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Dagar, Komal, Shankar Gupta, Alamjot Singh та Vivek Asati. "In silico studies for the identification of potential thiazolidine-2,4-diones as α-amylase inhibitors". Pharmaspire 15, № 01 (2023): 48–53. http://dx.doi.org/10.56933/pharmaspire.2023.15109.
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Type 2 diabetes, which is characterized by hyperglycemia, is a chronic endocrine metabolic condition. α-amylase inhibitors may have a major therapeutic impact in type 2 diabetic mellitus. In the present study, virtual screening database preparation by R-group enumeration, virtual screening, docking study, and pharmacokinetics analysis was performed by taking α-amylase as a target. The results highlight the important binding features of novel thiazolidine-2,4-dione compounds as α-amylase inhibitors. An R-group enumeration study was performed for the generation of novel thiazolidine-2,4-dione derivatives (6250 compounds). These derivatives further proceed for virtual screening study using Lipinski rule of 5, highthroughput virtual screening, standard precision, and extra precision (XP) screening filters. Only the top 4 compounds were selected after the XP docking process. The molecular docking study of virtual screening hits showed that compound 1 showed a good binding score of −9.129 kcal/mole on α-amylase enzyme (Protein Data Bank ID-3BAY). The present study may be used for the further development of potential compounds against type 2 diabetes.
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Osaka, Ichie, Jeffrey M. Hills, Sarah L. Kieweg, Heather E. Shinogle, David S. Moore, and P. Scott Hefty. "An Automated Image-Based Method for Rapid Analysis of Chlamydia Infection as a Tool for Screening Antichlamydial Agents." Antimicrobial Agents and Chemotherapy 56, no. 8 (2012): 4184–88. http://dx.doi.org/10.1128/aac.00427-12.
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ABSTRACTA major limitation in the identification of novel antichlamydial compounds is the paucity of effective methods for large-scale compound screening. The immunofluorescence assay is the preferred approach for accurate quantification of the intracellular growth ofChlamydia. In this study, an immunofluorescence image-based method (termed image-based automated chlamydial identification and enumeration [iBAChIE]) was customized for fully automated quantification ofChlamydiainfection using the freely available open-source image analysis software program CellProfiler and the complementary data exploration software program CellProfiler Analyst. The method yielded enumeration of different species and strains ofChlamydiahighly comparably to the conventional manual methods while drastically reducing the analysis time. The inhibitory capability of established antichlamydial activity was also evaluated. Overall, these data support that iBAChIE is a highly effective tool for automated quantification ofChlamydiainfection and assessment of antichlamydial activities of molecules. Furthermore, iBAChIE is expected to be amenable to high-throughput screening studies for inhibitory compounds and fluorescently labeled molecules to study host-pathogen interactions.
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Silverstein, J., T. F. Hess, N. Al Mutaari, and R. Brown. "Enumeration of Toxic Compound Degrading Bacteria in a Multi-Species Activated Sludge Biomass." Water Science and Technology 29, no. 7 (1994): 309–16. http://dx.doi.org/10.2166/wst.1994.0357.
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A most probable number (MPN) method has been described for the enumeration of bacteria responsible for 2,4-dinitrophenol (DNP) degradation in activated sludge cultures. Because of the encapsulation of cells within the activated sludge floc, the method of pretreatment may be critical for producing a homogeneous distribution of bacteria to insure accurate dilution and enumeration. In these experiments, pretreatments using mechanical shear and incubation of cultures in EDTA have been tested. The combination of mechanical shearing in a high speed blender and incubation in a 0.5% EDTA solution resulted in significantly higher MPN values for DNP-degrading organisms growing in activated sludge in sequencing batch reactors (SBRs) which had been supplemented with glucose. Shearing of flocs and the combination of shearing and EDTA treatment produced the identical MPN values in both pure and activated sludge cultures grown only in DNP.
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Smith, Bryan J. K., Melissa A. Boothe, Brice A. Fiddler, Tania M. Lozano, Russel K. Rahi, and Mark J. Krzmarzick. "Enumeration of Organohalide Respirers in Municipal Wastewater Anaerobic Digesters." Microbiology Insights 8s2 (January 2015): MBI.S31445. http://dx.doi.org/10.4137/mbi.s31445.
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Organohalide contaminants such as triclosan and triclocarban have been well documented in municipal wastewater treatment plants (WWTPs), but the degradation of these contaminants is not well understood. One possible removal mechanism is organohalide respiration by which bacteria reduce the halogenated compound. The purpose of this study was to determine the abundance of organohalide-respiring bacteria in eight WWTP anaerobic digesters. The obligate organohalide respiring Dehalococcoides mccartyi was the most abundant and averaged 3.3 × 107 copies of 16S rRNA genes per gram, while the Dehalobacter was much lower at 2.6 × 104 copies of 16S rRNA genes per gram. The genus Sulfurospirillum spp. was also detected at 1.0 × 107 copies of 16S rRNA genes per gram. No other known or putatively organohalide-respiring strains in the Dehalococcoidaceae family were found to be present nor were the genera Desulfitobacterium or Desulfomonile.
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Feuston, Bradley, Subhas Chakravorty, John Conway, et al. "Web Enabling Technology for the Design, Enumeration, Optimization and Tracking of Compound Libraries." Current Topics in Medicinal Chemistry 5, no. 8 (2005): 773–83. http://dx.doi.org/10.2174/1568026054637656.
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Hamdy, Rania, Bahgat Fayed, Ahmed Mostafa, et al. "Iterated Virtual Screening-Assisted Antiviral and Enzyme Inhibition Assays Reveal the Discovery of Novel Promising Anti-SARS-CoV-2 with Dual Activity." International Journal of Molecular Sciences 22, no. 16 (2021): 9057. http://dx.doi.org/10.3390/ijms22169057.
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Unfortunately, COVID-19 is still a threat to humankind and has a dramatic impact on human health, social life, the world economy, and food security. With the limited number of suggested therapies under clinical trials, the discovery of novel therapeutic agents is essential. Here, a previously identified anti-SARS-CoV-2 compound named Compound 13 (1,2,5-Oxadiazole-3-carboximidic acid, 4,4′-(methylenediimino) bis,bis[[(2-hydroxyphenyl)methylene]hydrazide) was subjected to an iterated virtual screening against SARS-CoV-2 Mpro using a combination of Ligand Designer and PathFinder. PathFinder, a computational reaction enumeration tool, was used for the rapid generation of enumerated structures via default reaction library. Ligand designer was employed for the computerized lead optimization and selection of the best structural modification that resulted in a favorable ligand–protein complex. The obtained compounds that showed the best binding to Mpro were re-screened against TMPRSS2, leading to the identification of 20 shared compounds. The compounds were further visually inspected, which resulted in the identification of five shared compounds M1–5 with dual binding affinity. In vitro evaluation and enzyme inhibition assay indicated that M3, an analogue of Compound 13 afforded by replacing the phenolic moiety with pyridinyl, possesses an improved antiviral activity and safety. M3 displayed in vitro antiviral activity with IC50 0.016 µM and Mpro inhibition activity with IC50 0.013 µM, 7-fold more potent than the parent Compound 13 and potent than the antivirals drugs that are currently under clinical trials. Moreover, M3 showed potent activity against human TMPRSS2 and furin enzymes with IC50 0.05, and 0.08 µM, respectively. Molecular docking, WaterMap analysis, molecular dynamics simulation, and R-group analysis confirmed the superiority of the binding fit to M3 with the target enzymes. WaterMap analysis calculated the thermodynamic properties of the hydration site in the binding pocket that significantly affects the biological activity. Loading M3 on zinc oxide nanoparticles (ZnO NPs) increased the antiviral activity of the compound 1.5-fold, while maintaining a higher safety profile. In conclusion, lead optimized discovery following an iterated virtual screening in association with molecular docking and biological evaluation revealed a novel compound named M3 with promising dual activity against SARS-CoV-2. The compound deserves further investigation for potential clinical-based studies.
