Understanding taste is key for optimizing the palatability of seaweeds and other non-animal-based foods rich in protein. The lingual papillae in the mouth hold taste buds with taste receptors for the five gustatory taste qualities. Each taste bud contains three distinct cell types, of which Type II cells carry various G protein-coupled receptors that can detect sweet, bitter, or umami tastants, while type III cells detect sour, and likely salty stimuli. Upon ligand binding, receptor-linked intracellular heterotrimeric G proteins initiate a cascade of downstream events which activate the afferent nerve fibers for taste perception in the brain. The taste of amino acids depends on the hydrophobicity, size, charge, isoelectric point, chirality of the alpha carbon, and the functional groups on their side chains. The principal umami ingredient monosodium l-glutamate, broadly known as MSG, loses umami taste upon acetylation, esterification, or methylation, but is able to form flat configurations that bind well to the umami taste receptor. Ribonucleotides such as guanosine monophosphate and inosine monophosphate strongly enhance umami taste when l-glutamate is present. Ribonucleotides bind to the outer section of the venus flytrap domain of the receptor dimer and stabilize the closed conformation. Concentrations of glutamate, aspartate, arginate, and other compounds in food products may enhance saltiness and overall flavor. Umami ingredients may help to reduce the consumption of salts and fats in the general population and increase food consumption in the elderly.
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How to encourage students to choose for a future in agrifood? Not like we always did. The labor market shows an increasing shortage. The agrifood sector plays a significant role in achieving global food security and environmental sustainability. Scholars hardly realize what they can contribute to these social, ecologic and economic issues. The sector needs to expand the range of career opportunities in the agriculture-food-nutrition-environment nexus. Most importantly, it means creating incentives that encourage young people to see agrifood as one of the best options for a career choice. We developed inspiring learning materials to achieve awareness in secondary schools in the Netherlands. A Genomics Cookbook with food metaphors to explain biological principles is highly appreciated by both teachers and students. It is a way to increase influx into green colleges and universities, and thereby efflux to the agrifood sector.
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There is a need to assess communication in daily life situations for people with speech and language disorders. Although language proficiency and communication in daily life are correlated, their relationship is far from linear or straightforward. This paper aims to demonstrate the usefulness of the construct of communicative participation by unravelling the relationship and overlap between participation and communication. We explored the relationship between communication, participation, and communicative participation by reviewing common definitions mentioned in the literature. Next, we evaluated to what extent communication plays a role in each of the World Health Organization’s International Classification of Functioning (ICF) “Activity and Participation” chapters by counting how many items in each chapter should be considered for describing communicative participation.
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BackgroundThe ROS1 G2032R mutation is the most common on-target resistance mutation in crizotinib treated ROS1-positive lung cancer patients. The aim of our study was to investigate resistance mechanisms in SCL34A2-ROS1G2032R positive Ba/F3 cells against second line treatment with lorlatinib.MethodsBa/F3 SLC34A2-ROS1G2032R cells were subjected to N-ethyl-N-nitrosourea (ENU) mutagenesis and clones were selected upon treatment with 1000 nM lorlatinib for 4 weeks. Resistant clones were analyzed for presence of on-target resistant mutations using Sanger sequencing. In addition, we generated subclones expressing SLC34A2-ROS1L2026M+G2032R and SLC34A2-ROS1L2026M in Ba/F3 cells. Sensitivity to ROS1 TKIs was determined by measuring cell viability and ROS1 phosphorylation. Molecular Dynamic simulations of the ATP binding pocket were performed for all ROS1 variants.ResultsThe ENU-screen of 41 lorlatinib resistant clones revealed one with a mutation in the kinase domain: L2026M. Cell viability assays of the ENU-induced resistant cell line and the Ba/F3 cells transfected with the mutant SCL34A2-ROS1 fusion gene constructs revealed a decreased sensitivity of SLC34A2-ROS1L2026M+G2032R cells for lorlatinib, crizotinib, entrectinib and repotrectinib compared to the single mutants. Consistent with these findings, we observed phosphorylation of ROS1 fusion protein in the double mutant cells which was not inhibited upon treatment with ROS1 TKIs. The single mutant cells showed as expected a clear reduction in phosphorylated ROS1 fusion protein . Molecular modeling to unravel the effect of the mutations demonstrated that the volume of the ATP-binding pocket was reduced in single and double mutants compared to wild type. The double L2026M+G2032R mutant displayed the smallest pocket.ConclusionsWe identified a novel on-target mutation after inducing lorlatinib resistance in SLC34A2-ROS1G2032R Ba/F3 cells. This SLC34A2-ROS1L2026M+G2032R cell line was also resistant to crizotinib, entrectinib and repotrectinib. The resistance can be explained by a smaller ATP binding pocket in the mutated ROS1 fusion protein preventing effective binding of the investigated TKIs.
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According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.
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Objective: The aim of this study was to obtain insight in specific elements influencing the use, non-use, satisfaction, and dissatisfaction of ankle foot orthoses (AFOs) and the presence of underexposed problems with respect to AFOs. Methods: A questionnaire was composed to obtain information from AFO users to investigate the variables associated with satisfaction and the relation between these variables. A specific feature of this study was the systematic analysis of the remarks made by the respondents about their AFO. Quantitative data analyses were used for analysing the satisfaction and qualitative analyses were used analysing the remarks of the respondents. A total of 211 users completed the questionnaire. Results: Our survey showed that 1 out of 15 AFOs were not used at all. About three quarters of the AFO users were satisfied and about one quarter was dissatisfied. Females and users living alone reported relatively high levels of dissatisfaction, especially in the field of dimensions, comfort, weight, safety and effectiveness. Dissatisfaction with respect to off-the-shelf AFOs for the item durability was higher than that for custom-made AFOs. In the delivery and maintenance process the items ‘maintenance’, ‘professionalism’ and ‘delivery follow-up’ were judged to be unsatisfactory. A large number of comments were made by the respondents to improve the device or process, mainly by the satisfied AFO users. These comments show that even satisfied users experience many problems and that a lot of problems of AFO users are ‘underexposed’. Conclusion: To improve user satisfaction, the user practice has to be identified as an important sub-process of the whole orthopaedic chain especially in the diagnosis and prescription, delivery tuning and maintenance, and evaluation phase.
