Effective repair of articular cartilage using human pluripotent stem cell-derived tissue

In an effort to develop an effective source of clinically relevant cells and tissues for cartilage repair a directed differentiation method was used to generate articular chondrocytes and cartilage tissues from human embryonic stem cells (hESCs). It has previously been demonstrated that chondrocytes derived from hESCs retain a stable cartilage-forming phenotype following subcutaneous implantation in mice. In this report, the potential of hESC-derived articular-like cartilage to repair osteochondral defects created in the rat trochlea was evaluated. Articular cartilage-like tissues were generated from hESCs and implanted into the defects. After 6 and 12 weeks, the defects were evaluated histologically and immunohistochemically, and the quality of repair was assessed using a modified ICRS II scoring system. Following 6 and 12 weeks after implantation, hESC-derived cartilage tissues maintained their proteoglycan and type II collagen-rich matrix and scored significantly higher than control defects, which had been filled with fibrin glue alone. Implants were found to be well integrated with native host tissue at the basal and lateral surfaces, although implanted human cells and host cells remained regionally separated. A subset of implants underwent a process of remodeling similar to endochondral ossification, suggesting the potential for a single cartilaginous implant to promote the generation of new subchondral bone in addition to repair of the articular cartilage. The ability to create cartilage tissues with integrative and reparative properties from an unlimited and robust cell source represents a significant advance for cartilage repair that can be further developed in large animal models before clinicalsetting application

Revisiting global fossil fuel and biofuel emissions of ethane

Recent measurements over the Northern Hemisphere indicate that the long-term decline in the atmospheric burden of ethane (C2H6) has ended and the abundance increased dramatically between 2010 and 2014. The rise in C2H6 atmospheric abundances has been attributed to oil and natural gas extraction in North America. Existing global C2H6 emission inventories are based on outdated activity maps that do not account for current oil and natural gas exploitation regions. We present an updated global C2H6 emission inventory based on 2010 satellite-derived CH4 fluxes with adjusted C2H6 emissions over the U.S. from the National Emission Inventory (NEI 2011). We contrast our global 2010 C2H6 emission inventory with one developed for 2001. The C2H6 difference between global anthropogenic emissions is subtle (7.9 versus 7.2 Tg yr−1), but the spatial distribution of the emissions is distinct. In the 2010 C2H6 inventory, fossil fuel sources in the Northern Hemisphere represent half of global C2H6 emissions and 95% of global fossil fuel emissions. Over the U.S., unadjusted NEI 2011 C2H6 emissions produce mixing ratios that are 14–50% of those observed by aircraft observations (2008–2014). When the NEI 2011 C2H6 emission totals are scaled by a factor of 1.4, the Goddard Earth Observing System Chem model largely reproduces a regional suite of observations, with the exception of the central U.S., where it continues to underpredict observed mixing ratios in the lower troposphere. We estimate monthly mean contributions of fossil fuel C2H6 emissions to ozone and peroxyacetyl nitrate surface mixing ratios over North America of ~1% and ~8%, respectively

Extraordinary lifespans in ants: a test of evolutionary theories of ageing

Senescence presents not only a medical problem, but also an evolutionary paradox because it should be opposed by natural selection. Evolutionary hypotheses propose that ageing evolves as the necessary cost of processes increasing early reproductive success(1,2), or because of weaker selection against late-acting mutations(3). A prediction of these hypotheses is that the rate of ageing should increase and the average lifespan decrease as the rate of extrinsic mortality increases(1-7). Alternatively, non-adaptive, purely mechanistic hypotheses invoke damage to DNA, cells, tissues and organs as being the unique cause of senescence and ineluctable death of organisms(8). Here we show that the evolution of eusociality is associated with a 100-fold increase in insect lifespan. Such an increase is predicted by evolutionary theories because termite, bee and ant queens live in colonies that are sheltered and heavily defended against predators. Moreover, a comparison of ants with contrasting life histories also reveals an association between lifespan and extrinsic rate of mortality. These results provide strong support for evolutionary theories of ageing, as purely mechanistic hypotheses of senescence do not propose any association between the rate of extrinsic mortality and lifespans

A single low-energy, iron-poor supernova as the source of metals in the star SMSS J 031300.36-670839.3

The element abundance ratios of four low-mass stars with extremely low metallicities indicate that the gas out of which the stars formed was enriched in each case by at most a few, and potentially only one low-energy, supernova. Such supernovae yield large quantities of light elements such as carbon but very little iron. The dominance of low-energy supernovae is surprising, because it has been expected that the first stars were extremely massive, and that they disintegrated in pair-instability explosions that would rapidly enrich galaxies in iron. What has remained unclear is the yield of iron from the first supernovae, because hitherto no star is unambiguously interpreted as encapsulating the yield of a single supernova. Here we report the optical spectrum of SMSS J031300.36- 670839.3, which shows no evidence of iron (with an upper limit of 10^-7.1 times solar abundance). Based on a comparison of its abundance pattern with those of models, we conclude that the star was seeded with material from a single supernova with an original mass of ~60 Mo (and that the supernova left behind a black hole). Taken together with the previously mentioned low-metallicity stars, we conclude that low-energy supernovae were common in the early Universe, and that such supernovae yield light element enrichment with insignificant iron. Reduced stellar feedback both chemically and mechanically from low-energy supernovae would have enabled first-generation stars to form over an extended period. We speculate that such stars may perhaps have had an important role in the epoch of cosmic reionization and the chemical evolution of early galaxies.Comment: 28 pages, 6 figures, Natur