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Mat Ripen, Adiratna, Hamidah Ghani, Chai Teng Chear, et al. "Whole exome sequencing identifies compound heterozygous variants of CR2 gene in monozygotic twin patients with common variable immunodeficiency." SAGE Open Medicine 8 (January 2020): 205031212092265. http://dx.doi.org/10.1177/2050312120922652.
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Objectives: A pair of female Malay monozygotic twins who presented with recurrent upper respiratory tract infections, hepatosplenomegaly, bronchiectasis and bicytopenia were recruited in this study. Both patients were suspected with primary immunodeficiency diseases. However, the definite diagnosis was not clear due to complex disease phenotypes. The objective of this study was to identify the causative gene mutation in these patients. Methods: Lymphocyte subset enumeration test and whole exome sequencing were performed. Results: We identified a compound heterozygous CR2 mutation (c.1916G>A and c.2012G>A) in both patients. These variants were then confirmed using Sanger sequencing. Conclusion: Whole exome sequencing analysis of the monozygotic twins revealed compound heterozygous missense mutations in CR2.
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Osaka, Ichie, and P. Scott Hefty. "Simple Resazurin-Based Microplate Assay for Measuring Chlamydia Infections." Antimicrobial Agents and Chemotherapy 57, no. 6 (2013): 2838–40. http://dx.doi.org/10.1128/aac.00056-13.
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ABSTRACTThe conventional method for quantification ofChlamydiainfection using fluorescence microscopy typically involves time- and labor-intensive manual enumeration, which is not applicable for a large-scale analysis required for an inhibitory compound screen. In this study, an alamarBlue (resazurin) assay was adopted to measureChlamydiainfection by measuring the redox capability of infected host cells in a 96-well format. The assay provided measurements comparable to those of the conventional microscopy method while drastically reducing the time required for analysis.
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Meringer, Markus, and H. James Cleaves. "Exploring astrobiology using in silico molecular structure generation." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 375, no. 2109 (2017): 20160344. http://dx.doi.org/10.1098/rsta.2016.0344.
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The origin of life is typically understood as a transition from inanimate or disorganized matter to self-organized, ‘animate’ matter. This transition probably took place largely in the context of organic compounds, and most approaches, to date, have focused on using the organic chemical composition of modern organisms as the main guide for understanding this process. However, it has gradually come to be appreciated that biochemistry, as we know it, occupies a minute volume of the possible organic ‘chemical space’. As the majority of abiotic syntheses appear to make a large set of compounds not found in biochemistry, as well as an incomplete subset of those that are, it is possible that life began with a significantly different set of components. Chemical graph-based structure generation methods allow for exhaustive in silico enumeration of different compound types and different types of ‘chemical spaces’ beyond those used by biochemistry, which can be explored to help understand the types of compounds biology uses, as well as to understand the nature of abiotic synthesis, and potentially design novel types of living systems. This article is part of the themed issue ‘Reconceptualizing the origins of life’.
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Stachelska, Milena Alicja, Adam Ekielski, Piotr Karpiński, Tomasz Żelaziński, and Bartosz Kruszewski. "New Genetic Determinants for qPCR Identification and the Enumeration of Selected Lactic Acid Bacteria in Raw-Milk Cheese." Molecules 29, no. 7 (2024): 1533. http://dx.doi.org/10.3390/molecules29071533.
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Lactic acid bacteria (LAB) play an important role in the ripening of cheeses and contribute to the development of the desired profile of aroma and flavor compounds. Therefore, it is very important to monitor the dynamics of bacterial proliferation in order to obtain an accurate and reliable number of their cells at each stage of cheese ripening. This work aimed to identify and conduct a quantitative assessment of the selected species of autochthonous lactic acid bacteria from raw cow’s milk cheese by the development of primers and probe pairs based on the uniqueness of the genetic determinants with which the target microorganisms can be identified. For that purpose, we applied real-time quantitative PCR (qPCR) protocols to quantify Lactobacillus delbrueckii subsp. bulgaricus, Streptococcus thermophilus, and Lactococcus lactis subsp. cremoris cells in cheese directly after production and over three-month and six-month ripening periods. While L. lactis subsp. cremoris shows good acidification ability and the ability to produce antimicrobial compounds, L. delbrueckii subsp. bulgaricus has good proteolytic ability and produces exo-polysaccharides, and S. thermophilus takes part in the formation of the diacetyl flavor compound by metabolizing citrate to develop aroma, they all play an important role in the cheese ripening. The proposed qPCR protocols are very sensitive and reliable methods for a precise enumeration of L. delbrueckii subsp. bulgaricus, S. thermophilus, and L. lactis subsp. cremoris in cheese samples.
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Ley, Arthur Newton, Raymond John Bowers та Saul Wolfe. "Indoxyl-β-D-glucuronide, a novel chromogenic reagent for the specific detection and enumeration of Escherichia coli in environmental samples". Canadian Journal of Microbiology 34, № 5 (1988): 690–93. http://dx.doi.org/10.1139/m88-115.
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About 97% of Escherichia coli strains produce β-glucuronidase, but almost all other Enterobacteriaceae lack this enzyme. A D-glucopyranosiduronic acid (glucuronide) possessing a readily detectable β-linked aglycone should, therefore, constitute a specific reagent for the detection of this organism. For this purpose, the title compound has been synthesized for the first time. The synthesis proceeds in eight steps from readily available D-glucuronolactone, anthranilic acid, and chloroacetic acid and can be carried out on a large scale. The compound has the predicted properties: when included in the standard membrane filter test for the analysis of water, indoxyl-β-D-glucuronide allows specific detection of E. coli through the formation of blue colonies that are the result of rapid conversion of the liberated aglycone to indigo. The recovery of E. coli is easily measured and almost quantitative.
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Osmulski, Pawel A., Jodie Cropper, Matt Giletto, et al. "Anticancer applications of allosteric inhibitors of proteasome." Journal of Clinical Oncology 35, no. 15_suppl (2017): e23066-e23066. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23066.
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e23066 Background: Proteasome as a hub protease of the ubiquitin proteasome pathway is an established anticancer drug target. Several drugs that inhibit proteasome are currently used to successfully treat aggressive blood cancers. These drugs are based on their competition with protein substrates of proteasome. However, efficacy of these drugs toward solid cancers is inadequate. Besides, the side effects and developing drug resistance are increasingly hampering the therapy. Therefore, there is an unmet challenge to develop new types of proteasome targeting compounds that are efficient against solid cancers and utilize other mechanisms to stop proteasome. Here we present a compound with a novel molecular mechanism, potentially bypassing limitations of the available drugs. Methods: We rationally designed and synthesized a series of small molecule “B” compounds, derivatives of a binding domain of seco-rapamycin that noncompetitively interfere with peptidase activities of proteasome. We tested effects of the compounds in vitro on purified proteasome, in cellulo with selected cancer cell lines and in a xenograft mouse model of prostate cancer. Results: We found that compound B1 binds to the catalytic core of proteasome far from the catalytic sites, destabilizes assembly of the 26S proteasome responsible for digest of polyUb substrates and allosterically inhibits its proteolytic activities. Molecularly, B1 impedes the gating mechanism responsible for substrate uptake as found with AFM. Tryptophan fluorescence indicates that B1 changes proteasome fold and the binding mode of competitive inhibitors. B1 substantially decreases viability of selected cancer cell lines and shifts their mechanical phenotype toward noncancerous status. B1 synergizes with bortezomib decreasing the IC50 5-10 fold. In a xenograft hormone resistant prostate cancer model, B1 treatment leads to shrinkage of the tumor size, decreases enumeration of aggressive, EpCAM+ CTCs and shifts the macrophage profile toward predator M1 type. Conclusions: B1 compounds constitute a new class of noncompetitive allosteric inhibitors of proteasome that could be useful to develop to treat aggressive prostate cancers alone or in synergy with competitive inhibitors.
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Bjerrum, Esben, and Boris Sattarov. "Improving Chemical Autoencoder Latent Space and Molecular De Novo Generation Diversity with Heteroencoders." Biomolecules 8, no. 4 (2018): 131. http://dx.doi.org/10.3390/biom8040131.
