Strong negative self regulation of Prokaryotic transcription factors increases the intrinsic noise of protein expression

Background Many prokaryotic transcription factors repress their own transcription. It is often asserted that such regulation enables a cell to homeostatically maintain protein abundance. We explore the role of negative self regulation of transcription in regulating the variability of protein abundance using a variety of stochastic modeling techniques. Results We undertake a novel analysis of a classic model for negative self regulation. We demonstrate that, with standard approximations, protein variance relative to its mean should be independent of repressor strength in a physiological range. Consequently, in that range, the coefficient of variation would increase with repressor strength. However, stochastic computer simulations demonstrate that there is a greater increase in noise associated with strong repressors than predicted by theory. The discrepancies between the mathematical analysis and computer simulations arise because with strong repressors the approximation that leads to Michaelis-Menten-like hyperbolic repression terms ceases to be valid. Because we observe that strong negative feedback increases variability and so is unlikely to be a mechanism for noise control, we suggest instead that negative feedback is evolutionarily favoured because it allows the cell to minimize mRNA usage. To test this, we used in silico evolution to demonstrate that while negative feedback can achieve only a modest improvement in protein noise reduction compared with the unregulated system, it can achieve good improvement in protein response times and very substantial improvement in reducing mRNA levels. Conclusions Strong negative self regulation of transcription may not always be a mechanism for homeostatic control of protein abundance, but instead might be evolutionarily favoured as a mechanism to limit the use of mRNA. The use of hyperbolic terms derived from quasi-steady-state approximation should also be avoided in the analysis of stochastic models with strong repressors

Investigation of attentional bias in obsessive compulsive disorder with and without depression in visual search

Copyright: © 2013 Morein-Zamir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedWhether Obsessive Compulsive Disorder (OCD) is associated with an increased attentional bias to emotive stimuli remains controversial. Additionally, it is unclear whether comorbid depression modulates abnormal emotional processing in OCD. This study examined attentional bias to OC-relevant scenes using a visual search task. Controls, non-depressed and depressed OCD patients searched for their personally selected positive images amongst their negative distractors, and vice versa. Whilst the OCD groups were slower than healthy individuals in rating the images, there were no group differences in the magnitude of negative bias to concern-related scenes. A second experiment employing a common set of images replicated the results on an additional sample of OCD patients. Although there was a larger bias to negative OC-related images without pre-exposure overall, no group differences in attentional bias were observed. However, OCD patients subsequently rated the images more slowly and more negatively, again suggesting post-attentional processing abnormalities. The results argue against a robust attentional bias in OCD patients, regardless of their depression status and speak to generalized difficulties disengaging from negative valence stimuli. Rather, post-attentional processing abnormalities may account for differences in emotional processing in OCD.Peer reviewedFinal Published versio

Compound double ileoileal and ileocecocolic intussusception caused by lipoma of the ileum in an adult patient: A case report

<p>Abstract</p> <p>Introduction</p> <p>The initial diagnosis of intussusception in adults very often can be missed and cause delayed treatment and possible serious complications. We report the case of an adult patient with complicated double ileoileal and ileocecocolic intussusception.</p> <p>Case presentation</p> <p>A 46-year-old Caucasian man was transferred from the gastroenterology service to the abdominal surgery service with severe abdominal pain, nausea, and vomiting. An abdominal ultrasound, barium enema, and abdominal computed tomography scan revealed an intraluminal obstruction of his ascending colon. Plain abdominal X-rays showed diffuse air-fluid levels in his small intestine. A double ileoileal and ileocecocolic intussusception was found during an emergent laparotomy. A right hemicolectomy, including resection of a long segment of his ileum, was performed. The postoperative period was complicated by acute renal failure, shock liver, and pulmonary thromboembolism. Our patient was discharged from the hospital after 30 days. An anatomical pathology examination revealed a lipoma of his ileum.</p> <p>Conclusions</p> <p>Intussusception in adults requires early surgical resection regardless of the nature of the initial cause. Delayed treatment can cause very serious complications.</p

K-Ras Mediated Murine Epidermal Tumorigenesis Is Dependent upon and Associated with Elevated Rac1 Activity

A common goal for potential cancer therapies is the identification of differences in protein expression or activity that would allow for the selective targeting of tumor vs. normal cells. The Ras proto-oncogene family (K-Ras, H-Ras and N-Ras) are amongst the most frequently mutated genes in human cancers. As a result, there has been substantial effort dedicated to determining which pathways are activated by Ras signaling and, more importantly, which of these contribute to cancer. Although the most widely studied Ras-regulated signaling pathway is the Raf/mitogen-activated protein kinase cascade, previous research in model systems has revealed that the Rac1 GTP-binding protein is also required for Ras-induced biological responses. However, what have been lacking are rigorous in vivo Rac1 target validation data and a clear demonstration that in Ras-driven hyperplastic lesions, Rac1 activity is increased. Using a combination of genetically-modified mouse models that allow for the tissue-selective activation or deletion of signaling molecules and an activation-state sensitive Rac1 antibody that detects GTP-bound Rac1, we found that Rac1 contributes to K-Ras induced epidermal papilloma initiation and growth and that Rac1 activity is elevated by oncogenic K-Ras in vivo. Previously, it was not practical to assess Rac1 activation status in the most commonly used format for clinical tumor specimens, formalin-fixed paraffin embedded (FFPE) tissues samples. However, this study clearly demonstrates that Rac1 is essential for K-Ras driven epithelial cell hyperproliferation and that Rac1 activity is elevated in tissues expressing mutant oncogenic K-Ras, while also characterizing the activation-state specific Rac1-GTP antibody as a probe to examine Rac1 activation status in FFPE samples. Our findings will facilitate further research on the status of Rac1 activity in human tumors and will help to define the tumor types of the patient population that could potentially benefit from therapies targeting Rac activation or downstream effector signaling pathways

