The role of input noise in transcriptional regulation

Even under constant external conditions, the expression levels of genes fluctuate. Much emphasis has been placed on the components of this noise that are due to randomness in transcription and translation; here we analyze the role of noise associated with the inputs to transcriptional regulation, the random arrival and binding of transcription factors to their target sites along the genome. This noise sets a fundamental physical limit to the reliability of genetic control, and has clear signatures, but we show that these are easily obscured by experimental limitations and even by conventional methods for plotting the variance vs. mean expression level. We argue that simple, global models of noise dominated by transcription and translation are inconsistent with the embedding of gene expression in a network of regulatory interactions. Analysis of recent experiments on transcriptional control in the early Drosophila embryo shows that these results are quantitatively consistent with the predicted signatures of input noise, and we discuss the experiments needed to test the importance of input noise more generally.Comment: 11 pages, 5 figures minor correction

Scratch lottery tickets are a poor incentive to respond to mailed questionnaires

BACKGROUND: It has been demonstrated that the enclosure of money with a mailed questionnaire increases the response rate significantly. We evaluated scratch lottery tickets as an alternative to cash. METHODS: 1500 randomly selected Norwegians between the ages of 40 and 65 years were sent a short questionnaire. 250 received one lottery scratch ticket worth 20 Norwegian kroner (approximately 3 US$) together with the questionnaire, 250 received two scratch tickets, and 250 were promised two scratch tickets if they replied within one week. A fourth group of 250 persons received a 50 kroner banknote with the questionnaire. The remaining 500 letters served as controls. RESULTS: The overall response rate after 6 weeks was 77%. Logistic regression analysis showed that only the 50 kroner group had a response rate that was statistically significantly higher than the controls (p < 0.0001). It was also significantly higher than that in any of the other incentive groups (p < 0.0001, p < 0.004 and p < 0.0001 respectively). Female sex (p < 0.001) and age (p < 0.002) increased the response rate significantly. CONCLUSION: It is possible that the recipients scratched their cards before completing the questionnaire, and that it was a disincentive for the majority that they did not win anything. Lottery scratch tickets are no substitute for cash as an incentive to respond to a questionnaire

Explaining why simple liquids are quasi-universal

It has been known for a long time that many simple liquids have surprisingly similar structure as quantified, e.g., by the radial distribution function. A much more recent realization is that the dynamics are also very similar for a number of systems with quite different pair potentials. Systems with such non-trivial similarities are generally referred to as "quasi-universal". From the fact that the exponentially repulsive pair potential has strong virial potential-energy correlations in the low-temperature part of its thermodynamic phase diagram, we here show that a liquid is quasi-universal if its pair potential can be written approximately as a sum of exponential terms with numerically large prefactors. Based on evidence from the literature we moreover conjecture the converse, i.e., that quasi-universality only applies for systems with this property

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

CCR3 and Choroidal Neovascularization

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly in industrialized countries. The “wet” AMD, characterized by the development of choroidal neovacularization (CNV), could result in rapid and severe loss of central vision. The critical role of vascular endothelial growth factor A (VEGF-A) in CNV development has been established and VEGF-A neutralization has become the standard care for wet AMD. Recently, CCR3 was reported to play an important role in CNV development and that CCR3 targeting was reported to be superior to VEGF-A targeting in CNV suppression. We investigated the role of CCR3 in CNV development using the Matrigel induced CNV and found that in both rats and mice, CNV was well-developed in the control eyes as well as in eyes treated with CCR3 antagonist SB328437 or CCR3 neutralizing antibodies. No statistically significant difference in CNV areas was found between the control and SB328437 or CCR3-ab treated eyes. Immunostaining showed no specific expression of CCR3 in or near CNV. In contrast, both VEGF-A neutralizing antibodies and rapamycin significantly suppressed CNV. These results indicate that CCR3 plays no significant role in CNV development and question the therapeutic approach of CCR3 targeting to suppress CNV. On the other hand, our data support the therapeutic strategies of VEGF-A and mTOR (mammalian target of rapamycin) targeting for CNV

Exploring the Contextual Sensitivity of Factors that Determine Cell-to-Cell Variability in Receptor-Mediated Apoptosis

Stochastic fluctuations in gene expression give rise to cell-to-cell variability in protein levels which can potentially cause variability in cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) variability manifests itself as dramatic differences in the time between ligand exposure and the sudden activation of the effector caspases that kill cells. However, the contribution of individual proteins to phenotypic variability has not been explored in detail. In this paper we use feature-based sensitivity analysis as a means to estimate the impact of variation in key apoptosis regulators on variability in the dynamics of cell death. We use Monte Carlo sampling from measured protein concentration distributions in combination with a previously validated ordinary differential equation model of apoptosis to simulate the dynamics of receptor-mediated apoptosis. We find that variation in the concentrations of some proteins matters much more than variation in others and that precisely which proteins matter depends both on the concentrations of other proteins and on whether correlations in protein levels are taken into account. A prediction from simulation that we confirm experimentally is that variability in fate is sensitive to even small increases in the levels of Bcl-2. We also show that sensitivity to Bcl-2 levels is itself sensitive to the levels of interacting proteins. The contextual dependency is implicit in the mathematical formulation of sensitivity, but our data show that it is also important for biologically relevant parameter values. Our work provides a conceptual and practical means to study and understand the impact of cell-to-cell variability in protein expression levels on cell fate using deterministic models and sampling from parameter distributions