Over the last ten years, there has been explosive development in methods for measuring gene expression. These methods can identify thousands of genes altered between conditions, but understanding ...these datasets and forming hypotheses based on them remains challenging. One way to analyze these datasets is to associate ontologies (hierarchical, descriptive vocabularies with controlled relations between terms) with genes and to look for enrichment of specific terms. Although Gene Ontology (GO) is available for Caenorhabditis elegans, it does not include anatomical information.
We have developed a tool for identifying enrichment of C. elegans tissues among gene sets and generated a website GUI where users can access this tool. Since a common drawback to ontology enrichment analyses is its verbosity, we developed a very simple filtering algorithm to reduce the ontology size by an order of magnitude. We adjusted these filters and validated our tool using a set of 30 gold standards from Expression Cluster data in WormBase. We show our tool can even discriminate between embryonic and larval tissues and can even identify tissues down to the single-cell level. We used our tool to identify multiple neuronal tissues that are down-regulated due to pathogen infection in C. elegans.
Our Tissue Enrichment Analysis (TEA) can be found within WormBase, and can be downloaded using Python's standard pip installer. It tests a slimmed-down C. elegans tissue ontology for enrichment of specific terms and provides users with a text and graphic representation of the results.
Purpose
Prior studies identified high variability in prevalence of withdrawal of life-sustaining treatment in the ICU. Variability in end-of-life decision-making has been reported at many levels: ...between countries, ICUs, and individual intensivists. We performed a systematic review examining regional, national, inter-hospital, and inter-physician variability in withdrawal of life-sustaining treatment in the ICU.
Methods
Using a predefined search strategy, we queried three electronic databases for peer-reviewed articles addressing withdrawal of life-sustaining treatment in adult patients in the ICU. Data were analyzed for variability in prevalence of withdrawal of life-sustaining treatment. Withholding of life-sustaining treatment was also examined where information was provided. An assessment tool was developed to quantify the risk of bias in the included articles.
Results
We identified 1284 studies, with 56 included after review. Most studies had unclear or high risk of bias, primarily due to unclear case definitions or potential confounding. The mean prevalence of withdrawal of life-sustaining treatment for patients who died varied from 0 to 84.1 % between studies, with standard deviation of 23.7 %. Sensitivity analysis of general ICU patients yielded similar results. Withholding also varied between 5.3 and 67.3 % (mean 27.3, SD 18.5 %). Substantial variability was found between world regions, countries, individual ICUs within a country, and individual intensivists within one ICU.
Conclusions
We identified substantial variability in the withdrawal of life-sustaining treatment across world regions and countries. Similar variability existed between ICUs within countries and even between providers within the same ICU. Further study is necessary, and could lead to interventions to improve end-of-life care in the ICU.
•The amount of added slag affected the formation of reaction product.•As the amount of added slag increased, the amount of C-S-H gel increased.•The aluminosilicate gel with the Q4 units was similar ...to a Ca-based geopolymer.
Few studies have described the reaction products of an alkali-activated, two-source binder and their characteristics due to the complexity of the mechanism. In this study, the microstructure, reaction products, and reactivity of alkali-activated, fly ash/slag binders synthesized at various mixture ratios of two raw materials were examined using various experimental techniques (NMR, ICP-OES, EDS, FT-IR and TGA) to systematically investigate the complex reaction mechanism of the binders. It was also intended to help assess durability of the binders. It was found that the amount of added slag primarily affected the amount of reaction product and its silicate structure, and as the amount of added slag increased, the amount of C-S-H gel increased and the amount of aluminosilicate gel decreased. Considering chemical composition and silicate structure, the aluminosilicate gel with the Q4 (nAl) units was found to be similar to a Ca-based geopolymer (N-C-A-S-H). The chemical composition ratios of the Ca-based geopolymer were nearly the same as those of C-S-H whereas their silicate structures were different.
We report reduced graphene oxide field effect transistor (R-GO FET) biosensor for label-free ultrasensitive detection of a prostate cancer biomarker, prostate specific antigen/α1-antichymotrypsin ...(PSA-ACT) complex. The R-GO channel in the device was formed by reduction of graphene oxide nanosheets networked by a self-assembly process. Immunoreaction of PSA-ACT complexes with PSA monoclonal antibodies on the R-GO channel surface caused a linear response in the shift of the gate voltage, Vg,min, where the minimum conductivity occurs. The R-GO FET can detect protein-protein interactions down to femtomolar level with a dynamic range over 6-orders of magnitude in the Vg,min shift as a sensitivity parameter. High association constants of 3.2nM−1 and 4.2nM−1 were obtained for the pH 6.2 and pH 7.4 analyte solutions, respectively. The R-GO FET biosensor showed a high specificity to other cancer biomarker in the phosphate buffered saline solutions as well as in the human serum.
► R-GO FFET was applied to the ultrasensitive detection of cancer biomarkers. ► Residue-free R-GO channel in the FET enables femtomolar detection of proteins. ► The change of charge neutrality point shows a good linearity and large dynamic range.