Search for Single Top Production at LEP

Single top production in e+e- annihilations is searched for in data collected by the L3 detector at centre-of-mass energies from 189 to 209 GeV, corresponding to a total integrated luminosity of 634 pb-1. Investigating hadronic and semileptonic top decays, no evidence of single top production at LEP is obtained and upper limits on the single top cross section as a function of the centre-of-mass energy are derived. Limits on possible anomalous couplings, as well as on the scale of contact interactions responsible for single top production are determined

The route to transcription initiation determines the mode of transcriptional bursting in E. coli

Transcription is fundamentally noisy, leading to significant heterogeneity across bacterial populations. Noise is often attributed to burstiness, but the underlying mechanisms and their dependence on the mode of promotor regulation remain unclear. Here, we measure E. coli single cell mRNA levels for two stress responses that depend on bacterial sigma factors with different mode of transcription initiation (σ70 and σ54). By fitting a stochastic model to the observed mRNA distributions, we show that the transition from low to high expression of the σ70-controlled stress response is regulated via the burst size, while that of the σ54-controlled stress response is regulated via the burst frequency. Therefore, transcription initiation involving σ54 differs from other bacterial systems, and yields bursting kinetics characteristic of eukaryotic systems

Impact of the solvent capacity constraint on E. coli metabolism

<p>Abstract</p> <p>Background</p> <p>Obtaining quantitative predictions for cellular metabolic activities requires the identification and modeling of the physicochemical constraints that are relevant at physiological growth conditions. Molecular crowding in a cell's cytoplasm is one such potential constraint, as it limits the solvent capacity available to metabolic enzymes.</p> <p>Results</p> <p>Using a recently introduced flux balance modeling framework (FBAwMC) here we demonstrate that this constraint determines a metabolic switch in <it>E. coli </it>cells when they are shifted from low to high growth rates. The switch is characterized by a change in effective optimization strategy, the excretion of acetate at high growth rates, and a global reorganization of <it>E. coli </it>metabolic fluxes, the latter being partially confirmed by flux measurements of central metabolic reactions.</p> <p>Conclusion</p> <p>These results implicate the solvent capacity as an important physiological constraint acting on <it>E. coli </it>cells operating at high metabolic rates and for the activation of a metabolic switch when they are shifted from low to high growth rates. The relevance of this constraint in the context of both the aerobic ethanol excretion seen in fast growing yeast cells (Crabtree effect) and the aerobic glycolysis observed in rapidly dividing cancer cells (Warburg effect) should be addressed in the future.</p

Dental microwear texture analysis of Homo sapiens sapiens: foragers, farmers, and pastoralists

Objectives. The current study seeks to determine if a sample of foragers, farmers, and pastoralists can be distinguished by their dental microwear texture signatures. Materials and Methods. The study included a sample of 719 individuals from 51 archaeological sites (450 farmers, 192 foragers, 77 pastoralists). All were over age 12 and sexes were pooled. Using a Sensofar® white-light confocal profiler we collected dental microwear texture analysis (DMTA) data from a single first or second molar from each individual. We leveled and cleaned data clouds following standard procedures and analyzed the data with Sfrax® and Toothfrax® software. The DMTA variables were complexity and anisotropy. Statistics included ANOVA with partial eta squared and Hedges's g. We also performed a follow-up K-means cluster analysis. Results. We found significant differences between foragers and farmers and pastoralists for complexity and anisotropy, with foragers having greater complexity than either the farmers or the pastoralists. The farmers and pastoralists had greater anisotropy than the foragers. The Old World foragers had significantly higher anisotropy values than New World foragers. Old and New World farmers did not differ. Among the Old World farmers, those dating from the Neolithic through the Late Bronze Age had higher complexity values than those from the Iron Age through the medieval period. The cluster analysis discerned foragers and farmers but also indicated similarity between hard food foragers and hard food farmers. Discussion. Our findings reaffirm that DMTA is capable of distinguishing human diets. We found that foragers and farmers, in particular, differ in their microwear signatures across the globe. There are some exceptions, but nothing that would be unexpected given the range of human diets and food preparation techniques. This study indicates that in general DMTA is an efficacious means of paleodietary reconstruction in humans