Rolling ES cells down the Waddington landscape with Oct4 and Sox2

Embryonic stem cell (ESC) pluripotency is maintained by core transcriptional circuits whereby critical factors sustain their own expression while preventing the expression of genes required for differentiation. Thomson et al. (2011) now show that two core components of the pluripotency circuit, Oct4 and Sox2, are also critical for germ layer fate choice

Trithorax group proteins: switching genes on and keeping them active

Cellular memory is provided by two counteracting groups of chromatin proteins termed Trithorax group (TrxG) and Polycomb group (PcG) proteins. TrxG proteins activate transcription and are perhaps best known because of the involvement of the TrxG protein MLL in leukaemia. However, in terms of molecular analysis, they have lived in the shadow of their more famous counterparts, the PcG proteins. Recent advances have improved our understanding of TrxG protein function and demonstrated that the heterogeneous group of TrxG proteins is of critical importance in the epigenetic regulation of the cell cycle, senescence, DNA damage and stem cell biology

The high-pressure behavior of CaMoO4

We report a high-pressure study of tetragonal scheelite-type CaMoO4 up to 29 GPa. In order to characterize its high-pressure behavior, we have combined Raman and optical-absorption measurements with density-functional theory calculations. We have found evidence of a pressure-induced phase transition near 15 GPa. Experiments and calculations agree in assigning the high-pressure phase to a monoclinic fergusonite-type structure. The reported results are consistent with previous powder x-ray-diffraction experiments, but are in contradiction with the conclusions obtained from earlier Raman measurements, which support the existence of more than one phase transition in the pressure range covered by our studies. The observed scheelite-fergusonite transition induces significant changes in the electronic band gap and phonon spectrum of CaMoO4. We have determined the pressure evolution of the band gap for the low- and high-pressure phases as well as the frequencies and pressure dependences of the Raman-active and infrared-active modes. In addition, based upon calculations of the phonon dispersion of the scheelite phase, carried out at a pressure higher than the transition pressure, we propose a possible mechanism for the reported phase transition. Furthermore, from the calculations we determined the pressure dependence of the unit-cell parameters and atomic positions of the different phases and their room-temperature equations of state. These results are compared with previous experiments showing a very good agreement. Finally, information on bond compressibility is reported and correlated with the macroscopic compressibility of CaMoO4. The reported results are of interest for the many technological applications of this oxide.Comment: 36 pages, 10 figures, 8 table

Dysphonia secondary to traumatic avulsion of the vocal fold in infants

Objective: Airway compromise due to paediatric intubation injuries is well documented; however, intubation injuries may also cause severe voice disorders. We report our experience and review the world literature on the voice effects of traumatic paediatric intubation. Case series: We report five cases of children referred to Great Ormond Street Hospital for Children who suffered traumatic avulsion of the vocal fold at the time of, or secondary to, endotracheal intubation. All children had significant dysphonia and underwent specialist voice therapy. Conclusions: The mechanisms of injury, risk factors and management of the condition are discussed. Children suffering traumatic intubation require follow up throughout childhood and beyond puberty as their vocal needs and abilities change. At the time of writing, none of the reported patients had yet undergone reconstructive or medialisation surgery. However, regular specialist voice therapy evaluation is recommended for such patients, with consideration of phonosurgical techniques including injection laryngoplasty or thyroplasty

INFLUENCE OF IMPLANT NUMBER, IMPLANT LENGTH AND CROWN HEIGHT ON BONE STRESS DISTRIBUTION FOR THREE-UNIT BRIDGES IN THE POSTERIOR MANDIBLE: A 3D FINITE ELEMENT ANALYSIS.

