Positional Information,Positional Error,and Readout Precision in Morphogenesis: A Mathematical Framework

The concept of positional information is central to our understanding of how cells determine their location in a multicellular structure and thereby their developmental fates. Nevertheless, positional information has neither been defined mathematically nor quantified in a principled way. Here we provide an information-theoretic definition in the context of developmental gene expression patterns and examine the features of expression patterns that affect positional information quantitatively. We connect positional information with the concept of positional error and develop tools to directly measure information and error from experimental data. We illustrate our framework for the case of gap gene expression patterns in the early Drosophila embryo and show how information that is distributed among only four genes is sufficient to determine developmental fates with nearly single-cell resolution. Our approach can be generalized to a variety of different model systems; procedures and examples are discussed in detail.     

Pre-analytical Factors Influence Accuracy of Urine Spot Iodine Assessment in Epidemiological Surveys

Urinary iodine concentration (UIC) is commonly used to assess iodine status of subjects in epidemiological surveys. As pre-analytical factors are an important source of measurement error and studies about this phase are scarce, our objective was to assess the influence of urine sampling conditions on UIC, i.e., whether the child ate breakfast or not, urine void rank of the day, and time span between last meal and urine collection. A nationwide, two-stage, stratified, cross-sectional study including 1560 children (6–12 years) was performed in 2012. UIC was determined by the Sandell-Kolthoff method. Pre-analytical factors were assessed from children’s mothers by using a questionnaire. Association between iodine status and pre-analytical factors were adjusted for one another and socio-economic characteristics by multivariate linear and multinomial regression models (RPR: relative prevalence ratios). Skipping breakfast prior to morning urine sampling decreased UIC by 40 to 50 μg/L and the proportion of UIC?<?100 μg/L was higher among children having those skipped breakfast (RPR?=?3.2[1.0–10.4]). In unadjusted analyses, UIC was less among children sampled more than 5 h from their last meal. UIC decreased with rank of urine void (e.g., first vs. second, P?<?0.001); also, the proportion of UIC?<?100 μg/L was greater among 4th rank samples (vs. second RPR?=?2.1[1.1–4.0]). Subjects’ breakfast status and urine void rank should be accounted for when assessing iodine status. Providing recommendations to standardize pre-analytical factors is a key step toward improving accuracy and comparability of survey results for assessing iodine status from spot urine samples. These recommendations have to be evaluated by future research.     

Epigallocatechin-3-gallate (EGCG) inhibits the migratory behavior of tumor bronchial epithelial cells

Background

Many studies associated the main polyphenolic constituent of green tea, (-)-Epigallocatechin-3-gallate (EGCG), with inhibition of cancers, invasion and metastasis. To date, most of the studies have focused on the effect of EGCG on cell proliferation or death. Since cell migration is an important mechanism involved in tumor invasion, the aim of the present work was to target another approach of the therapeutic effect of EGCG, by investigating its effect on the cell migratory behavior.

Methods

The effect of EGCG (at concentrations lower than 10 μg/ml) on the migration speed of invasive cells was assessed by using 2D and 3D models of cell culture. We also studied the effects of EGCG on proteinases expression by RT-PCR analysis. By immunocytochemistry, we analyzed alterations of vimentin organization in presence of different concentrations of EGCG.

Results

We observed that EGCG had an inhibitory effect of cell migration in 2D and 3D cell culture models. EGCG also inhibited MMP-2 mRNA and protein expression and altered the intermediate filaments of vimentin.

Conclusion

Taken together, our results demonstrate that EGCG is able to inhibit the migration of bronchial tumor cells and could therefore be an attractive candidate to treat tumor invasion and cell migration.     

Autoregulation of CCL26 synthesis and secretion in A549 cells: a possible mechanism by which alveolar epithelial cells modulate airway inflammation

Eotaxins (CCL11, CCL24, CCL26) originating from airway epithelial cells and leukocytes have been detected in bronchoalveolar lavage of asthmatics. Although the alveolar epithelium is the destination of uncleared allergens and other inflammatory products, scanty information exists on their contribution to the generation and regulation of the eotaxins. We envisioned a state whereby alveolar type II cells, a known source of other inflammatory proteins, could be involved in both the production and regulation of CCL24 and CCL26. Herein, we demonstrated that all three eotaxins are constitutively expressed in A549 cells. IL-4 and IL-13 stimulated a concentration-dependent secretion of CCL24 and CCL26. The cytokines did not act synergistically. Cycloheximide and actinomycin D abrogated IL-4- and IL-13-dependent CCL26 but not CCL24 secretion. Both IL-13 and IL-4 stimulated CCL26 synthesis that was inhibited in a concentration-dependent manner by CCL26 but not CCL24. Only CCL26 reduced expression of CCR3 receptors by 30-40%. On the other hand, anti-CCR3 pretreatment reduced IL-4+IL-13-dependent CCL26 secretion, implying autoregulation. A CCR3-specific antagonist (SB-328437) significantly decreased IL-4-dependent synthesis and release of CCL26. Eosinophils treated with medium from IL-4-stimulated A549 cells preincubated with anti-CCL26 showed a marked decrease of superoxide anion production compared with anti-CCL24 treated. These results suggest that CCL26 is a major eotaxin synthesized and released by alveolar epithelial cells and is involved in autoregulation of CCR3 receptors and other eotaxins. This CCL26-CCR3 ligand-receptor system may be an attractive target for development of therapeutics that limits progress of inflammation in airway disease.     