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Chemical autoencoders are attractive models as they combine chemical space navigation with possibilities for de novo molecule generation in areas of interest. This enables them to produce focused chemical libraries around a single lead compound for employment early in a drug discovery project. Here, it is shown that the choice of chemical representation, such as strings from the simplified molecular-input line-entry system (SMILES), has a large influence on the properties of the latent space. It is further explored to what extent translating between different chemical representations influences the latent space similarity to the SMILES strings or circular fingerprints. By employing SMILES enumeration for either the encoder or decoder, it is found that the decoder has the largest influence on the properties of the latent space. Training a sequence to sequence heteroencoder based on recurrent neural networks (RNNs) with long short-term memory cells (LSTM) to predict different enumerated SMILES strings from the same canonical SMILES string gives the largest similarity between latent space distance and molecular similarity measured as circular fingerprints similarity. Using the output from the code layer in quantitative structure activity relationship (QSAR) of five molecular datasets shows that heteroencoder derived vectors markedly outperforms autoencoder derived vectors as well as models built using ECFP4 fingerprints, underlining the increased chemical relevance of the latent space. However, the use of enumeration during training of the decoder leads to a marked increase in the rate of decoding to different molecules than encoded, a tendency that can be counteracted with more complex network architectures.
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Abedini, Amin, Marius Colin, Jane Hubert, et al. "Abundant Extractable Metabolites from Temperate Tree Barks: The Specific Antimicrobial Activity of Prunus Avium Extracts." Antibiotics 9, no. 3 (2020): 111. http://dx.doi.org/10.3390/antibiotics9030111.
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Tree barks are mainly considered as wood wastes from forestry activities, but represent valuable resources as they may contain antimicrobial compounds. Here, we aimed to evaluate the possible antimicrobial activities of bark extracts and to characterize the chemical composition of the most active extract. Ten methanol bark extracts were tested in vitro against 17 bacterial strains and 5 yeast strains, through minimum inhibitory concentration (MIC) and minimum bactericidal (or fungicidal) concentration (MBC/MFC) assays. The extract from Prunus avium (E2-4) displayed the largest bactericidal activity against Gram-positive bacteria, with a lethal effect on 6 out of 8 strains. Antibiofilm assays of E2-4 were performed by crystal violet staining and enumeration of adhered bacteria. Assays demonstrated a biofilm inhibitory effect of E2-4 against Staphylococcus aureus CIP 53.154 at concentrations equal to or higher than 250 µg/mL. Chemical profiling of E2-4 by 13C nuclear magnetic resonance (NMR) revealed the presence of dihydrowogonin as a major constituent of the extract. E2-4 was fractionated by centrifugal partition chromatography and the three fractions containing dihydrowogonin were tested for their antibacterial and antibiofilm activities, revealing similar activities to those of E2-4. Dihydrowogonin was positively assessed as an interesting antimicrobial compound, which could be valued from wastes of Prunus avium barks.
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Edwall, Christy. "Clare's Poetic Binomials." Romanticism 26, no. 2 (2020): 116–27. http://dx.doi.org/10.3366/rom.2020.0458.
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John Clare's confessed preference for the ‘vulgar’ names of flowers and his apparent dismissal of the sexual system as ‘darkness visible’ seems to keeps the taint of Linnaean influence at a distance. His enumeration of flowers in ‘The Wild Flower Nosgay’, however, looks very much like two eighteenth-century descriptive procedures: poetic diction and binomial nomenclature. Dryden's popular translation of Virgil's Georgics modified a classical inheritance of compound epithets into phrases later recognised as poetic diction. This inheritance finds an unexpected consonance in the binomial nomenclature of Linnaeus, who loved the Georgics and referred to them in his work. By comparing poetic diction and binomial nomenclature, this essay investigates the resources of compression or visibility which either procedure might offer to a bookish and keen-sighted poet like Clare. In doing so, it reiterates the case for Clare's immersion in eighteenth-century poetic procedure.
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YEWALE, SADANAND, ZEBA FARASH, SANMAN KOLHE, et al. "Benefits of Soleris® over the Conventional Method for Enumeration of Microbial Load in Salacia Herbal Extract." Polish Journal of Microbiology 69, no. 4 (2020): 453–62. http://dx.doi.org/10.33073/pjm-2020-048.
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Stems and roots of Salacia genus plants have been used as a specific remedy for early-stage diabetes, and one of the four sulphonium sulphates, salacinol is the compound responsible for the anti-diabetic activity. Salacia is prone to microbial contamination and insect infestation; hence, methods to estimate the microbial load in such plants will enhance its nutritional value. This paper highlights the novel use of Soleris® to quantify microbes of all types, namely bacteria, yeasts, molds, and coliforms in herbal extracts. The microbial analysis results obtained with Soleris® test vial have been compared with the conventional method, and the results indicate that Soleris® is equally efficient as the conventional method and in fact displays several advantages over the traditional method. The Soleris® method is a real time monitoring system that is highly sensitive, user-friendly, and environmentally friendly since it generates very little biomedical waste and saves a large amount of time. The data presented here demonstrate that for highly contaminated samples, results are available within 24 h. For yeasts and molds, the Soleris® method produces results in 48 h, thus offering considerable time savings compared to other commonly used methods.
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Wagle, B. R., K. Arsi, A. Upadhyay та ін. "β-Resorcylic Acid, a Phytophenolic Compound, Reduces Campylobacter jejuni in Postharvest Poultry". Journal of Food Protection 80, № 8 (2017): 1243–51. http://dx.doi.org/10.4315/0362-028x.jfp-16-475.
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ABSTRACTHuman Campylobacter infections, a leading foodborne illness globally, has been linked with the high prevalence of this bacterium on raw retail chicken products. Reduction of Campylobacter counts on poultry products would greatly reduce the risk of subsequent infections in humans. To this end, this study investigated the potential of the phytophenolic compound β-resorcylic acid (BR) to reduce Campylobacter counts on postharvest poultry (chicken skin or meat). Four trials in total, two each on thigh skin or breast meat, were conducted in which chicken skin or meat samples (2 ± 0.1 g; 10 samples per treatment) were inoculated with 50 μL (∼106 CFU per sample) of a cocktail of four wild strains of C. jejuni. After 30 min of attachment, inoculated samples were dipped in a 0, 0.5, 1, or 2% BR solution for 30 s immediately followed by vigorously vortexing the samples in Butterfield's phosphate diluent and plating the supernatant for Campylobacter enumeration. In addition, the effect of BR on the color of skin and meat samples was studied. Moreover, the change in the expression of survival and virulence genes of C. jejuni exposed to BR was evaluated. Data were analyzed by the PROC MIXED procedure of SAS (P < 0.05; SAS Institute Inc., Cary, NC). All BR treatments significantly reduced Campylobacter populations on both chicken or meat samples by 1 to 3 log CFU/g compared with non–BR-treated washed controls. No significant difference in the lightness, redness, and yellowness of skin and meat samples was observed on exposure to BR wash (P > 0.05). Real-time PCR results revealed that BR treatment down-regulated expression of select genes coding for motility (motA, motB) and attachment (cadF, ciaB) in the majority of C. jejuni strains. Stress response genes (sodB, katA) were upregulated in C. jejuni S-8 (P < 0.05). Overall, our results suggest that BR could be effectively used as antimicrobial dip treatment during poultry processing for reducing Campylobacter on chicken carcasses.
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Mangal, Anupam K., Chinmay Rath, Selim Mehmud, et al. "Medico-ethnobotanical Claims used against Gastrointestinal Disorders by Different Tribes of Assam, India." Journal of Drug Research in Ayurvedic Sciences 2, no. 3 (2017): 175–82. http://dx.doi.org/10.5005/jp-journals-10059-0017.