Background and aim: Reduced alveolar bone height due to ridge resorption represents a major limitation in the use of dental implants, in particular in the posterior sectors of jaws. It increases the probability of an invasion with related possible damage to some anatomical structures, such as the inferior alveolar nerve. Short dental implants' placement has been proposed as an alternative to surgical bone augmentation procedures and recent studies indicated that short implants could present survival and success rates similar to conventional implants in short and medium term. However doubts about biomechanical performances were risen because higher crowns are sometimes necessary to compensate the bone resorption, leading to a less favourable crown to implant ratio.\u2028Recently image-based approaches combined with Finite Element Analyses (FEA) have allowed effective stress\u2013strain investigations in biological systems and in particular stress distribution in bone. The objective of this study was to evaluate the stress transmitted to surrounding bone by different implant number, implant length and crown configurations in a three-unit bridge by means of finite element analysis. Material and methods: The 3D geometry of the edentulous mandible was reconstructed from computerized tomography (CT) scans. The symmetry of the structure permitted the reconstruction of a half maxilla.\u2028Bone material mechanical properties have been assigned to each tetrahedral element based on the Grey Value. The meshes of the implants (Astra Tech AB OsseoSpeedTM TX, Dentsply Implants) were placed in second premolar, first molar and second molar position for the three implants configurations and in second premolar and first molar position for the two implants configurations. A superstructure representing a porcelain three unit bridge was built using beam elements for each configuration. Six different implant configurations were compared: LS2) two 4 mm diameter x 11 mm long implants with 8 mm long crowns; LS3) three 4 mm diameter x 11 mm long implants with 8 mm long crowns SS2) two 4 mm diameter x 11 mm long implants with 8 mm long crowns; SS3) three 4 mm diameter x 11 mm long implants with 8 mm long crowns; SL2) two 4 mm diameter x 6 mm long implants with 13 mm long crowns; SL3) three 4 mm diameter x 6 mm long implants with 13 mm long crowns. A 200 N axial and 45\ub0 oblique loads were applied to each crown. For each configuration the effect of both loading scenarios was evaluated in terms of state of stress in the bone-implant interface (Von Mises stress, maximum and minimum principal stresses). Results: Under oblique load the stress distribution is more concentrated around the coronal part of the implant and it is several times higher than under axial load. In particular the tension represented by the maximum principal stress is from 15 to 35 times higher. In all configurations the stress was more concentrated in the cervical area of the peri-implant bone. Considering axial load the higher values of peri-implant stress were found in the SS2 and SL2 configurations while the lower values around in LC2 and LC3 configurations. Under oblique load the maximum peri-implant stress was found in the SL2 configuration while the minimum peri-implant stress was found in the LC3 configuration. The increase of stress parameters values in SS configurations respect to LS configuration were on average of the 40%. Even the average increase of stress values in SL configurations respect to SS configuration was about the 42% under tilted load.\u2028Configurations with 2 implants were recorded to undergo about the 50% more of stress on average than the respective 3 implants configurations. Conclusions: Crown heigh, implant number and implant length seem to be all influencing factors on implant bone stress, however the augmentation of crown heigh seems to have a greater effect than a reduction of implant length.\u2028Even if the stress observed in all configurations was within a physiological range, a three-unit bridge with 13 mm long crowns supported by two implants may be biomechanicaly hazardous in the presence of horizontal forces, and the addition of another short implant or increase of bone volume may be suggested to dissipate the stress at bone-implant interface. In conclusion the use of short dental implants to support a three unit bridge in the posterior mandible can be considered a potential alternative to standard length implants, but crown heigh and lateral forces have to be carefully analyzed in every patient

A highly conserved circular RNA is required to keep neural cells in a progenitor state in the mammalian brain

circSLC45A4 is the main RNA splice isoform produced from its genetic locus and one of the highest expressed circRNAs in the developing human frontal cortex. Knockdown of this highly conserved circRNA in a human neuroblastoma cell line is sufficient to induce spontaneous neuronal differentiation, measurable by increased expression of neuronal marker genes. Depletion of circSlc45a4 in the developing mouse cortex causes a significant reduction of the basal progenitor pool and increases the expression of neurogenic regulators. Furthermore, knockdown of circSlc45a4a induces a significant depletion of cells in the cortical plate. In addition, deconvolution of the bulk RNA-seq data with the help of single-cell RNA-seq data validates the depletion of basal progenitors and reveals an increase in Cajal-Retzius cells. In summary, we present a detailed study of a highly conserved circular RNA that is necessary to maintain the pool of neural progenitors in vitro and in vivo

Proteostasis Regulators in Cystic Fibrosis: Current Development and Future Perspectives

In cystic fibrosis (CF), the deletion of phenylalanine 508 (F508del) in the CF transmembrane conductance regulator (CFTR) leads to misfolding and premature degradation of the mutant protein. These defects can be targeted with pharmacological agents named potentiators and correctors. During the past years, several efforts have been devoted to develop and approve new effective molecules. However, their clinical use remains limited, as they fail to fully restore F508del-CFTR biological function. Indeed, the search for CFTR correctors with different and additive mechanisms has recently increased. Among them, drugs that modulate the CFTR proteostasis environment are particularly attractive to enhance therapy effectiveness further. This Perspective focuses on reviewing the recent progress in discovering CFTR proteostasis regulators, mainly describing the design, chemical structure, and structure-activity relationships. The opportunities, challenges, and future directions in this emerging and promising field of research are discussed, as well

In-depth analysis of the Naming Game dynamics: the homogeneous mixing case

Language emergence and evolution has recently gained growing attention through multi-agent models and mathematical frameworks to study their behavior. Here we investigate further the Naming Game, a model able to account for the emergence of a shared vocabulary of form-meaning associations through social/cultural learning. Due to the simplicity of both the structure of the agents and their interaction rules, the dynamics of this model can be analyzed in great detail using numerical simulations and analytical arguments. This paper first reviews some existing results and then presents a new overall understanding.Comment: 30 pages, 19 figures (few in reduced definition). In press in IJMP

Inference of population splits and mixtures from genome-wide allele frequency data

Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In this model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication, and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and "ancient" Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.comComment: 28 pages, 6 figures in main text. Attached supplement is 22 pages, 15 figures. This is an updated version of the preprint available at http://precedings.nature.com/documents/6956/version/