Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits.

The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell-derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes

Rotation Reversal Bifurcation and Energy Confinement Saturation in Tokamak Ohmic L-mode Plasmas

Direction reversals of intrinsic toroidal rotation have been observed in diverted Alcator C-Mod Ohmic L-mode plasmas following electron density ramps. For low density discharges, the core rotation is directed cocurrent, and reverses to countercurrent following an increase in the density above a certain threshold. Such reversals occur together with a decrease in density fluctuations with 2 cm(-1)≤k(θ)≤11 cm(-1) and frequencies above 70 kHz. There is a strong correlation between the reversal density and the density at which the Ohmic L-mode energy confinement changes from the linear to the saturated regime

Learning to dislike alcohol: conditioning negative implicit attitudes toward alcohol and its effect on drinking behavior

Rationale: Since implicit attitudes toward alcohol play an important role in drinking behavior, a possible way to obtain a behavioral change is changing these implicit attitudes. Objectives: This study examined whether a change in implicit attitudes and in drinking behavior can be achieved via evaluative conditioning. Methods: Participants were randomly assigned to an experimental condition and a control condition. In the experimental condition, participants were subjected to an evaluative conditioning procedure that consistently pairs alcohol-related cues with negative stimuli. In the control condition, alcohol-related cues were consistently paired with neutral stimuli during the evaluative conditioning phase. Implicit attitudes, explicit attitudes, and drinking behavior were measured before and after the evaluative conditioning phase. Results: Following the evaluative conditioning procedure, participants in the experimental condition showed stronger negative implicit attitudes toward alcohol and consumed less alcohol compared to participants in the control condition. However, this effect was only found when the evaluative conditioning task paired alcohol-related cues with general negative pictures, but not when using pictures of frowning faces. Conclusions: These results demonstrate that evaluative conditioning can effectively change implicit attitudes toward alcohol and also suggest that this procedure can be used to change drinking behavior. Hence, evaluative conditioning may be a useful new intervention tool to combat alcohol misuse

Fibril elongation mechanisms of HET-s prion-forming domain: Topological evidence for growth polarity

The prion-forming C-terminal domain of the fungal prion HET-s forms infectious amyloid fibrils at physiological pH. The conformational switch from the non-prion soluble form to the prion fibrillar form is believed to have a functional role, since HET-s in its prion form participates in a recognition process of different fungal strains. Based on the knowledge of the high-resolution structure of HET-s(218-289) (the prion forming-domain) in its fibrillar form, we here present a numerical simulation of the fibril growth process which emphasizes the role of the topological properties of the fibrillar structure. An accurate thermodynamic analysis of the way an intervening HET-s chain is recruited to the tip of the growing fibril suggests that elongation proceeds through a dock and lock mechanism. First, the chain docks onto the fibril by forming the longest $\beta$-strands. Then, the re-arrangement in the fibrillar form of all the rest of molecule takes place. Interestingly, we predict also that one side of the HET-s fibril is more suitable for substaining its growth with respect to the other. The resulting strong polarity of fibril growth is a consequence of the complex topology of HET-s fibrillar structure, since the central loop of the intervening chain plays a crucially different role in favouring or not the attachment of the C-terminus tail to the fibril, depending on the growth side.Comment: 16 pages, 10 figure

Susceptibility to Peer Pressure, Self-Esteem, and Health Locus of Control as Correlates of Adolescent Substance Abuse

As part of a school-based alcohol misuse prevention study, questionnaires were ad ministered to 2,589 fifth and sixth grade students to determine levels of use of alcohol, marijuana, and cigarettes, intentions to use these substances, and problems resulting from alcohol misuse. The questionnaire also included 45 items concerning susceptibil ity to peer pressure, self-esteem, and health locus of control. These 45 items were factor analyzed separately for two groups formed by random assignment. Six factors were identified which were both internally consistent and replicable, and indices were constructed. The indices measuring susceptibility to peer pressure, self-esteem, and internal health locus of control were significantly and negatively correlated with most of the substance use, misuse, and intention items, and an external health locus of con trol index was not significantly related to most of the substance use, misuse, and inten tion items. The "Susceptibility to Peer Pressure" index correlated more highly with the adolescent substance use, misuse, and intention items than the self-esteem or the health locus of control indices, and it had the highest alpha coefficient. Implications for the design of school-based substance abuse prevention programs are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68065/2/10.1177_109019818701400207.pd

SPARTAN: a global network to evaluate and enhance satellite-based estimates of ground-level particulate matter for global health applications

