Promoter architecture and the evolvability of gene expression

Evolutionary changes in gene expression are a main driver of phenotypic evolution. In yeast, genes that have rapidly diverged in expression are associated with particular promoter features, including the presence of a TATA box, a nucleosome-covered promoter and unstable tracts of tandem repeats. Here, we discuss how these promoter properties may confer an inherent capacity for flexibility of expression

The Structural Complexity of (Bi0.5Na0.5)TiO3-BaTiO3 as Revealed by Raman Spectroscopy

The structural phase diagram of the Pb-free ferroelectric (Na1/2Bi1/2)1-xBaxTiO3 (NBT-BT), x<0.1, has been explored by Raman spectroscopy at temperatures from 10 to 470 K. The data provide clear evidence for a proposed temperature-independent morphotropic phase boundary at x \approx 0.055. However, there is no evidence for a structural phase transition across T \approx 370 K for x > 0.055, where bulk-property anomalies appear to signal a transition to a nonpolar or antiferroelectric phase. The results identify that the phase above 370 K shows short-range ionic displacements that are identical to those in the long-range-ordered phase below 370 K. These conclusions provide a natural interpretation of the weak piezoelectric response in this system and have important implications for the search for Pb-free piezoelectrics.Comment: 21 pages, 5 figure

Porous Silicon-Based Aptasensors: Toward Cancer Protein Biomarker Detection

The anterior gradient homologue-2 (AGR2) protein is an attractive biomarker for various types of cancer. In pancreatic cancer, it is secreted to the pancreatic juice by premalignant lesions, which would be an ideal stage for diagnosis. Thus, designing assays for the sensitive detection of AGR2 would be highly valuable for the potential early diagnosis of pancreatic and other types of cancer. Herein, we present a biosensor for label-free AGR2 detection and investigate approaches for enhancing the aptasensor sensitivity by accelerating the target mass transfer rate and reducing the system noise. The biosensor is based on a nanostructured porous silicon thin film that is decorated with anti-AGR2 aptamers, where real-time monitoring of the reflectance changes enables the detection and quantification of AGR2, as well as the study of the diffusion and target-aptamer binding kinetics. The aptasensor is highly selective for AGR2 and can detect the protein in simulated pancreatic juice, where its concentration is outnumbered by orders of magnitude by numerous proteins. The aptasensor’s analytical performance is characterized with a linear detection range of 0.05-2 mg mL-1, an apparent dissociation constant of 21 ± 1 μM, and a limit of detection of 9.2 μg mL-1 (0.2 μM), which is attributed to mass transfer limitations. To improve the latter, we applied different strategies to increase the diffusion flux to and within the nanostructure, such as the application of isotachophoresis for the preconcentration of AGR2 on the aptasensor, mixing, or integration with microchannels. By combining these approaches with a new signal processing technique that employs Morlet wavelet filtering and phase analysis, we achieve a limit of detection of 15 nM without compromising the biosensor’s selectivity and specificity

Threshold responses to morphogen gradients by zero-order ultrasensitivity

Translating a graded morphogen distribution into tight response borders is central to all developmental processes. Yet, the molecular mechanisms generating such behavior are poorly understood. During patterning of the Drosophila embryonic ventral ectoderm, a graded mitogen-activated protein kinase (MAPK) activation is converted into an all-or-none degradation switch of the Yan transcriptional repressor. Replacing the cardinal phosphorylated amino acid of Yan by a phosphomimetic residue allowed its degradation in a MAPK-independent manner, consistent with Yan phosphorylation being the critical event in generating the switch. Several alternative threshold mechanisms that could, in principle, be realized by this phosphorylation, including first order, cooperativity, positive feedback and zero-order ultrasensitivity, were analyzed. We found that they can be distinguished by their kinetics and steady-state responses to Yan overexpression. In agreement with the predictions for zero-order kinetics, an increase in Yan levels did not shift the degradation border, but significantly elevated the time required to reach steady state. We propose that a reversible loop of Yan phosphorylation implements a zero-order ultrasensitivity-like threshold mechanism, with the capacity to form sharp thresholds that are independent of the level of Yan

Universal Statistical Behavior of Neural Spike Trains

We construct a model that predicts the statistical properties of spike trains generated by a sensory neuron. The model describes the combined effects of the neuron's intrinsic properties, the noise in the surrounding, and the external driving stimulus. We show that the spike trains exhibit universal statistical behavior over short times, modulated by a strongly stimulus-dependent behavior over long times. These predictions are confirmed in experiments on H1, a motion-sensitive neuron in the fly visual system.Comment: 7 pages, 4 figure