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ABSTRACT Aim The present communication deals with some newly reported Medico-ethnobotanical claims used for the treatment of various gastrointestinal disorders like blood dysentery, chronic dysentery, diarrhea, and cholera by using medicinal plants documented during field survey since last 3 years. Materials and methods Field surveys were conducted in different locations of Assam where many folk healers were interviewed for documentation of Medico-ethnobotanical information. The reported plants are collected, identified, and specimens are preserved. Results Nine different tribes and communities of Assam are newly recorded to use 30 medico-ethnobotanical claims for the concerned purpose, while use of similar claims is already reported elsewhere by other tribes of different regions; the other tribes using similar claim are highlighted. Out of total 47 medicinal plant specimens documented, 10 medicinal plants were recorded for 11 single formulations, 39 medicinal plants for 19 compound formulations, and among these 2 medicinal plants are repeated for both compound and single formulations. Conclusion Ethnic societies are still depending upon the medicinal plants for the treatment of various diseases including gastrointestinal disorders. Further scientific investigations are needed for validation of these folk claims. Clinical significance Cross-cultural study along with other tribes was done and highlighted against enumeration for further validation of folk claims. How to cite this article Bora D, Mehmud S, Baruah D, Bharali BK, Rath C, Mangal AK, Joseph GVR. Medico-ethnobotanical Claims used against Gastrointestinal Disorders by Different Tribes of Assam, India. J Drug Res Ayurvedic Sci 2017; 2(3):175-182.
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Sipiczki, Bojána. "Studies on the Suitability of Different Mould Media Compositions for the Mycological Evaluation of Hay Samples." Acta Agraria Debreceniensis, no. 10 (May 11, 2003): 34–38. http://dx.doi.org/10.34101/actaagrar/10/3459.
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t evaluating mould contamination of hay samples in more than the half of the cases Mucor spp. (and Trichoderma spp. in a smaller extent) overgrew slower developing moulds, spoiling the assessment of total mould CFU and the detection of fastidious organisms, among others the toxinogenic Fusaria. In parallel microbiological evaluation of hay samples comparing to the ISO 7954 medium as reference a) the overgrowth inhibiting effect of Rose Bengal (ISO 7954-RB); b) the combined inhibiting effect of Rose Bengal and Dichloran (dichloro-mononitroaniline) in DRBC; c) the inhibition of Dichlorane in ISO 7954 (ISO 7954-DC); d) the lowering of nutrient levels to 1/4 (1/4 N ISO 7954, 1/4 N-DRBC and 1/4 N-DC); e) the inhibiting effect of dinitro – salicylic – acid (DSA), a reducing sugar binding compound, as a potential growth inhibitor (RBC-DSA) were studied. The results showed, that 1) MSZ-ISO 7954 medium codified by the official method was unsuitable for the detemination of mould count and for the detection of toxinogic spp. in hay samples. In half of the cases the overgrowth of Mucor has spoiled CFU enumeration and recognition of toxinogenic moulds; 2) Inhibitor supplemented DRBC medium (King et al., 1979) enabled early CFU enumeration by uniforming colony sizes and by efficient suppression of Mucor, but the pink background colour of the medium was disturbing the observation of tints of conidia, which were characteristical to toxinogenic moulds like Fusaria. The hypha-staining property of Rose Bengal did not prove very important; 3) According to the recent stage of our studies, the ISO 7954-Dichloran combination can be recommended for the mycological evaluation of hays and dried roughages. CFU can be enumerated early, Mucor suppressed in the same extent as with DRBC and colours are easily observable; 4) 2-4-Dinitrosalicylic-acid (DSA) proved unsuitable as inhibitor, for its poor efficiency and for its intense yellow background coulour.
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Reindel, J. F., C. M. Hoorn, J. G. Wagner, and R. A. Roth. "Comparison of response of bovine and porcine pulmonary arterial endothelial cells to monocrotaline pyrrole." American Journal of Physiology-Lung Cellular and Molecular Physiology 261, no. 6 (1991): L406—L414. http://dx.doi.org/10.1152/ajplung.1991.261.6.l406.
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Monocrotaline (MCT)-induced vascular injury in liver and lung may be caused by interaction of MCT metabolites such as monocrotaline pyrrole (MCTP) with vascular cells. Responses of bovine and porcine pulmonary artery endothelial cells (BECs and PECs, respectively) to a single administration of MCTP were compared. MCTP caused a delayed and progressive release of lactate dehydrogenase (LDH) activity from BECs and a gradual decrease in monolayer cellularity. Surviving cells became markedly hypertrophic. PECs were less sensitive to the cytolytic effects of MCTP, showing minimal cell detachment and little release of LDH activity. However, monolayer cellularity, as assessed by PEC enumeration, decreased in a dose-dependent manner. Hypertrophy of surviving PECs was less pronounced than in BECs. MCTP caused enhanced release of prostacyclin from monolayers of BECs and PECs exposed to 10 micrograms MCTP/ml, and concentrations of 0.5 microgram/ml or greater caused equivalent reduction in colony-forming efficiency in both cell types. In summary, whereas BECs were more susceptible to the cytolytic and hypertrophic effects of MCTP, BECs and PECs responded similarly with regard to prostacyclin release and were equally sensitive to the cytostatic effects of this compound.
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Ushiyama, Masashi, and Mihoko Iwasaki. "Evaluation of Sanita-kun E. coli & Coliform Sheet Medium for the Enumeration of Total Coliforms and E. coli." Journal of AOAC INTERNATIONAL 93, no. 1 (2010): 163–83. http://dx.doi.org/10.1093/jaoac/93.1.163.
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Abstract The Sanita-kun E. coli & Coliform sheet medium consists of a transparent cover film, an adhesive sheet, a layer of nonwoven fabric, and a water-soluble compound film, including a culture medium formula for the enumeration of total coliforms and differentiation of Escherichia coli. The Sanita-kun E. coli & Coliform sheet is a chromogenic medium and contains X-Gal, which is hydrolyzed by β-galactosidase from coliforms to produce a visible blue dye and Salmon-glucuronic acid, which is hydrolyzed by β-glucuronidase from E. coli to produce a red-purple dye. It is easy to distinguish the difference between E. coli and coliform (other than E. coli) colonies. Total coliforms and E. coli can be enumerated by incubating the sheet medium at 35 ± 1°C for 2124 h without further confirmation. The Sanita-kun E. coli & Coliform sheets were validated as a medium for the enumeration of E. coli and total coliform in meats and meat products using processed meat and two types of raw and frozen meats using stomacher and blender homogenization. In the stomacher homogenization, all 100 samples showed no significant difference between Sanita-kun sheet and AOAC Method 966.24. The linear correlation coefficients (r2) were calculated as 0.90 (coliform) and 0.79 (E. coli). In the blender homogenization, out of 100 samples tested, 99 showed no significant difference between Sanita-kun sheet and AOAC Method 966.24, but the count of total coliforms of Sanita-kun in one sample of uninoculated raw beef was significantly higher than that obtained by AOAC Method 966.24. The linear r2 values were calculated as 0.84 (coliform) and 0.86 (E. coli). The inclusivity and exclusivity study indicated an inclusivity rate of 100 and an exclusivity rate of 95.4. The sensitivity study showed positive results when the homogenate or dilution contained 3 CFU/mL of coliform or E. coli. The performance of four different lots of the sheets was equivalent, and suggested no change of the performance at least for 3 years at 215C. The Sanita-kun E. coli & Coliform sheet medium has been granted Performance Tested MethodSM status.
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Venkatraman, Vishwesh, Jeremiah Gaiser, Daphne Demekas, Amitava Roy, Rui Xiong, and Travis J. Wheeler. "Do Molecular Fingerprints Identify Diverse Active Drugs in Large-Scale Virtual Screening? (No)." Pharmaceuticals 17, no. 8 (2024): 992. http://dx.doi.org/10.3390/ph17080992.
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Computational approaches for small-molecule drug discovery now regularly scale to the consideration of libraries containing billions of candidate small molecules. One promising approach to increased the speed of evaluating billion-molecule libraries is to develop succinct representations of each molecule that enable the rapid identification of molecules with similar properties. Molecular fingerprints are thought to provide a mechanism for producing such representations. Here, we explore the utility of commonly used fingerprints in the context of predicting similar molecular activity. We show that fingerprint similarity provides little discriminative power between active and inactive molecules for a target protein based on a known active—while they may sometimes provide some enrichment for active molecules in a drug screen, a screened data set will still be dominated by inactive molecules. We also demonstrate that high-similarity actives appear to share a scaffold with the query active, meaning that they could more easily be identified by structural enumeration. Furthermore, even when limited to only active molecules, fingerprint similarity values do not correlate with compound potency. In sum, these results highlight the need for a new wave of molecular representations that will improve the capacity to detect biologically active molecules based on their similarity to other such molecules.
