Exact solution of stochastic gene expression models with bursting, cell cycle and replication dynamics

The bulk of stochastic gene expression models in the literature do not have an explicit description of the age of a cell within a generation and hence they cannot capture events such as cell division and DNA replication. Instead, many models incorporate cell cycle implicitly by assuming that dilution due to cell division can be described by an effective decay reaction with first-order kinetics. If it is further assumed that protein production occurs in bursts then the stationary protein distribution is a negative binomial. Here we seek to understand how accurate these implicit models are when compared with more detailed models of stochastic gene expression. We derive the exact stationary solution of the chemical master equation describing bursty protein dynamics, binomial partitioning at mitosis, age-dependent transcription dynamics including replication, and random interdivision times sampled from Erlang or more general distributions; the solution is different for single lineage and population snapshot settings. We show that protein distributions are well approximated by the solution of implicit models (a negative binomial) when the mean number of mRNAs produced per cycle is low and the cell cycle length variability is large. When these conditions are not met, the distributions are either almost bimodal or else display very flat regions near the mode and cannot be described by implicit models. We also show that for genes with low transcription rates, the size of protein noise has a strong dependence on the replication time, it is almost independent of cell cycle variability for lineage measurements and increases with cell cycle variability for population snapshot measurements. In contrast for large transcription rates, the size of protein noise is independent of replication time and increases with cell cycle variability for both lineage and population measurements.Comment: 7 figure

Species-specific pace of development is associated with differences in protein stability

Although many molecular mechanisms controlling developmental processes are evolutionarily conserved, the speed at which the embryo develops can vary substantially between species. For example, the same genetic program, comprising sequential changes in transcriptional states, governs the differentiation of motor neurons in mouse and human, but the tempo at which it operates differs between species. Using in vitro directed differentiation of embryonic stem cells to motor neurons, we show that the program runs more than twice as fast in mouse as in human. This is not due to differences in signaling, nor the genomic sequence of genes or their regulatory elements. Instead, there is an approximately two-fold increase in protein stability and cell cycle duration in human cells compared with mouse cells. This can account for the slower pace of human development and suggests that differences in protein turnover play a role in interspecies differences in developmental tempo

Octopus maya white body show sex-specific transcriptomic profiles during the reproductive phase, with high differentiation in signaling pathways

White bodies (WB), multilobulated soft tissue that wraps the optic tracts and optic lobes, have been considered the hematopoietic organ of the cephalopods. Its glandular appearance and its lobular morphology suggest that different parts of the WB may perform different functions, but a detailed functional analysis of the octopus WB is lacking. The aim of this study is to describe the transcriptomic profile of WB to better understand its functions, with emphasis on the difference between sexes during reproductive events. Then, validation via qPCR was performed using different tissues to find out tissue-specific transcripts. High differentiation in signaling pathways was observed in the comparison of female and male transcriptomic profiles. For instance, the expression of genes involved in the androgen receptor-signaling pathway were detected only in males, whereas estrogen receptor showed higher expression in females. Highly expressed genes in males enriched oxidation-reduction and apoptotic processes, which are related to the immune response. On the other hand, expression of genes involved in replicative senescence and the response to cortisol were only detected in females. Moreover, the transcripts with higher expression in females enriched a wide variety of signaling pathways mediated by molecules like neuropeptides, integrins, MAPKs and receptors like TNF and Toll-like. In addition, these putative neuropeptide transcripts, showed higher expression in females' WB and were not detected in other analyzed tissues. These results suggest that the differentiation in signaling pathways in white bodies of O. maya influences the physiological dimorphism between females and males during the reproductive phase

ThresholdROC: Optimum Threshold Estimation Tools for Continuous Diagnostic Tests in R

We introduce an R package that estimates decision thresholds in diagnostic settings with a continuous marker and two or three underlying states. The package implements parametric and non-parametric estimation methods based on minimizing an overall cost function, as well as confidence interval estimation approaches to account for the sampling variability of the cut-off. Further features of the package include sample size determination and estimation of diagnostic accuracy measures. We used randomly generated data and two real datasets to illustrate the capabilities and characteristics of the package

Relationship Between Flicker Modulation Sensitivity and Retinal Ganglion Cell Related Layer Thicknesses

Purpose: Early detection of structural changes in retinal ganglion cells (RGCs) and corresponding changes in visual function is important in early degenerative diseases of the retina, but the sensitivity of both measurements is limited by the inherent variability in healthy subjects. This study investigates the relationships between RGC-related layer thicknesses and foveal and parafoveal flicker modulation sensitivity (FMS) across photopic and mesopic light levels in healthy subjects. Methods: Photopic and mesopic FMS was measured in 56 young adults, at the point of fixation and at an eccentricity of 5 degrees, in each of the four quadrants. Spectral-domain optical coherence tomography (SD-OCT) was used to measure retinal thicknesses. Relationships between foveal and parafoveal FMS and the retinal thickness in the corresponding region were examined after adjusting for confounding variables. Results: Total macular and inner retinal layer (IRL) thicknesses in the parafoveal ring were significant predictors of photopic (P = 0.034) and mesopic (P = 0.034) parafoveal FMS, respectively. The superior peripapillary retinal nerve fiber layer (pRNFL) thickness was a contributing factor to the inferior parafoveal FMS (photopic: P = 0.006 and mesopic: P = 0.021) and the inferior pRNFL thickness was also a contributing factor to the superior parafoveal FMS (photopic: P < 0.001 and mesopic: P = 0.015). Conclusions: The pRNFL thicknesses predict parafoveal FMS for both mesopic and photopic conditions in healthy eyes. Translational Relevance: The measurement of rapid flicker sensitivity in the parafoveal retina together with the pRNFL thickness profiles measured before the onset of disease, may provide a more sensitive biomarker for detecting loss of sensitivity caused by the earliest neurodegenerative changes in the eyes

