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small molecule imaging

David A Winkler, Tu C Le
Neural networks have generated valuable Quantitative Structure-Activity/Property Relationships (QSAR/QSPR) models for a wide variety of small molecules and materials properties. They have grown in sophistication and many of their initial problems have been overcome by modern mathematical techniques. QSAR studies have almost always used so-called "shallow" neural networks in which there is a single hidden layer between the input and output layers. Recently, a new and potentially paradigm-shifting type of neural network based on Deep Learning has appeared...
October 26, 2016: Molecular Informatics
Laura E Edgington-Mitchell, Matthew Bogyo, Martijn Verdoes
Since protease activity is highly regulated by structural and environmental influences, the abundance of a protease often does not directly correlate with its activity. Because in most of the cases it is the activity of a protease that gives rise to its biological relevance, tools to report on this activity are of great value to the research community. Activity-based probes (ABPs) are small molecule tools that allow for the monitoring and profiling of protease activities in complex biological systems. The class of fluorescent quenched ABPs (qABPs), being intrinsically "dark" and only emitting fluorescence after reaction with the target protease, are ideally suited for imaging techniques such as small animal noninvasive fluorescence imaging and live cell fluorescence microscopy...
2017: Methods in Molecular Biology
Jonathan B Grimm, Brian P English, Heejun Choi, Anand K Muthusamy, Brian P Mehl, Peng Dong, Timothy A Brown, Jennifer Lippincott-Schwartz, Zhe Liu, Timothée Lionnet, Luke D Lavis
Small-molecule fluorophores are important tools for advanced imaging experiments. We previously reported a general method to improve small, cell-permeable fluorophores which resulted in the azetidine-containing 'Janelia Fluor' (JF) dyes. Here, we refine and extend the utility of these dyes by synthesizing photoactivatable derivatives that are compatible with live-cell labeling strategies. Once activated, these derived compounds retain the superior brightness and photostability of the JF dyes, enabling improved single-particle tracking and facile localization microscopy experiments...
October 24, 2016: Nature Methods
Kalle Kipper, Ebba Gregorsson Lundius, Vladimir Curic, Ivana Nikic, Edward A Lemke, Manfred Wiessler, Johan Elf
Small synthetic fluorophores are in many ways superior to fluorescent proteins as labels for imaging. A major challenge is to use them for a protein-specific labeling in living cells. Here, we report on our use of noncanonical amino acids that are genetically encoded via the pyrrolysyl-tRNA/pyrrolysyl-RNA synthetase pair at artificially introduced TAG codons in a recoded E. coli strain. The strain is lacking endogenous TAG codons and the TAG-specific release factor RF1. The amino acids contain bioorthogonal groups that can be clicked to externally supplied dyes, thus enabling protein-specific labeling in live cells...
October 24, 2016: ACS Synthetic Biology
Tao Peng, Howard C Hang
Over the past years, fluorescent proteins (e.g., green fluorescent proteins) have been widely utilized to visualize recombinant protein expression and localization in live cells. Although powerful, fluorescent protein tags are limited by their relatively large sizes and potential perturbation to protein function. Alternatively, site-specific labeling of proteins with small-molecule organic fluorophores using bioorthogonal chemistry may provide a more precise and less perturbing method. This approach involves site-specific incorporation of unnatural amino acids (UAAs) into proteins via genetic code expansion, followed by bioorthogonal chemical labeling with small organic fluorophores in living cells...
October 21, 2016: Journal of the American Chemical Society
Gil Henkin, Daniel Berard, Francis Stabile, Marjan Shayegan, Jason S Leith, Sabrina R Leslie
We present a dynamically adjustable nanofluidic platform for formatting the conformations of and visualizing the interaction kinetics between biomolecules in solution, offering new time resolution and control of the reaction processes. This platform extends Convex Lens-induced Confinement (CLiC), a technique for imaging molecules under confinement, by introducing a system for in-situ modification of the chemical environment; this system uses a deep microchannel to diffusively exchange reagents within the nanoscale imaging region, whose height is fixed by a nanopost array...
October 21, 2016: Analytical Chemistry
Sahishna Phaniraj, Zhe Gao, Digamber Rane, Blake R Peterson
The endoplasmic reticulum (ER) of eukaryotic cells plays critical roles in the processing of secreted and transmembrane proteins. Defects in these functions are associated with a wide range of pathologies. To image this organelle, cells are often treated with fluorescent ER-Tracker dyes. Although these compounds are selective, existing red fluorescent probes of the ER are costly glibenclamide derivatives that inhibit ER-associated sulphonylurea receptors. To provide simpler and more cost-effective red fluorescent probes of the ER, we synthesized amino analogues of the fluorophore resorufin...
