Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma.

BACKGROUND: Aberrant activation of signaling pathways downstream of epidermal growth factor receptor (EGFR) has been hypothesized to be one of the mechanisms of cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to ligand stimulation and transfected with EGFR, RELA/p65, or HRASVal12D. RESULTS: The gene expression patterns that distinguished the HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12D further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. CONCLUSIONS: Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies

Redox changes during the cell cycle in the embryonic root meristem of Arabidopsis thaliana

Aims: The aim of this study was to characterize redox changes in the nuclei and cytosol occurring during the mitotic cell cycle in the embryonic roots of germinating Arabidopsis seedlings, and to determine how redox cycling was modified in mutants with a decreased capacity for ascorbate synthesis. Results: Using an in vivo reduction-oxidation (redox) reporter (roGFP2), we show that transient oxidation of the cytosol and the nuclei occurred at G1 in the synchronized dividing cells of the Arabidopsis root apical meristem, with reduction at G2 and mitosis. This redox cycle was absent from low ascorbate mutants in which nuclei were significantly more oxidized than controls. The cell cycle-dependent increase in nuclear size was impaired in the ascorbate-deficient mutants, which had fewer cells per unit area in the root proliferation zone. The transcript profile of the dry seeds and size of the imbibed seeds was strongly influenced by low ascorbate but germination, dormancy release and seed aging characteristics were unaffected. Innovation: These data demonstrate the presence of a redox cycle within the plant cell cycle and that the redox state of the nuclei is an important factor in cell cycle progression. Conclusions: Controlled oxidation is a key feature of the early stages of the plant cell cycle. However, sustained mild oxidation restricts nuclear functions and impairs progression through the cell cycle leading to fewer cells in the root apical meristem

Flavonoid-Rich Apple Improves Endothelial Function in Individuals at Risk for Cardiovascular Disease: A Randomized Controlled Clinical Trial

Scope The cardioprotective effects of apples are primarily attributed to flavonoids, found predominantly in the skin. This study aimed to determine if acute and/or chronic (4 weeks) ingestion of flavonoid-rich apples improves endothelial function, blood pressure (BP), and arterial stiffness in individuals at risk for cardiovascular diseases (CVD). Methods and results In this randomized, controlled cross-over trial, acute and 4 week intake of apple with skin (high flavonoid apple, HFA) is compared to intake of apple flesh only (low flavonoid apple, LFA) in 30 participants. The primary outcome is endothelial function assessed using flow-mediated dilation (FMD) of the brachial artery, while main secondary outcomes are 24 h ambulatory BP and arterial stiffness. Other outcomes include fasting serum glucose and lipoprotein profile, plasma heme oxygenase-1 (Hmox-1), F2-isoprostanes, flavonoid metabolites, and plasma and salivary nitrate (NO3−) and nitrite (NO2−) concentrations. Compared to LFA control, the HFA results in a significant increase in FMD acutely (0.8%, p \u3c 0.001) and after 4 weeks chronic intake (0.5%, p \u3c 0.001), and in plasma flavonoid metabolites (p \u3c 0.0001). Other outcomes are not altered significantly. Conclusion A lower risk of CVD with higher apple consumption could be mediated by the beneficial effect of apple skin on endothelial function, both acutely and chronically

Three-dimensional food printing: Its readiness for a food and nutrition insecure world

Three-dimensional (3D) food printing is a rapidly emerging technology offering unprecedented potential for customised food design and personalised nutrition. Here, we evaluate the technological advances in extrusion-based 3D food printing and its possibilities to promote healthy and sustainable eating. We consider the challenges in implementing the technology in real-world applications. We propose viable applications for 3D food printing in health care, health promotion and food waste upcycling. Finally, we outline future work on 3D food printing in food safety, acceptability and economics, ethics and regulations. .