Ground-based observations have insufficient spatial coverage to assess long-term human exposure to fine particulate matter (PM2.5) at the global scale. Satellite remote sensing offers a promising approach to provide information on both short-and long-term exposure to PM2.5 at local-to-global scales, but there are limitations and outstanding questions about the accuracy and precision with which ground-level aerosol mass concentrations can be inferred from satellite remote sensing alone. A key source of uncertainty is the global distribution of the relationship between annual average PM2.5 and discontinuous satellite observations of columnar aerosol optical depth (AOD). We have initiated a global network of ground-level monitoring stations designed to evaluate and enhance satellite remote sensing estimates for application in health-effects research and risk assessment. This Surface PARTiculate mAtter Network (SPARTAN) includes a global federation of ground-level monitors of hourly PM2.5 situated primarily in highly populated regions and collocated with existing ground-based sun photometers that measure AOD. The instruments, a three-wavelength nephelometer and impaction filter sampler for both PM2.5 and PM10, are highly autonomous. Hourly PM2.5 concentrations are inferred from the combination of weighed filters and nephelometer data. Data from existing networks were used to develop and evaluate network sampling characteristics. SPARTAN filters are analyzed for mass, black carbon, water-soluble ions, and metals. These measurements provide, in a variety of regions around the world, the key data required to evaluate and enhance satellite-based PM2.5 estimates used for assessing the health effects of aerosols. Mean PM2.5 concentrations across sites vary by more than 1 order of magnitude. Our initial measurements indicate that the ratio of AOD to ground-level PM2.5 is driven temporally and spatially by the vertical profile in aerosol scattering. Spatially this ratio is also strongly influenced by the mass scattering efficiency.Fil: Snider, G.. Dalhousie University Halifax; CanadáFil: Weagle, C. L.. Dalhousie University Halifax; CanadáFil: Martin, R. V.. Dalhousie University Halifax; Canadá. University of Cambridge; Reino UnidoFil: van Donkelaar, A.. Dalhousie University Halifax; CanadáFil: Conrad, K.. Dalhousie University Halifax; CanadáFil: Cunningham, D.. Dalhousie University Halifax; CanadáFil: Gordon, C.. Dalhousie University Halifax; CanadáFil: Zwicker, M.. Dalhousie University Halifax; CanadáFil: Akoshile, C.. University of Ilorin; NigeriaFil: Artaxo, P.. Governo Do Estado de Sao Paulo; BrasilFil: Anh, N. X.. Vietnam Academy of Science and Technology. Institute of Geophysics; VietnamFil: Brook, J.. University of Toronto; CanadáFil: Dong, J.. Tsinghua University; ChinaFil: Garland, R. M.. North-West University; SudáfricaFil: Greenwald, R.. Rollins School of Public Health; Estados UnidosFil: Griffith, D.. Council for Scientific and Industrial Research; SudáfricaFil: He, K.. Tsinghua University; ChinaFil: Holben, B. N.. NASA Goddard Space Flight Center; Estados UnidosFil: Kahn, R.. NASA Goddard Space Flight Center; Estados UnidosFil: Koren, I.. Weizmann Institute Of Science Israel; IsraelFil: Lagrosas, N.. Manila Observatory, Ateneo de Manila University campus; FilipinasFil: Lestari, P.. Institut Teknologi Bandung; IndonesiaFil: Ma, Z.. Rollins School of Public Health; Estados UnidosFil: Vanderlei Martins, J.. University of Maryland; Estados UnidosFil: Quel, Eduardo Jaime. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rudich, Y.. Weizmann Institute Of Science Israel; IsraelFil: Salam, A.. University Of Dhaka; BangladeshFil: Tripathi, S. N.. Indian Institute Of Technology, Kanpur; IndiaFil: Yu, C.. Rollins School of Public Health; Estados UnidosFil: Zhang, Q.. Tsinghua University; ChinaFil: Zhang, Y.. Tsinghua University; ChinaFil: Brauer, M.. University of British Columbia; CanadáFil: Cohen, A.. Health Effects Institute; Estados UnidosFil: Gibson, M. D.. Dalhousie University Halifax; CanadáFil: Liu, Y.. Rollins School of Public Health; Estados Unido

Intraday rallies and crashes : spillovers of trading halts

This paper analyses a set of intraday rally and crash events at the firm level during the single stock circuit breaker (SSCB) program, and documents the cross-sectional spillover effects of such events on non-halted stocks. We test whether such major price jumps, and subsequent trading halts, affect related stocks through the destabilizing arbitrage channel. We find that extreme price movements that trigger the circuit breakers at the firm level are accompanied by a massive surge in volume, spread and short-term volatility, which gradually revert back to normal. Speculative strategies of arbitrageurs such as momentum and pairs trading cause cross-sectional spillovers in volume and volatility during the trading halt

Ohmic energy confinement saturation and core toroidal rotation reversal in Alcator C-Mod plasmas

Ohmic energy confinement saturation is found to be closely related to core toroidal rotation reversals in Alcator C-Mod tokamak plasmas. Rotation reversals occur at a critical density, depending on the plasma current and toroidal magnetic field, which coincides with the density separating the linear Ohmic confinement regime from the saturated Ohmic confinement regime. The rotation is directed co-current at low density and abruptly changes direction to counter-current when the energy confinement saturates as the density is increased. Since there is a bifurcation in the direction of the rotation at this critical density, toroidal rotation reversal is a very sensitive indicator in the determination of the regime change. The reversal and confinement saturation results can be unified, since these processes occur in a particular range of the collisionality.United States. Dept. of Energy (Contract DE-FC02-99ER54512