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Cluff, Christopher W., Jory R. Baldridge, Axel G. Stöver, et al. "Synthetic Toll-Like Receptor 4 Agonists Stimulate Innate Resistance to Infectious Challenge." Infection and Immunity 73, no. 5 (2005): 3044–52. http://dx.doi.org/10.1128/iai.73.5.3044-3052.2005.
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ABSTRACT A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.
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Novak, Igor. "Isonumeric Compounds: Derivative Enumeration." Zeitschrift für Naturforschung A 49, no. 7-8 (1994): 790–92. http://dx.doi.org/10.1515/zna-1994-7-810.
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Granados-Chinchilla, Fabio, Carol Valenzuela-Martínez, Berny García-Murillo, David Aguilar-Madrigal, Mauricio Redondo-Solano, and Andrea Molina. "Microbiological Safety and Presence of Major Mycotoxins in Animal Feed for Laboratory Animals in a Developing Country: The Case of Costa Rica." Animals 11, no. 8 (2021): 2389. http://dx.doi.org/10.3390/ani11082389.
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Safety and quality of compound feed for experimental animals in Costa Rica is unknown. Some contaminants, such as Salmonella spp. and mycotoxins, could elicit confounding effects in laboratory animals used for biomedical research. In this study, different batches of extruded animal feed, intended for laboratory rodents in Costa Rica, were analyzed to determine mycotoxin and microbiological contamination (i.e., Salmonella spp., Escherichia coli, total coliform bacteria, and total yeast and molds enumeration). Two methods for Salmonella decontamination (UV light and thermal treatment) were assessed. Only n = 2 of the samples were negative (representing 12.50%) for the 26 mycotoxins tested. Enniatins and fumonisins were among the most frequent toxins found (with n = 4+ hits), but the level of contamination and the type of mycotoxins depended on the supplier. None of the indicator microorganisms, nor Salmonella, were found in any of the tested batches, and no mold contamination, nor Salmonella growth, occurs during storage (i.e., 2–6 months under laboratory conditions). However, mycotoxins, such as enniatins and fumonisins tend to decrease after the fourth month of storage, and Salmonella exhibited a lifespan of 64 days at 17 °C even in the presence of UV light. The D-values for Salmonella were between 65.58 ± 2.95 (65 °C) and 6.21 ± 0.11 (80 °C) min, and the thermal destruction time (z-value) was calculated at 15.62 °C. Results from this study suggest that laboratory rodents may be at risk of contamination from animal feed that could significantly affect the outcomes of biomedical experiments. Thus, improved quality controls and handling protocols for the product are suggested.
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Watmough, Gary R., Charlotte L. J. Marcinko, Clare Sullivan, et al. "Socioecologically informed use of remote sensing data to predict rural household poverty." Proceedings of the National Academy of Sciences 116, no. 4 (2019): 1213–18. http://dx.doi.org/10.1073/pnas.1812969116.
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Tracking the progress of the Sustainable Development Goals (SDGs) and targeting interventions requires frequent, up-to-date data on social, economic, and ecosystem conditions. Monitoring socioeconomic targets using household survey data would require census enumeration combined with annual sample surveys on consumption and socioeconomic trends. Such surveys could cost up to $253 billion globally during the lifetime of the SDGs, almost double the global development assistance budget for 2013. We examine the role that satellite data could have in monitoring progress toward reducing poverty in rural areas by asking two questions: (i) Can household wealth be predicted from satellite data? (ii) Can a socioecologically informed multilevel treatment of the satellite data increase the ability to explain variance in household wealth? We found that satellite data explained up to 62% of the variation in household level wealth in a rural area of western Kenya when using a multilevel approach. This was a 10% increase compared with previously used single-level methods, which do not consider details of spatial landscape use. The size of buildings within a family compound (homestead), amount of bare agricultural land surrounding a homestead, amount of bare ground inside the homestead, and the length of growing season were important predictor variables. Our results show that a multilevel approach linking satellite and household data allows improved mapping of homestead characteristics, local land uses, and agricultural productivity, illustrating that satellite data can support the data revolution required for monitoring SDGs, especially those related to poverty and leaving no one behind.
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Pizon, Monika, Dorothea Zimon, Ulrich A. Pachmann, and Katharina Pachmann. "In vitro chemosensitivity testing of mammospheres cultured from circulating epithelial tumor cells (CETCs) of breast cancer patients: Comparision to chemosensitivity of total CETCs." Journal of Clinical Oncology 32, no. 26_suppl (2014): 50. http://dx.doi.org/10.1200/jco.2014.32.26_suppl.50.
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50 Background: In vitro chemosensitivity testing of circulating epithelial tumor cells (CETCs) provides real-time information about the sensitivity of the tumor cells present in the patient. Nevertheless, a fraction of CETCs can survive after conventional chemotherapy and grow into distant metastasis. This may be a subpopulation of CETCs with proliferation activity which has the ability to form floating spheres in suspension culture. Spheroids exhibit stem cell-like properties and may be responsible for chemotherapeutic resistance. Therefore, the aim of our study was to determine the efficacy of chemotherapeutics on spheroids cultured from CETCs. Methods: The enumeration of CETCs from patients with solid tumors in clinical stage I to IV was performed using the maintrac method. Subsequently, CETCs in the context of the surrounding white blood cells were cultured in a suspension culture allowing for spheroid formation. To evaluate the cytotoxic effect of drugs on CETCs and spheroids we exposed them to anticancer drugs in short time culture in different concentrations and for different periods of time. Results: In contrast to CETCs, spheroids were significantly more chemotherapy resistant. Active drugs led to disintegration of tumor spheres. Interestingly, some cells in the spheres were able to survive. Epirubicin and especially salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, showed high efficacy in a high proportion of cells. Furthermore, our data suggested that curcumin, a natural biologically active compound that is extracted from the plant Curcuma longais a promising agent for cancer treatment. Docetaxel, cyclophosphamide, and 5-fluoruracil showed lower cytotoxic effects onto the cells in the spheres. Conclusions: Our results show, for the first time, that stem cells circulating in peripheral blood, capable of forming spheroids are way more resistant to anticancer drugs than the remnant circulating tumor cells. We, furthermore, demonstrate that salinomycin and curcumin efficiently destroy spheroids cultured from CETCs, strengthening their role as promising anticancer therapeutics.
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Henderson-Walshe, George, Michael Langton, Jeanette McLeod, and Phillip Wilson. "Algebraic Enumeration of Polypolyhedra." PUMP Journal of Undergraduate Research 7 (October 20, 2024): 207–30. http://dx.doi.org/10.46787/pump.v7i0.3936.
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Polypolyhedra are edge-transitive compounds of polyhedra. In this paper we use group theory to determine the number of distinct polypolyhedra whose symmetry group is any given finite irreducible Coxeter group. We apply this result in order to enumerate the 3-dimensional polypolyhedra.
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Bentley, Victoria L., Chansey J. Veinotte, Dale Corkery, et al. "Zebrafish Xenotransplantation and Focused Chemical Genomics: A Preclinical Therapeutic Model For T-Cell Acute Lymphoblastic Leukemia." Blood 122, no. 21 (2013): 2670. http://dx.doi.org/10.1182/blood.v122.21.2670.2670.