Community recommendations on terminology and procedures used in flooding and low oxygen stress research

Apart from playing a key role in important biochemical reactions, molecular oxygen (O2) and its by-products also have crucial signaling roles in shaping plant developmental programs and environmental responses. Even under normal conditions, sharp O2 gradients can occur within the plant when cellular O2 demand exceeds supply, especially in dense organs such as tubers, seeds and fruits. Spatial and temporal variations in O2 concentrations are important cues for plants to modulate development (van Dongen & Licausi, 2015; Considine et al., 2016). Environmental conditions can also expand the low O2 regions within the plant. For example, excessive rainfall can lead to partial or complete plant submergence resulting in O2 deficiency in the root or the entire plant (Voesenek & Bailey-Serres, 2015). Climate change-associated increases in precipitation events have made flooding a major abiotic stress threatening crop production and food sustainability. This increased flooding and associated crop losses highlight the urgency of understanding plant flooding responses and tolerance mechanisms. Timely manifestation of physiological and morphological changes triggering developmental adjustments or flooding survival strategies requires accurate sensing of O2 levels. Despite progress in understanding how plants sense and respond to changes in intracellular O2 concentrations (van Dongen & Licausi, 2015), several questions remain unanswered due to a lack of high resolution tools to accurately and noninvasively monitor (sub)cellular O2 concentrations. In the absence of such tools, it is therefore critical for researchers in the field to be aware of how experimental conditions can influence plant O2 levels, and thus on the importance of accurately reporting specific experimental details. This also requires a consensus on the definition of frequently used terms. At the 15th New Phytologist Workshop on Flooding stress (Voesenek et al., 2016), community members discussed and agreed on unified nomenclature and standard norms for low O2 and flooding stress research. This consensus on terminology and experimental guidelines is presented here. We expect that these norms will facilitate more effective interpretation, comparison and reproducibility of research in this field. We also highlight the current challenges in noninvasively monitoring and measuring O2 concentrations in plant cells, outlining the technologies currently available, their strengths and drawbacks, and their suitability for use in flooding and low O2 research

Molecular Genetic Features of Polyploidization and Aneuploidization Reveal Unique Patterns for Genome Duplication in Diploid Malus

Polyploidization results in genome duplication and is an important step in evolution and speciation. The Malus genome confirmed that this genus was derived through auto-polyploidization, yet the genetic and meiotic mechanisms for polyploidization, particularly for aneuploidization, are unclear in this genus or other woody perennials. In fact the contribution of aneuploidization remains poorly understood throughout Plantae. We add to this knowledge by characterization of eupolyploidization and aneuploidization in 27,542 F1 seedlings from seven diploid Malus populations using cytology and microsatellite markers. We provide the first evidence that aneuploidy exceeds eupolyploidy in the diploid crosses, suggesting aneuploidization is a leading cause of genome duplication. Gametes from diploid Malus had a unique combinational pattern; ova preserved euploidy exclusively, while spermatozoa presented both euploidy and aneuploidy. All non-reduced gametes were genetically heterozygous, indicating first-division restitution was the exclusive mode for Malus eupolyploidization and aneuploidization. Chromosome segregation pattern among aneuploids was non-uniform, however, certain chromosomes were associated for aneuploidization. This study is the first to provide molecular evidence for the contribution of heterozygous non-reduced gametes to fitness in polyploids and aneuploids. Aneuploidization can increase, while eupolyploidization may decrease genetic diversity in their newly established populations. Auto-triploidization is important for speciation in the extant Malus. The features of Malus polyploidization confer genetic stability and diversity, and present heterozygosity, heterosis and adaptability for evolutionary selection. A protocol using co-dominant markers was proposed for accelerating apple triploid breeding program. A path was postulated for evolution of numerically odd basic chromosomes. The model for Malus derivation was considerably revised. Impacts of aneuploidization on speciation and evolution, and potential applications of aneuploids and polyploids in breeding and genetics for other species were evaluated in depth. This study greatly improves our understanding of evolution, speciation, and adaptation of the Malus genus, and provides strategies to exploit polyploidization in other species