Phenothiazines alter plasma membrane properties and sensitize cancer cells to injury by inhibiting annexin-mediated repair

Repair of damaged plasma membrane in eukaryotic cells is largely dependent on the binding of annexin repair proteins to phospholipids. Changing the biophysical properties of the plasma membrane may provide means to compromise annexin-mediated repair and sensitize cells to injury. Since, cancer cells experience heightened membrane stress and are more dependent on efficient plasma membrane repair, inhibiting repair may provide approaches to sensitize cancer cells to plasma membrane damage and cell death. Here, we show that derivatives of phenothiazines, which have widespread use in the fields of psychiatry and allergy treatment, strongly sensitize cancer cells to mechanical-, chemical-, and heat-induced injury by inhibiting annexin-mediated plasma membrane repair. Using a combination of cell biology, biophysics, and computer simulations, we show that trifluoperazine acts by thinning the membrane bilayer, making it more fragile and prone to ruptures. Secondly, it decreases annexin binding by compromising the lateral diffusion of phosphatidylserine, inhibiting the ability of annexins to curve and shape membranes, which is essential for their function in plasma membrane repair. Our results reveal a novel avenue to target cancer cells by compromising plasma membrane repair in combination with noninvasive approaches that induce membrane injuries.     

Alternate partial root-zone irrigation induced dry/wet cycles of soils stimulate N mineralization and improve N nutrition in tomatoes

Given the same amount of irrigation volume, applying alternate partial root-zone irrigation (PRI) has improved crop N nutrition as compared to deficit irrigation (DI), yet the mechanisms underlying this effect remain unknown. Therefore, the objective of this study was to investigate whether PRI induced soil dry/wet cycles facilitate soil organic N mineralization hereby contributing to the improvement of N nutrition in tomatoes. The plants were grown in split-root pots in a climate-controlled glasshouse and were subjected to PRI and DI treatments during early fruiting stage. ¹⁵N-labeled maize residues were incorporated into the soils. Results showed that PRI resulted in 25% higher net ¹⁵N mineralization than did DI, indicating that the enhanced mineralization of soil organic N alone could account for the 16% increase of N accumulation in the PRI than in the DI plants. The higher net N mineralization under PRI was coincided with an intensified soil microbial activity. In addition, even though soil chloroform fumigation labile carbon (CFL-C, as an index of microbial biomass) was similar for the two irrigation treatments, a significant increase of chloroform fumigation labile nitrogen (CFL-N) was found in the PRI wetting soil. Consequently, the C:N ratio of the chloroform fumigation labile pool was remarkably modified by the PRI treatment, which might indicate physiological changes of soil microbes or changes in labiality of soil organic C and N due to the dry/wet cycles of soils, altering conditions for net N mineralization. Moreover, in both soil compartments PRI caused significantly less extractable organic carbon (EOC) as compared with DI; whilst in the PRI wetting soil significantly higher extractable organic nitrogen (EON) was observed. A low EOC:EON ratio in the PRI wetting soil may indicate an increasing net mineralization of the organic N as a result of microbial metabolism. Conclusively, PRI induced greater microbial activity and higher microbial substrates availability are seemingly responsible for the enhanced net N mineralization and improved N nutrition in tomato plants.     

Socio-Demographic and Geographical Factors in Esophageal and Gastric Cancer Mortality in Sweden

Background

Socio-demographic factors and area of residence might influence the development of esophageal and gastric cancer. Large-scale population-based research can determine the role of such factors.

Methods

This population-based cohort study included all Swedish residents aged 30–84 years in 1990–2007. Educational level, marital status, place of birth, and place of residence were evaluated with regard to mortality from esophageal or gastric cancer. Cox regression yielded hazard ratios (HR) with 95% confidence intervals (CI), adjusted for potential confounding.

Results

Among 84 920 565 person-years, 5125 and 12 230 deaths occurred from esophageal cancer and gastric cancer, respectively. Higher educational level decreased the HR of esophageal cancer (HR = 0.61, 95%CI 0.42–0.90 in women, HR = 0.71, 95%CI 0.60–0.84 in men) and gastric cancer (HR = 0.80, 95%CI 0.63–1.03 in women, HR = 0.73, 95%CI 0.64–0.83 in men). Being unmarried increased HR of esophageal cancer (HR = 1.64, 95%CI 1.35–1.99 in women, HR = 1.64, 95%CI 1.50–1.80 in men), but not of gastric cancer. Being born in low density populated areas increased HR of gastric cancer (HR = 1.23, 95%CI 1.10–1.38 in women, HR = 1.37, 95%CI 1.25–1.50 in men), while no strong association was found with esophageal cancer. Living in densely populated areas increased HR of esophageal cancer (HR = 1.31, 95%CI 1.14–1.50 in women, HR = 1.40, 95%CI 1.29–1.51 in men), but not of gastric cancer.