Millimagnitude Photometry for Transiting Extrasolar Planetary Candidates IV: The Puzzle of the Extremely Red OGLE-TR-82 Primary Solved

We present precise new V, I, and K-band photometry for the planetary transit candidate star OGLE-TR-82. Good seeing V-band images acquired with VIMOS instrument at ESO VLT allowed us to measure V=20.6+-0.03 mag star in spite of the presence of a brighter neighbour about 1" away. This faint magnitude answers the question why it has not been possible to measure radial velocities for this object. One transit of this star has been observed with GMOS-S instrument of GEMINI-South telescope in i and g-bands. The measurement of the transit allows us to verify that this is not a false positive, to confirm the transit amplitude measured by OGLE, and to improve the ephemeris. The transit is well defined in i-band light curve, with a depth of A_i=0.034 mag. It is however, less well defined, but deeper (A_g=0.1 mag) in the g-band, in which the star is significantly fainter. The near-infrared photometry obtained with SofI array at the ESO-NTT yields K=12.2+-0.1 and V-K=8.4+-0.1, so red that it is unlike any other transit candidate studied before. Due to the extreme nature of this object, we have not yet been able to measure velocities for this star, but based on the new data we consider two different possible configurations:(1) a nearby M7V star, or (2) a blend with a very reddened distant red giant. The nearby M7V dwarf hypothesis would give a radius for the companion of R_p=0.3+-0.1 R_J, i.e. the size of Neptune. Quantitative analysis of near-IR spectroscopy finally shows that OGLE-TR-82 is a distant, reddened metal poor early K giant. This result is confirmed by direct comparison with stellar templates that gives the best match for a K3III star. Therefore, we discard the planetary nature of the companion. Based on all the new data, we conclude that this system is a main-sequence binary blended with a background red giant.Comment: 26 pages, 9 figures, ApJ accepte

Acute neuromuscular and perceptual responses to blood flow restriction exercise in adults with severe haemophilia:A pilot study

Introduction: No previous studies have implemented a standard blood flow restriction (BFR) training session in people with severe haemophilia (PwH), where this type of training has been contraindicated.Aims: The purpose of this study was to evaluate the tolerability, adverse events, and neuromuscular and perceptual responses to an acute session of low load (LL) knee extensions with BFR in PwH under prophylaxis.Methods: Eight PwH performed one LL-BFR session with 40% arterial occlusion pressure (AOP). Perceptual responses and adverse effects were assessed, together with high-density surface electromyography of vastusmedialis (VM) and lateralis (VL).Results: Significant normalized root mean square differences were found within each set, but not between sets. Spatial distribution (centroid displacement (p &gt; .05), modified entropy (VM, set two, cycles three and five, p = .032) and coefficient of variation (VM, set two, cycles four and five lower than cycle three (p = .049; p = .036)) showed changes within each set.Median frequency showed a slight increase during cycle four of set four (p = .030). Rate of perceived exertion slightly increased with each set while tolerability slightly decreased in the last set and fear of training with BFR generally decreased after the session.Conclusions: In PwH, a LL-BFR session at 40% AOP is safe and feasible. Our results suggest that potential muscle impairments may blunt neuromuscular adaptations induced by BFR

Gender equality, austerity, vulnerabilities and resistance in the Spanish neo-liberal life cycle

We examine how austerity measures have affected gender equality in the context of women workers in Spain. We adopt a feminist perspective to explore the multiple nature of the impact of the recession, emerging policy scenarios and forms of gender action that have developed. One of the unforeseen outcomes of the economic crisis in Spain is the opening up of new forms of collective action that have emerged in two political movements: ‘Podemos’ and ‘Barcelona en Comú’ and two examples of feminist activism: ‘La Vaga de Totes’ and ‘Igualdad de género frente a la crisis económica’—initiatives which point to alternative ways of engaging with work and working lives, in the hope of redressing the inequalities that have increased over recent years. New forms of organization have been successful in mobilizing people by developing the struggle against austerity from a progressive perspective and radical democratic forms of action have come to the fore

Resolving Structure and Mechanical Properties at the Nanoscale of Viruses with Frequency Modulation Atomic Force Microscopy

Structural Biology (SB) techniques are particularly successful in solving virus structures. Taking advantage of the symmetries, a heavy averaging on the data of a large number of specimens, results in an accurate determination of the structure of the sample. However, these techniques do not provide true single molecule information of viruses in physiological conditions. To answer many fundamental questions about the quickly expanding physical virology it is important to develop techniques with the capability to reach nanometer scale resolution on both structure and physical properties of individual molecules in physiological conditions. Atomic force microscopy (AFM) fulfills these requirements providing images of individual virus particles under physiological conditions, along with the characterization of a variety of properties including local adhesion and elasticity. Using conventional AFM modes is easy to obtain molecular resolved images on flat samples, such as the purple membrane, or large viruses as the Giant Mimivirus. On the contrary, small virus particles (25–50 nm) cannot be easily imaged. In this work we present Frequency Modulation atomic force microscopy (FM-AFM) working in physiological conditions as an accurate and powerful technique to study virus particles. Our interpretation of the so called “dissipation channel” in terms of mechanical properties allows us to provide maps where the local stiffness of the virus particles are resolved with nanometer resolution. FM-AFM can be considered as a non invasive technique since, as we demonstrate in our experiments, we are able to sense forces down to 20 pN. The methodology reported here is of general interest since it can be applied to a large number of biological samples. In particular, the importance of mechanical interactions is a hot topic in different aspects of biotechnology ranging from protein folding to stem cells differentiation where conventional AFM modes are already being used