Trifluoromethoxy (OCF3) and difluoromethoxy (OCF2H) groups are fluorinated structural motifs that exhibit unique physicochemical characteristics. Incorporation of these substituents into organic ...molecules is a highly desirable approach used in medicinal chemistry and drug discovery processes to alter the properties of a parent compound. Recently, tri‐ and difluoromethyl ethers have received increasing attention and several innovative strategies to access these valuable functional groups have been developed. The focus of this Minireview is the use of visible‐light photoredox catalysis in the synthesis of tri‐ and difluoromethyl ethers. Recent photocatalytic strategies for the formation of O−CF3, C−OCF3, O−CF2H, and C−OCF2H bonds as well as other transformations leading to the construction of ORF groups are discussed herein.
Illuminating OCF3 and OCF2H: Tri‐ and difluoromethyl ethers are privileged moieties in the realm of medicinal chemistry and are found in marketed pharmaceuticals and agrichemicals. The recent advances in visible‐light photocatalytic synthesis of these moieties will likely render their introduction routine as a part of drug design and drug discovery processes.
The ascending cholinergic system dynamically regulates sensory perception and cognitive function, but it remains unclear how this modulation is executed in neocortical circuits. Here, we demonstrate ...that the cholinergic system controls the integrative operations of neocortical principal neurons by modulating dendritic excitability. Direct dendritic recordings revealed that the optogenetic-evoked release of acetylcholine (ACh) transformed the pattern of dendritic integration in layer 5B pyramidal neurons, leading to the generation of dendritic plateau potentials which powerfully drove repetitive action potential output. In contrast, the synaptic release of ACh did not positively modulate axo-somatic excitability. Mechanistically, the transformation of dendritic integration was mediated by the muscarinic ACh receptor-dependent enhancement of dendritic R-type calcium channel activity, a compartment-dependent modulation which decisively controlled the associative computations executed by layer 5B pyramidal neurons. Our findings therefore reveal a biophysical mechanism by which the cholinergic system controls dendritic computations causally linked to perceptual detection.
•Optogenetic release of ACh positively modulates neocortical principal neuron excitability•Optogenetic release of ACh selectively controls dendritic excitability•Dendritic excitability is transformed by a mAChR-mediated modulation of calcium channels•Cholinergic modulation impacts behaviorally relevant dendritic integration
Williams and Fletcher use optogenetic and high-resolution electrophysiological techniques to demonstrate that the cholinergic system directly controls the electrical excitability of the dendrites of neocortical principal neurons, through the modulation of calcium channels, to powerfully enhance behaviorally relevant associative computations.
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•A robust one-step method is proposed to synthesize geopolymer-supported zeolites.•Zeolite yield was highly correlated with time, pressure, molarity and slag content.•Synthesized ...samples exhibited the characteristics of mesoporous materials.•A high adsorption capacity of 37.9 mg, Pb2+/g, bulk-type adsorbents was achieved.
The present study proposes a robust one-step hydrothermal treatment method for synthesis of high strength geopolymer-supported zeolites utilizing industrial by-products (fly ash and blast furnace slag), which can be potentially used as bulk-type solid adsorbents. The results revealed that the geopolymer-supported zeolites, possessing distinct strengths, zeolite phases (Na-P1, Na-chabazite, and analcime) and pore features depending on the mix design and synthesis conditions, can be easily synthesized employing the proposed one-step method. The geopolymer-supported zeolites exhibited the characteristics of mesoporous materials which are typically desired for commercial adsorbents. The maximum adsorption capacity for Pb2+ was found to be about 37.9 mg/g which is relatively higher than the other bulk-type adsorbents reported for Pb2+ to date. Since industrial by-products are used for synthesis of these materials, it will help in reducing the environmental hazards associated with the permanent disposal of such by-products, with an added advantage that these bulk-type solid adsorbents can be easily retrieved after use unlike granular adsorbents.
There is a growing awareness that complex 3-dimensional (3D) organs are not well represented by monolayers of a single cell type - the standard format for many drug screens. To address this ...deficiency, and with the goal of improving screens so that drugs with good efficacy and low toxicity can be identified, microphysiological systems (MPS) are being developed that better capture the complexity of in vivo physiology. We have previously described an organ-on-a-chip platform that incorporates perfused microvessels, such that survival of the surrounding tissue is entirely dependent on delivery of nutrients through the vessels. Here we describe an arrayed version of the platform that incorporates multiple vascularized micro-organs (VMOs) on a 96-well plate. Each VMO is independently-addressable and flow through the micro-organ is driven by hydrostatic pressure. The platform is easy to use, requires no external pumps or valves, and is highly reproducible. As a proof-of-concept we have created arrayed vascularized micro tumors (VMTs) and used these in a blinded screen to assay a small library of compounds, including FDA-approved anti-cancer drugs, and successfully identified both anti-angiogenic and anti-tumor drugs. This 3D platform is suitable for efficacy/toxicity screening against multiple tissues in a more physiological environment than previously possible.
BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages ...following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBPα in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBPα, whereas expression of the erythroid regulator GATA1 directs SMAD1 loss on nonerythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity.
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► BMP and Wnt pathways regulate hematopoietic regeneration ► SMAD1 and TCF7L2 co-occupy genomic regions with GATA factors in erythroid cells ► Regions co-occupied by signaling factors and lineage regulators are enhancers ► Expressing myeloid lineage regulator C/EBP in erythroid cells redirects SMAD binding
Lineage-determining transcription factors direct erythroid and myeloid differentiation and hematopoietic regeneration by driving factors in the BMP and Wnt signaling pathways to cell-specific genes.
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