A random cell motility gradient downstream of FGF controls elongation of amniote embryos

Vertebrate embryos are characterized by an elongated antero-posterior (AP) body axis, which forms by progressive cell deposition from a posterior growth zone in the embryo. Here, we used tissue ablation in the chicken embryo to demonstrate that the caudal presomitic mesoderm (PSM) has a key role in axis elongation. Using time-lapse microscopy, we analysed the movements of fluorescently labelled cells in the PSM during embryo elongation, which revealed a clear posterior-to-anterior gradient of cell motility and directionality in the PSM. We tracked the movement of the PSM extracellular matrix in parallel with the labelled cells and subtracted the extracellular matrix movement from the global motion of cells. After subtraction, cell motility remained graded but lacked directionality, indicating that the posterior cell movements associated with axis elongation in the PSM are not intrinsic but reflect tissue deformation. The gradient of cell motion along the PSM parallels the fibroblast growth factor (FGF)/mitogen-activated protein kinase (MAPK) gradient1, which has been implicated in the control of cell motility in this tissue2. Both FGF signalling gain- and loss-of-function experiments lead to disruption of the motility gradient and a slowing down of axis elongation. Furthermore, embryos treated with cell movement inhibitors (blebbistatin or RhoK inhibitor), but not cell cycle inhibitors, show a slower axis elongation rate. We propose that the gradient of random cell motility downstream of FGF signalling in the PSM controls posterior elongation in the amniote embryo. Our data indicate that tissue elongation is an emergent property that arises from the collective regulation of graded, random cell motion rather than by the regulation of directionality of individual cellular movements

Selective Constraints on Amino Acids Estimated by a Mechanistic Codon Substitution Model with Multiple Nucleotide Changes

Empirical substitution matrices represent the average tendencies of substitutions over various protein families by sacrificing gene-level resolution. We develop a codon-based model, in which mutational tendencies of codon, a genetic code, and the strength of selective constraints against amino acid replacements can be tailored to a given gene. First, selective constraints averaged over proteins are estimated by maximizing the likelihood of each 1-PAM matrix of empirical amino acid (JTT, WAG, and LG) and codon (KHG) substitution matrices. Then, selective constraints specific to given proteins are approximated as a linear function of those estimated from the empirical substitution matrices. Akaike information criterion (AIC) values indicate that a model allowing multiple nucleotide changes fits the empirical substitution matrices significantly better. Also, the ML estimates of transition-transversion bias obtained from these empirical matrices are not so large as previously estimated. The selective constraints are characteristic of proteins rather than species. However, their relative strengths among amino acid pairs can be approximated not to depend very much on protein families but amino acid pairs, because the present model, in which selective constraints are approximated to be a linear function of those estimated from the JTT/WAG/LG/KHG matrices, can provide a good fit to other empirical substitution matrices including cpREV for chloroplast proteins and mtREV for vertebrate mitochondrial proteins. The present codon-based model with the ML estimates of selective constraints and with adjustable mutation rates of nucleotide would be useful as a simple substitution model in ML and Bayesian inferences of molecular phylogenetic trees, and enables us to obtain biologically meaningful information at both nucleotide and amino acid levels from codon and protein sequences.Comment: Table 9 in this article includes corrections for errata in the Table 9 published in 10.1371/journal.pone.0017244. Supporting information is attached at the end of the article, and a computer-readable dataset of the ML estimates of selective constraints is available from 10.1371/journal.pone.001724

The EMBLA survey - metal-poor stars in the Galactic bulge

Cosmological models predict the oldest stars in the Galaxy should be found closest to the centre of the potential well, in the bulge. The Extremely Metal-poor BuLge stars with AAOmega survey (EMBLA) successfully searched for these old, metal-poor stars by making use of the distinctive SkyMapper photometric filters to discover candidate metal-poor stars in the bulge. Their metal-poor nature was then confirmed using the AAOmega spectrograph on the Anglo-Australian Telescope. Here we present an abundance analysis of 10 bulge stars with −2.8 < [Fe/H] < −1.7 from MIKE/Magellan observations, in total determining the abundances of 22 elements. Combining these results with our previous high-resolution data taken as part of the Gaia-ESO Survey, we have started to put together a picture of the chemical and kinematic nature of the most metal-poor stars in the bulge. The currently available kinematic data are consistent with the stars belonging to the bulge, although more accurate measurements are needed to constrain the stars’ orbits. The chemistry of these bulge stars deviates from that found in halo stars of the same metallicity. Two notable differences are the absence of carbon-enhanced metal-poor bulge stars, and the α element abundances exhibit a large intrinsic scatter and include stars which are underabundant in these typically enhanced elements.LMH and MA have been supported by the Australian Research Council (grant FL110100012). ARC acknowledges support from the European Union FP7 programme through ERC grant number 320360. DY is supported through an Australian Research Council Future Fellowship (FT140100554). Research on metal-poor stars with SkyMapper is supported through Australian Research Council Discovery Projects grants DP120101237 and DP150103294 (PI: Da Costa). This publication makes use of data products from the Two Micron All Sky Survey, which is a joint project of the University of Massachusetts and the Infrared Processing and Analysis Center/California Institute of Technology, funded by the National Aeronautics and Space Administration and the National Science Foundation. This paper includes data gathered with the 6.5 metre Magellan Telescopes located at Las Campanas Observatory, Chile.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/mnras/stw100