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Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subset of ALL, for which there is a need for new therapeutic strategies and efficient preclinical screening methods. We have pioneered an innovative zebrafish human cancer xenotransplantation (XT) model to examine drug-tumor interactions in vivo. T-ALL cell lines and primary patient T-ALL samples were microinjected into 48-hour zebrafish embryos, a stage at which the adaptive immune system has not yet developed. Fluorescent labelling of tumor cells prior to injection and use of casper pigment mutant fish facilitates evaluation of drug response both by direct observation in transparent fish and enumeration of human cells following embryo dissociation. Proliferation rates are rapidly determined by directly counting fluorescent cells using in silico-based programs and/or utilizing immunohistochemical approaches to distinguish human cancer cells from host cell populations. T-ALL cell lines harboring defined mutations in the NOTCH1, phosphoinositide 3-kinase (PI3K)/AKT and mTOR pathways differentially responded to targeted inhibition using the γ-secretase inhibitor Compound E, triciribine, and rapamycin, when xenografted into embryos, consistent with responses in vitro. Primary patient-derived T-ALL bone marrow samples similarly engrafted and proliferated in zebrafish embryos. Using this in vivo chemical genomic approach, a targetable mutation sensitive to γ-secretase inhibition was identified from the diagnostic bone marrow sample of a child with T-ALL, which was confirmed by exome Sanger sequencing, and validated as a gain-of-function mutation in the NOTCH1 gene by luciferase assay and Western blot. Focused chemical genomics using the zebrafish T-ALL XT model provides a means of tailoring therapy using a real time in vivo assay that more accurately recapitulates the tumor microenvironment than in vitro methods and more rapidly than mouse xenografts. Moreover, the efficiency and cost-effectiveness of this innovative platform provides a novel intermediary for the prioritization of much-needed drug candidates in the preclinical pipeline. Disclosures: No relevant conflicts of interest to declare.
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ZHAO, YANG, MORIHIRO HAYASHIDA, JIRA JINDALERTUDOMDEE, HIROSHI NAGAMOCHI, and TATSUYA AKUTSU. "BREADTH-FIRST SEARCH APPROACH TO ENUMERATION OF TREE-LIKE CHEMICAL COMPOUNDS." Journal of Bioinformatics and Computational Biology 11, no. 06 (2013): 1343007. http://dx.doi.org/10.1142/s0219720013430075.
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Molecular enumeration plays a basic role in the design of drugs, which has been studied by mathematicians, computer scientists, and chemists for quite a long time. Although many researchers are involved in developing enumeration algorithms specific to drug design systems, molecular enumeration is still a hard problem to date due to its exponentially increasing large search space with larger number of atoms. To alleviate this defect, we propose efficient algorithms, BfsSimEnum and BfsMulEnum to enumerate tree-like molecules without and with multiple bonds, respectively, where chemical compounds are represented as molecular graphs. In order to reduce the large search space, we adjust some important concepts such as left-heavy, center-rooted, and normal form to molecular tree graphs. Different from many existing approaches, BfsSimEnum and BfsMulEnum firstly enumerate tree-like compounds by breadth-first search order. Computational experiments are performed to compare with several existing methods. The results suggest that our proposed methods are exact and more efficient.
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Merris, Russell, G. Polya, and R. C. Read. "Combinatorial Enumeration of Groups, Graphs, and Chemical Compounds." American Mathematical Monthly 96, no. 3 (1989): 269. http://dx.doi.org/10.2307/2325230.
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Anderson, I., G. Polya, and R. C. Read. "Combinatorial Enumeration of Groups, Graphs and Chemical Compounds." Mathematical Gazette 72, no. 461 (1988): 244. http://dx.doi.org/10.2307/3618278.
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King, R. B., and D. H. Rouvray. "ISOMER ENUMERATION IN POLYTERTIARY PHOSPHINES AND RELATED COMPOUNDS." Phosphorus and Sulfur and the Related Elements 22, no. 2 (1985): 177–82. http://dx.doi.org/10.1080/03086648508073445.
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Kvasnička, Vladimír, and Jiří Pospíchal. "Constructive enumeration of acyclic molecules." Collection of Czechoslovak Chemical Communications 56, no. 9 (1991): 1777–802. http://dx.doi.org/10.1135/cccc19911777.
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Simple combinatorial theory of constructive enumeration of rooted trees and trees is suggested. As a byproduct of this approach very simple recursive formulae for numerical (i.e. nonconstructive) enumeration are obtained. The method may be simply generalized for (rooted) trees with edges evaluated by multiplicities and vertices evaluated by alphabetic – atomic symbols. In the process of constructive enumeration the (rooted) trees are represented by unambiguous linear code composed of valences of vertices, edge multiplicities, and atomic symbols assigned to vertices. The elaborated theory may serve as a simple algorithmic background of computer programs for contsructive enumeration of acyclic molecular structures containing heteroatoms and multiple bonds.
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li, Zhaoang, Chenyu Lin, David J. Bearss, and Hariprasad Vankayalapati. "Abstract 4587: Development of highly selective, potent, orally available PIM1 inhibitor BLX0631 shows a therapeutics potential in multiple myeloma models." Cancer Research 84, no. 6_Supplement (2024): 4587. http://dx.doi.org/10.1158/1538-7445.am2024-4587.
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Abstract Background: The Proto-oncogenic PIMs family are nuclear and cytoplasmic Ser/Thr kinases (PIM1, PIM2, and PIM3) that are constitutively active and play a vital role in proliferation and survival in Multiple Myeloma (MM). Activated PIM1 kinase can induce progression of the cell cycle, inhibition of apoptosis, and modulation of other signal transduction pathways. Methods: BLX-0631 and a few analogs evaluated against a panel of MM cell lines (EJM, IM-9, L-363, LP-1, MM-1R, MM.1S, MOLP-2, NCI-H929, OPM-2, RPMI8226 and U-266) and primary MM patient samples by CellTiter-Glo® (CTG) assays. Cellular apoptosis, Cell cycle analysis, Flow Cytometry, and bone marrow microenvironment experiments on the most sensitive cells were performed. PIM1 and downstream targets by western blot, cell migration, and invasion on our lead PIM1 inhibitor BLX-0631 along with, kinome selectivity, ADME-Tox, PK, and in vivo MM.1S efficacy experiments were conducted. Results: The application of our empirical MolecuLernTM fragment library, PIM1 crystal structure, scaffold hopping, and the enumeration features of MolecuLernTM in combination with 3, 6, and 7-group analysis on pyridazine, lead to a synthesizable potential new lead series, representing Med Chem tractability and developable characteristics. Further, the consensus scoring, binding energies, and MolecuLern tractability filters were applied and led to the discovery of the BLX-0631 series that inhibits the PIM1 kinase. The active compounds, with their binding modes and lead optimization strategies, lead to the synthesis and testing of over 60 novel entities as PIM1 kinase inhibitors. Thus, based on our previous chemotype series and scaffold hopping method, the impact of changing the 3, 6, and 7 positions, while retaining the pyridazine core led to the discovery of BLX-0631 and its series of compounds exhibiting <5 nM potency. BLX-0631 in CTG assay demonstrated 100% cell growth inhibition across all MM cell lines tested. The lead compound BLX-0631 is a very potent inhibitor with an IC50 of 5.0/17/5.0 nM when tested against PIM1, PIM2, and PIM3 kinases respectively, and selective against a panel of 468 kinase panels. Dosing through IV and PO delivery routes, formulations, salt forms of BLX-0631 in mice, PK properties along with ADME-Tox, P450, and hERG results will be presented. In vivo MM.1S mouse xenograft models of BLX-0631 at 15, 30 and 45 mg/Kg, p.o, QD demonstrated TGI of 16.28%, 31.81% & 35.16% dose-dependently. Conclusions: The present study demonstrates that PIM1 plays a vital role in the proliferation and survival of Multiple Myeloma. BLX-0631 induces full inhibition of all MM cell lines, suppresses cancer cell proliferation in vitro, and exhibits promising efficacy in MM tumor models. BLX-0631, a nominated IND candidate can serve as a novel targeted agent for treating Multiple Myeloma patients. Citation Format: Zhaoang li, Chenyu Lin, David J. Bearss, Hariprasad Vankayalapati. Development of highly selective, potent, orally available PIM1 inhibitor BLX0631 shows a therapeutics potential in multiple myeloma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4587.