Rethinking trophic niches: Speed and body mass colimit prey space of mammalian predators

1. Realized trophic niches of predators are often characterized along a one‐dimensional range in predator–prey body mass ratios. This prey range is constrained by an “energy limit” and a “subdue limit” toward small and large prey, respectively. Besides these body mass ratios, maximum speed is an additional key component in most predator–prey interactions.
2. Here, we extend the concept of a one‐dimensional prey range to a two‐dimensional prey space by incorporating a hump‐shaped speed‐body mass relation. This new “speed limit” additionally constrains trophic niches of predators toward fast prey.
3. To test this concept of two‐dimensional prey spaces for different hunting strategies (pursuit, group, and ambush predation), we synthesized data on 63 terrestrial mammalian predator–prey interactions, their body masses, and maximum speeds.
4. We found that pursuit predators hunt smaller and slower prey, whereas group hunters focus on larger but mostly slower prey and ambushers are more flexible. Group hunters and ambushers have evolved different strategies to occupy a similar trophic niche that avoids competition with pursuit predators. Moreover, our concept suggests energetic optima of these hunting strategies along a body mass axis and thereby provides mechanistic explanations for why there are no small group hunters (referred to as “micro‐lions”) or mega‐carnivores (referred to as “mega‐cheetahs”).
5. Our results demonstrate that advancing the concept of prey ranges to prey spaces by adding the new dimension of speed will foster a new and mechanistic understanding of predator trophic niches and improve our predictions of predator–prey interactions, food web structure, and ecosystem functions.

     

Major Cardiovascular Risk Factors in Latin America: A Comparison with the United States. The Latin American Consortium of Studies in Obesity (LASO)

Background

Limited knowledge on the prevalence and distribution of risk factors impairs the planning and implementation of cardiovascular prevention programs in the Latin American and Caribbean (LAC) region.

Methods and Findings

Prevalence of hypertension, diabetes mellitus, abnormal lipoprotein levels, obesity, and smoking were estimated from individual-level patient data pooled from population-based surveys (1998–2007, n = 31,009) from eight LAC countries and from a national survey of the United States (US) population (1999–2004) Age and gender specific prevalence were estimated and age-gender adjusted comparisons between both populations were conducted. Prevalence of diabetes mellitus, hypertension, and low high-density lipoprotein (HDL)-cholesterol in LAC were 5% (95% confidence interval [95% CI]: 3.4, 7.9), 20.2% (95% CI: 12.5, 31), and 53.3% (95% CI: 47, 63.4), respectively. Compared to LAC region’s average, the prevalence of each risk factor tended to be lower in Peru and higher in Chile. LAC women had higher prevalence of obesity and low HDL-cholesterol than men. Obesity, hypercholesterolemia, and hypertriglyceridemia were more prevalent in the US population than in LAC population (31 vs. 16.1%, 16.8 vs. 8.9%, and 36.2 vs. 26.5%, respectively). However, the prevalence of low HDL-cholesterol was higher in LAC than in the US (53.3 vs. 33.7%).

Conclusions

Major cardiovascular risk factors are highly prevalent in LAC region, in particular low HDL-cholesterol. In addition, marked differences do exist in this prevalence profile between LAC and the US. The observed patterns of obesity-related risk factors and their current and future impact on the burden of cardiovascular diseases remain to be explained.     

Biarylimidazoles as inhibitors of microsomal prostaglandin E2 synthase-1

Microsomal prostaglandin E(2) synthase (mPGES-1) represents a potential target for novel analgesic and anti-inflammatory agents. High-throughput screening identified several leads of mPGES-1 inhibitors which were further optimized for potency and selectivity. A series of inhibitors bearing a biaryl imidazole scaffold exhibits excellent inhibition of PGE(2) production in enzymatic and cell-based assays. The synthesis of these molecules and their activities will be discussed.