December 2016: Dyes and Pigments: An International Journal
Wilson Kc Leung, L Gao, Parco M Siu, Christopher Wk Lai
An explosion in global epidemic of type 2 diabetes mellitus poses major rise in cases with vascular endothelial dysfunction ranging from micro- (retinopathy, nephropathy and neuropathy) to macro-vascular (atherosclerosis and cardiomyopathy) conditions. Functional destruction of endothelium is regarded as an early event that lays the groundwork for the development of renal microangiopathy and subsequent clinical manifestation of nephropathic symptoms. Recent research has shed some light on the molecular mechanisms of type 2 diabetes-associated comorbidity of endothelial dysfunction and nephropathy...
October 17, 2016: Life Sciences
Eugen Widmeier, Weizhen Tan, Merlin Airik, Friedhelm Hildebrandt
INTRODUCTION: Steroid-resistant nephrotic syndrome (SRNS) inevitably progresses to end-stage kidney disease, requiring dialysis or transplantation for survival. However, treatment modalities and drug discovery remain limited. Mutations in over 30 genes have been discovered as monogenic causes of SRNS. Most of these genes are predominantly expressed in the glomerular epithelial cell, the podocyte, placing it at the center of the pathogenesis of SRNS. Podocyte migration rate (PMR) represents a relevant intermediate phenotype of disease in monogenic causes of SRNS...
October 19, 2016: American Journal of Physiology. Renal Physiology
Jeroen Aerts, Annelies Laeremans, Laurens Minerva, Kurt Boonen, Budamgunta Harshavardhan, Rudi D'hooge, Dirk Valkenborg, Geert Baggerman, Lutgarde Arckens
The Morris water maze (MWM) spatial learning task has been demonstrated to involve a cognitive switch of action control to serve the transition from an early towards a late learning phase. However, the molecular mechanisms governing this switch are largely unknown. We employed MALDI MS imaging (MSI) to screen for changes in expression of small proteins in brain structures implicated in the different learning phases. We compared mice trained for 3days and 30days in the MWM, reflecting an early and a late learning phase in relation to the acquisition of a spatial learning task...
October 17, 2016: Biochimica et Biophysica Acta
Katie Pollock, Guanglin Yu, Ralph Moller-Trane, Marissa Koran, Peter Dosa, David McKenna, Allison Hubel
There is demand for non-DMSO cryoprotective agents that maintain cell viability without causing poor post thaw function or systemic toxicity. The focus of this investigation involves expanding our understanding of multicomponent osmolyte solutions and their ability to preserve cell viability during freezing. Controlled cooling rate freezing, Raman microscopy, and differential scanning calorimetry (DSC) were utilized to evaluate the differences in recovery and ice crystal formation behavior for solutions containing multiple cryoprotectants including sugars, sugar alcohols, and small molecule additives...
October 19, 2016: Tissue Engineering. Part C, Methods
Jessica J Gruskos, Guangqian Zhang, Daniela Buccella
The study of intracellular metal ion compartmentalization and trafficking involved in cellular processes demands sensors with controllable localization for the measurement of organelle-specific levels of cations with sub-cellular resolution. We introduce herein a new two-step strategy for in situ anchoring and activation of a fluorescent Mg(2+) sensor within an organelle of choice, using a fast fluorogenic reaction between a tetrazine-functionalized pro-sensor, Mag-S-Tz, and a strained bicyclononyne conjugated to a genetically encoded HaloTag fusion protein of known cellular localization...
October 17, 2016: Journal of the American Chemical Society
Sudath Hapuarachchige, Dmitri Artemov
Click chemistry provides fast, convenient, versatile, and reliable chemical reactions that take place between pairs of functional groups of small molecules that can be purified without chromatographic methods. Due to the fast kinetics and low or no elimination of byproducts, click chemistry is a promising approach that is rapidly gaining acceptance in drug discovery, radiochemistry, bioconjugation, and nanoscience applications. Increasing use of click chemistry in synthetic procedures or as a bioconjugation technique in diagnostic imaging is occurring because click reactions are fast, provide a quantitative yield, and produce a minimal amount of nontoxic byproducts...