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KALCHAYANAND, NORASAK, TERRANCE M. ARTHUR, JOSEPH M. BOSILEVAC, et al. "Efficacy of Antimicrobial Compounds on Surface Decontamination of Seven Shiga Toxin–Producing Escherichia coli and Salmonella Inoculated onto Fresh Beef†." Journal of Food Protection 78, no. 3 (2015): 503–10. http://dx.doi.org/10.4315/0362-028x.jfp-14-268.
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Several antimicrobial compounds have been used in commercial meat processing plants for decontamination of pathogens on beef carcasses, but there are many commercially available, novel antimicrobial compounds that may be more effective and suitable for use in beef processing pathogen-reduction programs. Sixty-four prerigor beef flanks (cutaneous trunci) were used in a study to determine whether hypobromous acid, neutral acidified sodium chlorite, and two citric acid–based antimicrobial compounds effectively reduce seven Shiga toxin–producing Escherichia coli (STEC) serogroups and Salmonella on the surface of fresh beef. Two cocktail mixtures were inoculated onto prerigor beef flank surfaces. Cocktail mixture 1 was composed of STEC serogroups O26, O103, O111, O145, and O157; and cocktail mixture 2 was composed of STEC serogroups O45, O121, and O157 and Salmonella. The inoculated fresh beef flanks were subjected to spray treatments with four antimicrobial compounds. Following antimicrobial treatments, both control and treated fresh beef samples were either enumerated immediately or were stored for 48 h at 4°C before enumeration. All four antimicrobial compounds caused 0.7- to 2.0-log reductions of STEC, Salmonella, aerobic plate counts, and Enterobacteriaceae. Results also indicated that the four antimicrobial compounds were as effective at reducing the six non-O157 STEC strains as they were at reducing E. coli O157:H7 on the surfaces of fresh beef. The recovery of all seven STEC strains and Salmonella in a low-inoculation study indicated that none of the four antimicrobial compounds eliminated all of the tested pathogens.
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Sood, Raman, Linda Rivera, Jagman Chahal, et al. "Generation of Zebrafish Lines with New Gata1 Mutations and Their Characterization with a Novel In Vitro Colony-Forming Assay." Blood 108, no. 11 (2006): 1336. http://dx.doi.org/10.1182/blood.v108.11.1336.1336.
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Abstract Gata1 is a transcription factor critical for erythroid and megakaryocyte differentiation. We have shown previously that the lethal bloodless phenotype of the zebrafish mutant vlad tepes (vlt) is due to a nonsense mutation in gata1, suggesting that hematopoietic regulation is conserved between zebrafish and mammals. We have now generated fish with 2 novel missense mutations, T301K and K333R, identified by sequencing exons 5 and 6 in 1235 F1 fish derived from ENU-mutagenized males. Both mutations change conserved residues in the C-terminal zinc finger domain of gata1. Embryos homozygous for either T301K or K333R mutation showed normal circulation and survived to adulthood. Reduced hemoglobin levels were observed in T301K homozygous embryos compared to K333R homozygotes and wildtype by o-dianisidine staining. We crossed both mutations to vlt carrier fish and generated compound heterozygotes for further evaluation. T301K/vlt compound heterozygous embryos lacked circulation and hemoglobin staining, whereas K333R/vlt embryos had normal circulation and hemoglobin staining. These data suggest that the T301K mutation acts as a hypomorphic allele, having stronger phenotype in the presence of a null allele. Fish with both T301K/vlt and K333R/vlt genotypes survive to adulthood in expected Mendelian ratios. Time course observations show that T301K/vlt fish regain circulation around day 14, which is the time when most vlt/vlt fish die. These data suggest that during definitive hematopoiesis cells may be less sensitive to gata1 deficiency. In addition, we observed reduced number of circulating platelets in vlt/vlt embryos but normal in T301K/vlt embryos, suggesting that megakaryocyte maturation is regulated by gata1 in zebrafish. The in vitro culture of hematopoietic progenitors has been a powerful tool to study mammalian hematopoiesis, but similar techniques have not been available in the zebrafish. We hypothesized that the use of the zebrafish orthologs of Stem Cell Factor (scf) and Erythropoietin (epo) in semi soild medium would allow the growth and enumeration of colonies derived from zebrafish kidney cells. Based on homology to mammalian proteins, we identified zebrafish scf and epo cDNA clones (40.8% and 49.7% similarities to human SCF and EPO respectively), and expressed them in 293 cells. Methylcellulose medium containing conditioned medium from transfected cells was mixed with 105 to 106 adult kidney cells. No colonies developed in cultures with mock transfected 293 conditioned medium. In contrast, small erythroid colonies appeared between 2 to 6 days in cultures containing epo and/or scf conditioned medium. Larger erythroid colonies were detected in 8 to12 days. In the presence of scf, additional distinct colonies comprising of monocytes, neutrophils and/or erythroid cells were observed. Cultures of adult kidney cells from T301K/vlt and T301K/T301K fish showed 2–6 fold reduction (p=0.01 and 0.006 respectively) in the number of colonies. These results are consistent with the reduced number of hematopoietic cells observed in kidney sections of adult T301K homozygotes. In conclusion, we have generated gata1 mutant fish that revealed a conserved role of gata1 in zebrafish erythroid and megakaryocyte developments. The viable gata1 mutants and our novel in vitro differentiation system will be useful for studying the role of gata1 in adult hematopoiesis and in leukemogenesis. The mutants will also serve as an ideal system for genetic modifier screens.
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Morikawa, Tetsuo. "Graph-Theoretical Enumeration of Conjugated Patterns for Carbocyclic and Heterocyclic Compounds*." Zeitschrift für Naturforschung A 49, no. 3 (1994): 511–14. http://dx.doi.org/10.1515/zna-1994-0310.
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Abstract An algorithmic analysis of the existence of conjugated patterns for carbocyclic and heterocyclic compounds is presented. This graph theoretical method is applicable to the enumeration of Kekulé patterns for hydrocarbon benzenoids, as a special case.
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Chávez-Hernández, Ana L., Johny R. Rodríguez-Pérez, Héctor F. Cortés-Hernández, Hoover A. Valencia-Sanchez, Miguel Á. Chávez-Fumagalli, and José L. Medina-Franco. "Fragment Library of Colombian Natural Products: Generation and Comparative Chemoinformatic Analysis." Drugs and Drug Candidates 3, no. 4 (2024): 736–50. http://dx.doi.org/10.3390/ddc3040042.
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Fragment libraries have a major significance in drug discovery due to their role in de novo design and enumerating large and ultra-large compound libraries. Although several fragment libraries are commercially available, most are derived from synthetic compounds. The number of fragment libraries derived from natural products is still being determined. Still, they represent a rich source of building blocks to generate pseudo-natural products and bioactive synthetic compounds inspired by natural products. In this work, we generated and analyzed a fragment library of natural products from Colombia, a highly diverse geographical region where fragment libraries are yet to be reported. We also generated and reported fragment libraries of three novel natural product libraries and, as a reference, the most updated version of FDA-approved drugs. In line with the principles of open science, the fragment libraries developed in this study are freely available.
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Mesarch, Matthew B., Cindy H. Nakatsu, and Loring Nies. "Development of Catechol 2,3-Dioxygenase-Specific Primers for Monitoring Bioremediation by Competitive Quantitative PCR." Applied and Environmental Microbiology 66, no. 2 (2000): 678–83. http://dx.doi.org/10.1128/aem.66.2.678-683.2000.
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ABSTRACT Benzene, toluene, xylenes, phenol, naphthalene, and biphenyl are among a group of compounds that have at least one reported pathway for biodegradation involving catechol 2,3-dioxygenase enzymes. Thus, detection of the corresponding catechol 2,3-dioxygenase genes can serve as a basis for identifying and quantifying bacteria that have these catabolic abilities. Primers that can successfully amplify a 238-bp catechol 2,3-dioxygenase gene fragment from eight different bacteria are described. The identities of the amplicons were confirmed by hybridization with a 238-bp catechol 2,3-dioxygenase probe. The detection limit was 102 to 103 gene copies, which was lowered to 100 to 101 gene copies by hybridization. Using the dioxygenase-specific primers, an increase in catechol 2,3-dioxygenase genes was detected in petroleum-amended soils. The dioxygenase genes were enumerated by competitive quantitative PCR with a 163-bp competitor that was amplified using the same primers. Target and competitor sequences had identical amplification kinetics. Potential PCR inhibitors that could coextract with DNA, nonamplifying DNA, soil factors (humics), and soil pollutants (toluene) did not impact enumeration. Therefore, this technique can be used to accurately and reproducibly quantify catechol 2,3-dioxygenase genes in complex environments such as petroleum-contaminated soil. Direct, non-cultivation-based molecular techniques for detecting and enumerating microbial pollutant-biodegrading genes in environmental samples are powerful tools for monitoring bioremediation and developing field evidence in support of natural attenuation.