Conclusion

These socio-demographic inequalities in cancer mortality warrant efforts to investigate possible preventable mechanisms and to promote and support healthier lifestyles among deprived groups.     

Optimal information storage in noisy synapses under resource constraints

Experimental investigations have revealed that synapses possess interesting and, in some cases, unexpected properties. We propose a theoretical framework that accounts for three of these properties: typical central synapses are noisy, the distribution of synaptic weights among central synapses is wide, and synaptic connectivity between neurons is sparse. We also comment on the possibility that synaptic weights may vary in discrete steps. Our approach is based on maximizing information storage capacity of neural tissue under resource constraints. Based on previous experimental and theoretical work, we use volume as a limited resource and utilize the empirical relationship between volume and synaptic weight. Solutions of our constrained optimization problems are not only consistent with existing experimental measurements but also make nontrivial predictions.     

An evaluation of analysis pipelines for DNA methylation profiling using the Illumina HumanMethylation450 BeadChip platform

The proper identification of differentially methylated CpGs is central in most epigenetic studies. The Illumina HumanMethylation450 BeadChip is widely used to quantify DNA methylation; nevertheless, the design of an appropriate analysis pipeline faces severe challenges due to the convolution of biological and technical variability and the presence of a signal bias between Infinium I and II probe design types. Despite recent attempts to investigate how to analyze DNA methylation data with such an array design, it has not been possible to perform a comprehensive comparison between different bioinformatics pipelines due to the lack of appropriate data sets having both large sample size and sufficient number of technical replicates. Here we perform such a comparative analysis, targeting the problems of reducing the technical variability, eliminating the probe design bias and reducing the batch effect by exploiting two unpublished data sets, which included technical replicates and were profiled for DNA methylation either on peripheral blood, monocytes or muscle biopsies. We evaluated the performance of different analysis pipelines and demonstrated that: (1) it is critical to correct for the probe design type, since the amplitude of the measured methylation change depends on the underlying chemistry; (2) the effect of different normalization schemes is mixed, and the most effective method in our hands were quantile normalization and Beta Mixture Quantile dilation (BMIQ); (3) it is beneficial to correct for batch effects. In conclusion, our comparative analysis using a comprehensive data set suggests an efficient pipeline for proper identification of differentially methylated CpGs using the Illumina 450K arrays.     

A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons

Pyramidal neurons in the cerebral cortex span multiple cortical layers. How the excitable properties of pyramidal neuron dendrites allow these neurons to both integrate activity and store associations between different layers is not well understood, but is thought to rely in part on dendritic backpropagation of action potentials. Here we demonstrate that the sign of synaptic plasticity in neocortical pyramidal neurons is regulated by the spread of the backpropagating action potential to the synapse. This creates a progressive gradient between LTP and LTD as the distance of the synaptic contacts from the soma increases. At distal synapses, cooperative synaptic input or dendritic depolarization can switch plasticity between LTD and LTP by boosting backpropagation of action potentials. This activity-dependent switch provides a mechanism for associative learning across different neocortical layers that process distinct types of information.     

Arv1 Regulates PM and ER Membrane Structure and Homeostasis But is Dispensable for Intracellular Sterol Transport

The pan‐eukaryotic endoplasmic reticulum (ER) membrane protein Arv1 has been suggested to play a role in intracellular sterol transport. We tested this proposal by comparing sterol traffic in wild‐type and Arv1‐deficient Saccharomyces cerevisiae. We used fluorescence microscopy to track the retrograde movement of exogenously supplied dehydroergosterol (DHE) from the plasma membrane (PM) to the ER and lipid droplets and high performance liquid chromatography to quantify, in parallel, the transport‐coupled formation of DHE esters. Metabolic labeling and subcellular fractionation were used to assay anterograde transport of ergosterol from the ER to the PM. We report that sterol transport between the ER and PM is unaffected by Arv1 deficiency. Instead, our results indicate differences in ER morphology and the organization of the PM lipid bilayer between wild‐type and arv1Δ cells suggesting a distinct role for Arv1 in membrane homeostasis. In arv1Δ cells, specific defects affecting single C‐terminal transmembrane domain proteins suggest that Arv1 might regulate membrane insertion of tail‐anchored proteins involved in membrane homoeostasis .     

Fluctuating water levels control water chemistry and metabolism of a charophyte‐dominated pond

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