Bistable State Switch Enables Ultrasensitive Feedback Control in Heterogeneous Microbial Populations

Molecular feedback control circuits can improve robustness of gene expression at the single cell level. This achievement can be offset by requirements of rapid protein expression, that may induce cellular stress, known as burden, that reduces colony growth. To begin to address this challenge we take inspiration by 'division-of-labor' in heterogeneous cell populations: we propose to combine bistable switches and quorum sensing systems to coordinate gene expression at the population level. We show that bistable switches in individual cells operating in parallel yield an ultrasensitive response, while cells maintain heterogeneous levels of gene expression to avoid burden across all cells. Within a feedback loop, these switches can achieve robust reference tracking and adaptation to disturbances at the population-level. We also demonstrate that molecular sequestration enables tunable hysteresis in individual switches, making it possible to obtain a wide range of stable population-level expressions

Measuring diet in primary school children aged 8-11 years: validation of the Child and Diet Evaluation Tool (CADET) with an emphasis on fruit and vegetable intake.

Background/Objectives:The Child And Diet Evaluation Tool (CADET) is a 24-h food diary that measures the nutrition intake of children aged 3-7 years, with a focus on fruit and vegetable consumption. Until now CADET has not been used to measure nutrient intake of children aged 8-11 years. To ensure that newly assigned portion sizes for this older age group were valid, participants were asked to complete the CADET diary (the school and home food diary) concurrently with a 1-day weighed record. Subjects/Methods:A total of 67 children with a mean age of 9.3 years (s.d.: ± 1.4, 51% girls) participated in the study. Total fruit and vegetable intake in grams and other nutrients were extracted to compare the mean intakes from the CADET diary and Weighed record using t-tests and Pearson's r correlations. Bland-Altman analysis was also conducted to assess the agreement between the two methods. Results: Correlations comparing the CADET diary to the weighed record were high for fruit, vegetables and combined fruit and vegetables (r=0.7). The results from the Bland-Altman plots revealed a mean difference of 54 g (95% confidence interval: -88, 152) for combined fruit and vegetables intake. CADET is the only tool recommended by the National Obesity Observatory that has been validated in a UK population and provides nutrient level data on children's diets. Conclusions:The results from this study conclude that CADET can provide high-quality nutrient data suitable for evaluating intervention studies now for children aged 3-11 years with a focus on fruit and vegetable intake

Oral Bisphosphonate Exposure and the Risk of Upper Gastrointestinal Cancers

The association between oral bisphosphonate use and upper gastrointestinal cancer has been controversial. Therefore, we examined the association with esophageal and gastric cancer within the Kaiser Permanente, Northern California population. A total of 1,011 cases of esophageal (squamous cell carcinoma and adenocarcinoma) and 1,923 cases of gastric adenocarcinoma (cardia, non-cardia and other) diagnosed between 1997 and 2011 from the Kaiser Permanente, Northern California cancer registry were matched to 49,886 and 93,747 controls, respectively. Oral bisphosphonate prescription fills at least one year prior to the index date were extracted. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between prospectively evaluated oral bisphosphonate use with incident esophageal and gastric cancer diagnoses with adjustment for potential confounders. After adjustment for potential confounders, no significant associations were found for esophageal squamous cell carcinoma (OR 0.88; 95% CI: 0.51, 1.52), esophageal adenocarcinoma (OR 0.68; 95% CI: 0.37, 1.24), or gastric non-cardia adenocarcinoma (OR 0.83, 95% CI: 0.59, 1.18), but we observed an adverse association with gastric cardia adenocarcinoma (OR 1.64; 95% CI: 1.07, 2.50). In conclusion, we observed no association between oral bisphosphonate use and esophageal cancer risk within a large community-based population. A significant association was detected with gastric cardia and other adenocarcinoma risk, although this needs to be replicated

The Emerging Role of Protein Phosphorylation as a Critical Regulatory Mechanism Controlling Cellulose Biosynthesis

