Functional roles for noise in genetic circuits

The genetic circuits that regulate cellular functions are subject to stochastic fluctuations, or ‘noise’, in the levels of their components. Noise, far from just a nuisance, has begun to be appreciated for its essential role in key cellular activities. Noise functions in both microbial and eukaryotic cells, in multicellular development, and in evolution. It enables coordination of gene expression across large regulons, as well as probabilistic differentiation strategies that function across cell populations. At the longest timescales, noise may facilitate evolutionary transitions. Here we review examples and emerging principles that connect noise, the architecture of the gene circuits in which it is present, and the biological functions it enables. We further indicate some of the important challenges and opportunities going forward

Iterative solution of elliptic problems by approximate factorization

AbstractAn iterative method for the numerical solution of singularly perturbed second-order linear elliptic problems is presented. It is a defect correction iteration in which the approximate operator is the product of two first-order operators, which is readily inverted numerically. The approximate operator is generated by formal asymptotic factorization of the original operator. Hence this is a QUasi Analytic Defect correction iteration (QUAD). Both its continuous and discrete versions are analyzed in one dimension. The scheme is extended to a variety of two dimensional operators and it is analyzed for a model advection-diffusion equation. Numerical calculations show the effectiveness of the scheme over a wide range of values of the small parameter

Hierarchical inference as a source of human biases

The finding that human decision-making is systematically biased continues to have an immense impact on both research and policymaking. Prevailing views ascribe biases to limited computational resources, which require humans to resort to less costly resource-rational heuristics. Here, we propose that many biases in fact arise due to a computationally costly way of coping with uncertainty—namely, hierarchical inference—which by nature incorporates information that can seem irrelevant. We show how, in uncertain situations, Bayesian inference may avail of the environment’s hierarchical structure to reduce uncertainty at the cost of introducing bias. We illustrate how this account can explain a range of familiar biases, focusing in detail on the halo effect and on the neglect of base rates. In each case, we show how a hierarchical-inference account takes the characterization of a bias beyond phenomenological description by revealing the computations and assumptions it might reflect. Furthermore, we highlight new predictions entailed by our account concerning factors that could mitigate or exacerbate bias, some of which have already garnered empirical support. We conclude that a hierarchical inference account may inform scientists and policy makers with a richer understanding of the adaptive and maladaptive aspects of human decision-making

Glaucomatous optic disc changes despite normal baseline intraocular pressure in a child

Purpose: We describe a case of normal tension glaucoma in the setting of sickle cell disease in a 9-year-old patient with a five-year follow up. Observations: A 9-year-old male patient with a history of sickle cell disease presented initially at the age of 4 years for evaluation of a brief episode of nonspecific eye pain that had spontaneously resolved prior to the clinic visit. Over the course of several years, the patient was noted to have progressive optic disc cupping bilaterally, retinal nerve fiber layer thinning bilaterally, and has developed a corresponding inferior arcuate defect on automated visual field testing in the right eye, all without elevated intraocular pressures (IOP). After neuro-ophthalmic pathologies were ruled out, the patient was diagnosed with glaucoma associated with sickle cell disease and normal baseline IOP, and brimonidine therapy was initiated. Conclusions and Importance: To our knowledge, this is the first reported case of normal-tension glaucoma in a pediatric patient. Normal-tension glaucoma may be a consideration in the evaluation of pediatric glaucoma suspects, but remains a diagnosis of exclusion

Cosmological Density and Power Spectrum from Peculiar Velocities: Nonlinear Corrections and PCA

We allow for nonlinear effects in the likelihood analysis of galaxy peculiar velocities, and obtain ~35%-lower values for the cosmological density parameter Om and the amplitude of mass-density fluctuations. The power spectrum in the linear regime is assumed to be a flat LCDM model (h=0.65, n=1, COBE) with only Om as a free parameter. Since the likelihood is driven by the nonlinear regime, we "break" the power spectrum at k_b=0.2 h/Mpc and fit a power law at k>k_b. This allows for independent matching of the nonlinear behavior and an unbiased fit in the linear regime. The analysis assumes Gaussian fluctuations and errors, and a linear relation between velocity and density. Tests using proper mock catalogs demonstrate a reduced bias and a better fit. We find for the Mark3 and SFI data Om_m=0.32+-0.06 and 0.37+-0.09 respectively, with sigma_8*Om^0.6 = 0.49+-0.06 and 0.63+-0.08, in agreement with constraints from other data. The quoted 90% errors include cosmic variance. The improvement in likelihood due to the nonlinear correction is very significant for Mark3 and moderately so for SFI. When allowing deviations from LCDM, we find an indication for a wiggle in the power spectrum: an excess near k=0.05 and a deficiency at k=0.1 (cold flow). This may be related to the wiggle seen in the power spectrum from redshift surveys and the second peak in the CMB anisotropy. A chi^2 test applied to modes of a Principal Component Analysis (PCA) shows that the nonlinear procedure improves the goodness of fit and reduces a spatial gradient of concern in the linear analysis. The PCA allows addressing spatial features of the data and fine-tuning the theoretical and error models. It shows that the models used are appropriate for the cosmological parameter estimation performed. We address the potential for optimal data compression using PCA.Comment: 18 pages, LaTex, uses emulateapj.sty, ApJ in press (August 10, 2001), improvements to text and figures, updated reference

Finding the center reliably: robust patterns of developmental gene expression

We investigate a mechanism for the robust identification of the center of a developing biological system. We assume the existence of two morphogen gradients, an activator emanating from the anterior, and a co-repressor from the posterior. The co-repressor inhibits the action of the activator in switching on target genes. We apply this system to Drosophila embryos, where we predict the existence of a hitherto undetected posterior co-repressor. Using mathematical modelling, we show that a symmetric activator-co-repressor model can quantitatively explain the precise mid-embryo expression boundary of the hunchback gene, and the scaling of this pattern with embryo size.Comment: 4 pages, 3 figure

Quality of targeted temperature management and outcome of out-of-hospital cardiac arrest patients : A post hoc analysis of the TTH48 study

Background: No data are available on the quality of targeted temperature management (TTM) provided to out-of-hospital cardiac arrest (OHCA) patients and its association with outcome. Methods: Post hoc analysis of the TTH48 study (NCT01689077), which compared the effects of prolonged TTM at 33 degrees C for 48 h to standard 24-h TTM on neurologic outcome. Admission temperature, speed of cooling, rewarming rates, precision (i.e. temperature variability), overcooling and overshooting as post-cooling fever (i.e. >38.0 degrees C) were collected. A specific score, ranging from 1 to 9, was computed to define the "quality of TTM". Results: On a total of 352 patients, most had a moderate quality of TTM (n = 217; 62% - score 4-6), while 80 (23%) patients had a low quality of TTM (score 1-3) and only 52 (16%) a high quality of TTM (score 7-9). The proportion of patients with unfavorable neurological outcome (UO; Cerebral Performance Category of 3-5 at 6 months) was similar between the different quality of TTM groups (p = 0.90). Although a shorter time from arrest to target temperature and a lower proportion of time outside the target ranges in the TTM 48-h than in the TTM 24-h group, quality of TTM was similar between groups. Also, the proportion of patients with UO was similar between the different quality of TTM groups when TTM 48-h and TTM 24-h were compared. Conclusions: In this study, high quality of TTM was provided to a small proportion of patients. However, quality of TTM was not associated with patients' outcome.Peer reviewe