Clustering and conservation patterns of human microRNAs

MicroRNAs (miRNAs) are ∼22 nt-long non-coding RNA molecules, believed to play important roles in gene regulation. We present a comprehensive analysis of the conservation and clustering patterns of known miRNAs in human. We show that human miRNA gene clustering is significantly higher than expected at random. A total of 37% of the known human miRNA genes analyzed in this study appear in clusters of two or more with pairwise chromosomal distances of at most 3000 nt. Comparison of the miRNA sequences with their homologs in four other organisms reveals a typical conservation pattern, persistent throughout the clusters. Furthermore, we show enrichment in the typical conservation patterns and other miRNA-like properties in the vicinity of known miRNA genes, compared with random genomic regions. This may imply that additional, yet unknown, miRNAs reside in these regions, consistent with the current recognition that there are overlooked miRNAs. Indeed, by comparing our predictions with cloning results and with identified miRNA genes in other mammals, we corroborate the predictions of 18 additional human miRNA genes in the vicinity of the previously known ones. Our study raises the proportion of clustered human miRNAs that are <3000 nt apart to 42%. This suggests that the clustering of miRNA genes is higher than currently acknowledged, alluding to its evolutionary and functional implications

International travel to obtain medical treatment for primary retinoblastoma : A global cohort study

Early diagnosis and treatment of retinoblastoma (Rb), the most common intraocular malignancy, can save both the child's life and vision. However, access to services and hence chances for survival and preserving the eye and its vision vary widely across the globe. Some families have to, or make a choice to, leave their home country to seek planned medical treatment abroad. We aimed to investigate how frequently this cross-border travel occurs and the factors associated with it. A total of 278 Rb centres in 153 countries were recruited to participate in a global cross-sectional analysis of newly diagnosed Rb patients in 2017. Number and proportions of children who travelled from their home country for treatment were analysed by country, continent, socioeconomic stratum and clinical and demographic features. The cohort included 4351 new patients of whom 223 [5.1%, 95% confidence interval 4.5-5.8] were taken across country borders for planned medical treatment. Independently significant predictors of travelling across borders included: being from a country with a smaller population, being from a country classified as low socioeconomic status, having bilateral Rb and having intraocular disease without extraocular spread. The factors that determine international travel for Rb treatment are complex and deserve further investigation. We may need to rethink the way services are delivered in the light of the threat of severe curtailment of international travel from pandemics like corona virus disease 2019.Peer reviewe

Excitation of Small Quantum Systems by High-Frequency Fields

The excitation by a high frequency field of multi--level quantum systems with a slowly varying density of states is investigated. A general approach to study such systems is presented. The Floquet eigenstates are characterized on several energy scales. On a small scale, sharp universal quasi--resonances are found, whose shape is independent of the field parameters and the details of the system. On a larger scale an effective tight--binding equation is constructed for the amplitudes of these quasi--resonances. This equation is non--universal; two classes of examples are discussed in detail.Comment: 4 pages, revtex, no figure

Parametric investigation of water loading on heavily carbonaceous syngases

An outwardly propagating spherical flame was used to characterise the influence of water loading on the premixed combustion of an applied high CO/H2 ratio syngas fuel blend (converter gas). A nonlinear extrapolative technique was used to obtain values of laminar flame speed for combustion with air, for varying temperature, pressure and equivalence ratio. With increased attention given to the accurate measurement of laminar flame speed, a concerted effort was made to quantify experimental uncertainty, and a detailed methodology is presented. Change in relative humidity was shown to have a substantial impact on laminar flame speed for the syngas, increasing measured values by up to 70% from the driest cases. This observed increase results from the dissociative influence of H2O addition, and enhancement in the formation of chain carriers that catalyse CO oxidation, increasing net heat release rate. In addition to relative humidity, the decoupled influences of initial temperature and pressure were investigated parametrically; holding the mass ratios of fuel and H2O constant for a step change in condition. Temperature rise was shown to enhance H2O induced acceleration, with greater relative change in heat release rate for a corresponding drop in flame temperature, and the opposite effect observed for increased pressure. The effect of water addition was shown to be non-monotonic, with flame speed reduction achieved at the highest water loadings for the hottest tests, and discussed as a function of initial CO/H2 ratio. Attention was given to the dominant reaction kinetics, with the performance of several published reaction mechanisms evaluated against experimental data using CHEMKIN-PRO; with flame speed consistently overpredicted when H2O was added to the mixture. A modified reaction mechanism is presented for the humidified combustion of high CO/H2 mixtures, changing the rate parameters of two chain branching reactions to give higher relative indeterminate H2O formation, and a reduction in OH carriers. Results obtained using the modified mechanism demonstrate improved agreement with all experimental data presented here and from a previous study, including changes in H2O concentration at elevated temperatures and pressures. The results also highlight relative humidity as a potential source of error in the experimental measurement of uL, significant for fuels comprising large CO fractions, but also potentially for other gaseous fuels, emphasising that relative humidity should be carefully considered when comparing experimental data