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Control of plant growth is an important aspect of crop productivity and yield in agriculture. Overexpression of the At CHR12/ 23 genes in Arabidopsis thaliana reduced growth habit without other morphological changes. These two genes encode Snf2 chromatin remodelling ATPases. Here, we translate this approach to the horticultural crop tomato ( Solanum lycopersicum). We identified and cloned the single tomato ortholog of the two Arabidopsis Snf2 genes, designated Sl CHR1. Transgenic tomato plants (cv. Micro-Tom) that constitutively overexpress the coding sequence of Sl CHR1 show reduced growth in all developmental stages of tomato. This confirms that Sl CHR1 combines the functions of both Arabidopsis genes in tomato. Compared to the wild type, the transgenic seedlings of tomato have significantly shorter roots, hypocotyls and reduced cotyledon size. Transgenic plants have a much more compact growth habit with markedly reduced plant height, severely compacted reproductive structures with smaller flowers and smaller fruits. The results indicate that either GMO-based or non- GMO-based approaches to modulate the expression of chromatin remodelling ATPase genes could develop into methods to control plant growth, for example to replace the use of chemical growth retardants. This approach is likely to be applicable and attractive for any crop for which growth habit reduction has added value.
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Phylogenetic patterns show the presence or absence of certain genes in a set of full genomes derived from different species. They can also be used to determine sets of genes that occur only in certain evolutionary branches. Previously, we presented a database named PhyloPat which allows the complete Ensembl gene database to be queried using phylogenetic patterns. Here, we describe an updated version of PhyloPat which can be queried by an improved web server. We used a single linkage clustering algorithm to create 241 697 phylogenetic lineages, using all the orthologies provided by Ensembl v49. PhyloPat offers the possibility of querying with binary phylogenetic patterns or regular expressions, or through a phylogenetic tree of the 39 included species. Users can also input a list of Ensembl, EMBL, EntrezGene or HGNC IDs to check which phylogenetic lineage any gene belongs to. A link to the FatiGO web interface has been incorporated in the HTML output. For each gene, the surrounding genes on the chromosome, color coded according to their phylogenetic lineage can be viewed, as well as FASTA files of the peptide sequences of each lineage. Furthermore, lists of omnipresent, polypresent, oligopresent and anticorrelating genes have been included. PhyloPat is freely available at http://www.cmbi.ru.nl/phylopat. © 2008 The Author(s).
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Carnitine/choline acyltransferases play diverse roles in energy metabolism and neuronal signalling. Our knowledge of their evolutionary relationships, important for functional understanding, is incomplete. Therefore, we aimed to determine the evolutionary relationships of these eukaryotic transferases. We performed extensivephylogenetic and intron position analyses. We found that mammalian intramitochondrial CPT2 is most closely related to cytosolic yeast carnitine transferases (Sc-YAT1 and 2), whereas the other members of the family are related to intraorganellar yeast Sc-CAT2. Therefore, the cytosolically active CPT1 more closely resembles intramitochondrial ancestors than CPT2. The choline acetyltransferase is closely related to carnitine acetyltransferase and shows lower evolutionary rates than long chain acyltransferases. In the CPT1 family several duplications occurred during animal radiation, leading to the isoforms CPT1A, CPT1B and CPT1C. In addition, we found five CPT1-like genes in Caenorhabditis elegans that strongly group to the CPT1 family. The long branch leading to mammalian brain isoform CPT1C suggests that either strong positive or relaxed evolution has taken place on this node. The presented evolutionary delineation of carnitine/choline acyltransferases adds to current knowledge on their functions and provides tangible leads for further experimental research.
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Microencapsulation of cells is a promising approach to prevent rejection in the absence of immunosuppression. Clinical application, however, is hampered by insufficient insight in factors influencing biocompatibility of the capsules in humans. In the present study we exposed alginate-based capsules prepared of different types of alginate to human peritoneal fluid. Subsequently we studied the physicochemical changes of the capsule's surface by applying micro-Fourier Transform Infrared Spectroscopy. We did test alginate-beads and alginate-poly-L-lysine capsules prepared of different types of alginate. In all tested capsule formulations we found adsorption of components from human peritoneal fluid and clear physicochemical changes of the surface. These changes were alginate-dependent. The adsorption had no significant effects on the permselective properties of the capsule but we found a strong increase of TNFα production by human peripheral blood mononuclear cells when exposed to alginate-beads treated with human peritoneal fluid. This elevated responsiveness was not observed with alginate-PLL capsules. The results show that alginate-based capsule surfaces always undergo physicochemical changes of the surface when exposed to human peritoneal fluid. This adsorption may lead to enhancement of the inflammatory responses against the microcapsules. Our result implicate that biocompatibility measurements should not only been done with freshly prepared capsules but also with capsules that have been exposed to fluid from the implantation site in order to predict the in vivo responses. Copyright © 2011 Wiley Periodicals, Inc.
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