Plant cell walls are extracellular matrices that surround plant cells and critically influence basic cellular processes, such as cell division and expansion. Cellulose is a major constituent of plant cell walls, and this paracrystalline polysaccharide is synthesized at the plasma membrane by a large protein complex known as the cellulose synthase complex (CSC). Recent efforts have identified numerous protein components of the CSC, but relatively little is known about regulation of cellulose biosynthesis. Numerous phosphoproteomic surveys have identified phosphorylation events in CSC associated proteins, suggesting that protein phosphorylation may represent an important regulatory control of CSC activity. In this review, we discuss the composition and dynamics of the CSC in vivo, the catalogue of CSC phosphorylation sites that have been identified, the function of experimentally examined phosphorylation events, and potential kinases responsible for these phosphorylation events. Additionally, we discuss future directions in cellulose synthase kinase identification and functional analyses of CSC phosphorylation sites

A post-IR IRSL chronology and dustmass accumulation rates of the Nosak loess-palaeosol sequence in northeastern Serbia

In the Middle Danube Basin, Quaternary deposits are widely distributed in the Vojvodina region where they cover about 95% of the area.Major research during the last two decades has been focused on loess deposits in the Vojvodina region. During this period, loess in the Vojvodina region has become one of the most important Pleistocene European continental climatic and environmental records.Herewe present the dating results of 15 samples taken from theNosak loess-palaeosol sequence in northeastern Serbia in order to establish a chronology over the last three glacial– interglacial cycles. We use the pIRIR290 signal of the 4–11 lm polymineral grains. The calculated ages are within the error limits partially consistent with the proposed multi-millennial chronostratigraphy for Serbian loess. The average mass accumulation rate for the last three glacial–interglacial cycles is 265 g m�2 a�1 , which is in agreement with the values of most sites in the Carpathian Basin. Our results indicate a highly variable deposition rate of loess, especially during the MIS 3 and MIS 6 stages, which is contrary to most studies conducted in Serbia where linear sedimentation rates were assume

Nutritional Control of DNA Replication Initiation through the Proteolysis and Regulated Translation of DnaA

Bacteria can arrest their own growth and proliferation upon nutrient depletion and under various stressful conditions to ensure their survival. However, the molecular mechanisms responsible for suppressing growth and arresting the cell cycle under such conditions remain incompletely understood. Here, we identify post-transcriptional mechanisms that help enforce a cell-cycle arrest in Caulobacter crescentus following nutrient limitation and during entry into stationary phase by limiting the accumulation of DnaA, the conserved replication initiator protein. DnaA is rapidly degraded by the Lon protease following nutrient limitation. However, the rate of DnaA degradation is not significantly altered by changes in nutrient availability. Instead, we demonstrate that decreased nutrient availability downregulates dnaA translation by a mechanism involving the 5' untranslated leader region of the dnaA transcript; Lon-dependent proteolysis of DnaA then outpaces synthesis, leading to the elimination of DnaA and the arrest of DNA replication. Our results demonstrate how regulated translation and constitutive degradation provide cells a means of precisely and rapidly modulating the concentration of key regulatory proteins in response to environmental inputs.National Institutes of Health (U.S.) (Grant 5R01GM082899

Household wealth and neurocognitive development disparities among school-aged children in Nepal.

BACKGROUND: Wealth disparities in child developmental outcomes are well documented in developed countries. We sought to (1) describe the extent of wealth-based neurocognitive development disparities and (2) examine potential mediating factors of disparities among a population-based cohort of children in rural Nepal. METHODS: We investigated household wealth-based differences in intellectual, executive and motor function of n = 1692 children aged between 7 and 9 years in Nepal. Using linear mixed models, wealth-based differences were estimated before and after controlling for child and household demographic characteristics. We further examined wealth-based differences adjusted for three sets of mediators: child nutritional status, home environment, and schooling pattern. RESULTS: We observed a positive gradient in child neurocognitive performance by household wealth. After adjusting for child and household control factors, disparities between children in the highest and lowest wealth quintiles persisted in intellectual and motor function, but not executive function. No statistically significant wealth-based differentials in outcomes remained after accounting for nutritional status, home environment, and schooling patterns. The largest differences in neurocognitive development were associated with schooling pattern. CONCLUSIONS: Household wealth patterns child neurocognitive development in rural Nepal, likely through its influence on nutritional status, the home environment, and schooling. In the current context, improving early and regular schooling in this setting is critical to addressing wealth-based disparities in outcomes