October 2016: Topics in Magnetic Resonance Imaging: TMRI
Andraž Mavrič, Artem Badasyan, Mattia Fanetti, Matjaz Valant
Solubility of polysilane macromolecules has so far been a scientific as well as technological problem due to a lack of understanding of their proper molecular size and agglomeration/de-agglomeration conditions. Here we show that, in contrary to previous reports, the polysilane molecules are inherently small enough to be, under right conditions, dissolved. We used a dynamic light scattering and a differential scanning calorimetry to show that even under a dilute regime the polymer molecules are agglomerated at room temperature and undergo de-agglomeration at slightly elevated temperatures of around 40 °C...
October 17, 2016: Scientific Reports
Bryce Chiang, Nitin Venugopal, Henry F Edelhauser, Mark R Prausnitz
The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25-150 μL Hank's Balanced Salt Solution (HBSS) containing 0.2 μm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount...
October 11, 2016: Experimental Eye Research
Xiao-Peng He, Yi Zang, Tony D James, Jia Li, Guo-Rong Chen, Juan Xie
The development of small-molecule fluorescent probes for the detection of ions and biomacromolecules and for cellular and in vivo imaging has been a very active research area. Nevertheless, many problems exist for traditional probes including their poor water solubility, toxicity and the inability to target specific tissues. Because of the enhanced water solubility, biocompatibility and targeting ability for specific cells, there has been an emerging movement to use carbohydrates as either the backbone or as a warhead to decorate conventional fluorescent probes, producing "glycoprobes" with enhanced properties...
October 14, 2016: Chemical Communications: Chem Comm
Harrison Liu, Steven Chen, Kevin Huang, Jeffrey Kim, Han Mo, Raffael Iovine, Julie Gendre, Pauline Pascal, Qiang Li, Yaping Sun, Zhiqiang Dong, Michelle Arkin, Su Guo, Bo Huang
Drug discovery in whole-organisms such as zebrafish is a promising approach for identifying biologically-relevant lead compounds. However, high content imaging of zebrafish at cellular resolution is challenging due to the difficulty in orienting larvae en masse such that the cell type of interest is in clear view. We report the development of the multi-pose imaging method, which uses 96-well round bottom plates combined with a standard liquid handler to repose the larvae within each well multiple times, such that an image in a specific orientation can be acquired...
2016: PloS One
W Joon Chung, Jennifer L Goeckeler-Fried, Viktoria Havasi, Annette Chiang, Steven M Rowe, Zackery E Plyler, Jeong S Hong, Marina Mazur, Gary A Piazza, Adam B Keeton, E Lucile White, Lynn Rasmussen, Allan M Weissman, R Aldrin Denny, Jeffrey L Brodsky, Eric J Sorscher
Small molecules that correct the folding defects and enhance surface localization of the F508del mutation in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) comprise an important therapeutic strategy for cystic fibrosis lung disease. However, compounds that rescue the F508del mutant protein to wild type (WT) levels have not been identified. In this report, we consider obstacles to obtaining robust and therapeutically relevant levels of F508del CFTR. For example, markedly diminished steady state amounts of F508del CFTR compared to WT CFTR are present in recombinant bronchial epithelial cell lines, even when much higher levels of mutant transcript are present...
2016: PloS One
Romina J Pagliero, Diego S D'Astolfo, Daphne Lelieveld, Riyona D Pratiwi, Sonja Aits, Marja Jaattela, Nathaniel I Martin, Judith Klumperman, David A Egan
The lysosomal cell death (LCD) pathway is a caspase 3-independent cell death pathway that has been suggested as a possible target for cancer therapy, making the development of sensitive and specific high-throughput (HT) assays to identify LCD inducers highly desirable. In this study, we report a two-step HT screening platform to reliably identify such molecules. First, using a robust HT primary screen based on propidium iodide uptake, we identified compounds that kill through nonapoptotic pathways. A phenotypic image-based assay using a galectin-3 (Gal-3) reporter was then used to further classify hits based on lysosomal permeabilization, a hallmark of LCD...
October 2016: Assay and Drug Development Technologies
Johanna M U Silvola, Helena Virtanen, Riikka Siitonen, Sanna Hellberg, Heidi Liljenbäck, Olli Metsälä, Mia Ståhle, Tiina Saanijoki, Meeri Käkelä, Harri Hakovirta, Seppo Ylä-Herttuala, Pekka Saukko, Matti Jauhiainen, Tibor Z Veres, Sirpa Jalkanen, Juhani Knuuti, Antti Saraste, Anne Roivainen
Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms...
October 12, 2016: Scientific Reports
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