatial rainfall, malaria endemicity and population data to identify areas likely to have highly seasonal malaria incidence, and estimate the population at risk and malaria burden in areas where seasonal malaria chemoprevention would be appropriate. We estimate that in areas suitable for seasonal malaria chemoprevention, there are 39 million children under 5 years of age, who experience 33.7 million malaria episodes and 152,000 childhood deaths from malaria each year. The majority of this burden occurs in the Sahelian or sub-Sahelian regions of Africa. Our data suggest that seasonal malaria chemoprevention has the potential to avert several million malaria cases and tens of thousands of childhood deaths each year if successfully delivered to the populations at risk

Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration

Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine

Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data

Background:Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods.Methods and Findings:Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone.The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000-380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000-180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%-31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys.Conclusions:With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns.Please see later in the article for the Editors' Summary