MFGE8 does not influence chorio-retinal homeostasis or choroidal neovascularization in vivo

Purpose: Milk fat globule-epidermal growth factor-factor VIII (MFGE8) is necessary for diurnal outer segment phagocytosis and promotes VEGF-dependent neovascularization. The prevalence of two single nucleotide polymorphisms (SNP) in MFGE8 was studied in two exsudative or “wet” Age-related Macular Degeneration (AMD) groups and two corresponding control groups. We studied the effect of MFGE8 deficiency on retinal homeostasis with age and on choroidal neovascularization (CNV) in mice. Methods: The distribution of the SNP (rs4945 and rs1878326) of MFGE8 was analyzed in two groups of patients with “wet” AMD and their age-matched controls from Germany and France. MFGE8-expressing cells were identified in Mfge8+/− mice expressing ß-galactosidase. Aged Mfge8+/− and Mfge8−/− mice were studied by funduscopy, histology, electron microscopy, scanning electron microscopy of vascular corrosion casts of the choroid, and after laser-induced CNV. Results: rs1878326 was associated with AMD in the French and German group. The Mfge8 promoter is highly active in photoreceptors but not in retinal pigment epithelium cells. Mfge8−/− mice did not differ from controls in terms of fundus appearance, photoreceptor cell layers, choroidal architecture or laser-induced CNV. In contrast, the Bruch's membrane (BM) was slightly but significantly thicker in Mfge8−/− mice as compared to controls. Conclusions: Despite a reproducible minor increase of rs1878326 in AMD patients and a very modest increase in BM in Mfge8−/− mice, our data suggests that MFGE8 dysfunction does not play a critical role in the pathogenesis of AMD

Effect of prostaglandin E2 injection on the structural properties of the rat patellar tendon

Background: Increased tendon production of the inflammatory mediator prostaglandin E2 (PGE2) has been suggested to be a potential etiologic agent in the development of tendinopathy. Repeated injection of PGE2 into tendon has been proposed as a potential animal model for studying treatments for tendinopathy. In contrast, nonsteroidal anti-inflammatory drugs (NSAIDs) which inhibit PGE2 production and are commonly prescribed in treating tendinopathy have been shown to impair the healing of tendon after acute injury in animal models. The contradictory literature suggests the need to better define the functional effects of PGE2 on tendon. Our objective was to characterize the effects of PGE2 injection on the biomechanical and biochemical properties of tendon and the activity of the animals. Our hypothesis was that weekly PGE2 injection to the rat patellar tendon would lead to inferior biomechanical properties. Methods: Forty rats were divided equally into four groups. Three groups were followed for 4 weeks with the following peritendinous injection procedures: No injection (control), 4 weekly injections of saline (saline), 4 weekly injections of 800 ng PGE2 (PGE2-4 wks). The fourth group received 4 weekly injections of 800 ng PGE2 initially and was followed for a total of 8 weeks. All animals were injected bilaterally. The main outcome measurements included: the structural and material properties of the patellar tendon under tensile loading to failure, tendo

Molecular Characterization of the Gastrula in the Turtle Emys orbicularis: An Evolutionary Perspective on Gastrulation

Due to the presence of a blastopore as in amphibians, the turtle has been suggested to exemplify a transition form from an amphibian- to an avian-type gastrulation pattern. In order to test this hypothesis and gain insight into the emergence of the unique characteristics of amniotes during gastrulation, we have performed the first molecular characterization of the gastrula in a reptile, the turtle Emys orbicularis. The study of Brachyury, Lim1, Otx2 and Otx5 expression patterns points to a highly conserved dynamic of expression with amniote model organisms and makes it possible to identify the site of mesoderm internalization, which is a long-standing issue in reptiles. Analysis of Brachyury expression also highlights the presence of two distinct phases, less easily recognizable in model organisms and respectively characterized by an early ring-shaped and a later bilateral symmetrical territory. Systematic comparisons with tetrapod model organisms lead to new insights into the relationships of the blastopore/blastoporal plate system shared by all reptiles, with the blastopore of amphibians and the primitive streak of birds and mammals. The biphasic Brachyury expression pattern is also consistent with recent models of emergence of bilateral symmetry, which raises the question of its evolutionary significance