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Tkhagazitov, Yuri M., Takhir Z. Tolgurov, and Fatima T. Uzdenova. "Introverted Spatial Narrative: Azimuths and Linearity." Current Issues in Philology and Pedagogical Linguistics, no. 4 (December 25, 2022): 204–16. http://dx.doi.org/10.29025/2079-6021-2022-4-204-216.
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The article is devoted to the analysis of topological models of L.N. Tolstoy. The goal is to recearch the narrative and suggestive functions of the writer’s individual spatial representations, as well as their role in creating the emotive-evaluative structure of the narrative. The material of the study was the works: “Childhood”, “Foray”, “Master and Worker”, “Resurrection”. In modern literary criticism, there are de facto no studies of the writer’s spatial reflection, which already ensures a high level of relevance of the material presented. The main research methods were comparative, structural and descriptive, hermeneutic and interpretive, historical and functional, as well as the method of semantic analysis. In modern literary criticism, there are no actually studies of the spatial reflection of the writer, which already ensures a high level of relevance of the material presented. As a result of referring to the texts of several, especially illustrative works of the prose writer, the authors of the article come to two important conclusions. Firstly, the texts of L. Tolstoy testify that the writer did not focus on the linear and distance characteristics of the described topoi, limiting himself to the degree of their completeness and detail, which made it possible to create a reliable picture of the emotional and psychological state of the characters (this was explained by the artist’s overwhelming interest in the inner world of the characters, to revealing their mental and moral and ethical dominants). The objects described in the writer’s works, although they give some idea of the areas of the ongoing action, in most cases act as sets of isolated points and objects. In the first case, such references are presented as a space of stable emotional and evaluative states of the characters (“Compound”, “road”, “field”), in the second case, by means of a concentrated enumeration of them, the author creates paintings saturated with traditional everyday associations, again, in order to create an effect of emotional contrast. Secondly, the writer, in general, tended to describe limited locations, to depict the closest to the point of observation of the author and the hero. According to the authors, it’s explained, by the peculiarities of L. Tolstoy’s psychotype, which were formed in the deep childhood of the writer. The study revealed that in the formation of the topology of narrative episodes, the writer was primarily interested in the internal movement of the human soul and he could well experiment with the narrative space in order to “obscure”, dematerialize it in order to fully concentrate on the main object of his attention.
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Shestakov, V. A., and E. V. Grachev. "Enumeration of Melting Diagrams for Four-Component Systems Comprising Stoichiometric Compounds." Russian Journal of Inorganic Chemistry 67, no. 4 (2022): 488–91. http://dx.doi.org/10.1134/s0036023622040179.
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Kosyakov, V. I., V. A. Shestakov, and E. V. Grachev. "Enumeration of melting diagrams of three-component systems with stoichiometric compounds." Russian Journal of Inorganic Chemistry 55, no. 4 (2010): 611–19. http://dx.doi.org/10.1134/s0036023610040194.
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Cole, Jacqueline M. "Enumerating Intramolecular Charge Transfer in Conjugated Organic Compounds." Journal of Chemical Information and Modeling 60, no. 12 (2020): 6095–108. http://dx.doi.org/10.1021/acs.jcim.0c00913.
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Fujita, Shinsaku. "Combinatorial enumeration of ethane derivatives as three-dimensional chemical structures, not as graphs. A systematic approach for enumerating and characterizing stereoisomers of tartaric acids and related compounds." Journal of Mathematical Chemistry 38, no. 2 (2005): 175–94. http://dx.doi.org/10.1007/s10910-005-5189-y.
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Johnson, Wesley, Ifeoluwa Idowu, Olga Francisco, et al. "Enumeration of the constitutional isomers of environmentally relevant substituted polycyclic aromatic compounds." Chemosphere 202 (July 2018): 9–16. http://dx.doi.org/10.1016/j.chemosphere.2018.03.035.
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Fujita, Shinsaku. "Pseudo-Point Groups for Symmetry Characterization and Combinatorial Enumeration of Nonrigid Compounds." Bulletin of the Chemical Society of Japan 67, no. 11 (1994): 2927–34. http://dx.doi.org/10.1246/bcsj.67.2927.
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Shestakov, V. A., E. V. Grachev, and V. I. Kosyakov. "Classification and Enumeration of Subsolidus Sections in Five-Component Systems with Stoichiometric Compounds." Russian Journal of Inorganic Chemistry 66, no. 11 (2021): 1730–35. http://dx.doi.org/10.1134/s0036023621110164.
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Babich, Alexander, Yingzhe Li, Francois Gaudet, et al. "Immunoprofiling of Normal Human Donor Blood Identified Potential Pharmacodynamic Markers for JNJ-63709178 (CD123xCD3) Duobody® Antibody Treatment." Blood 128, no. 22 (2016): 5215. http://dx.doi.org/10.1182/blood.v128.22.5215.5215.
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Abstract Background JNJ-63709178 (CD123xCD3) is a promising new bispecific antibody currently being investigated for the treatment for acute myeloid leukemia (AML), a disorder of early hematopoietic progenitor cells characterized by the proliferation and accumulation of immature, clonal, myeloid cells. Constitutive overexpression of the α-subunit of the interleukin-3 receptor (ie, IL-3αR/CD123) is a hallmark of the early AML progenitor cell population (ie, leukemic stem cells [LSC]), as well as leukemic blasts. CD123 is unique to the IL-3 receptor and is responsible for the high specificity and low affinity binding of IL-3. Under physiological conditions, activation of the IL-3 receptor induces proliferative, anti-apoptotic, and differentiating signals. JNJ-63709178, a humanized IgG4 bispecific DuoBody® antibody with high affinity anti-CD123 and -CD3 arms, recognizes CD123 on myeloid cells and CD3 on T cells, leading to T-cell activation, with subsequent lysis of CD123+ AML blasts. JNJ-63709178 induces potent tumor cell killing in vitro, ex vivo, and in murine AML models, and is currently being evaluated in first-in-human clinical trials. Although CD123 is distinctively expressed on leukemic cells, some populations of normal myeloid cells have been reported to express CD123. The goals of this study were to determine CD123 receptor density on various leukocyte populations in normal human peripheral blood and evaluate the effects of JNJ-63709178 on those cells to identify potential pharmacodynamic markers. Methods Peripheral blood samples from 6 normal human donors were analyzed ex vivo for CD123 expression on various leukocyte populations to determine receptor density. Receptor density on cells was quantified using Quantibrite PE enumeration kit. Subsequently, blood samples were treated with escalating concentrations of JNJ-63709178 (CD123xCD3) or the control compound CNTO 7008 (nullxCD3) DuoBody® antibodies and incubated at 37°C for 48 hours. After incubation, blood samples were stained and processed for analysis of T-cell activation (CD25 expression) and population persistence or depletion (frequencies within leukocytes). In the myeloid compartment, basophils, myeloid dendritic cells (mDCs), monocytes, neutrophils, and eosinophils were analyzed. In the lymphoid compartment, plasmacytoid dendritic cells (pDCs), B cells (naïve and memory), T cells (helper and cytotoxic), and natural killer (NK) cells (CD56bright and CD56dim) were analyzed. Results In normal human peripheral blood samples, CD123 expression was highest on pDCs and basophils (above 10,000 receptors per cell). Intermediate expression (300-3,000 receptors per cell) was observed on mDCs, monocytes, eosinophils, and naïve B cells. Low expression (10-200 receptors per cell) was observed on neutrophils, memory B cells, T cells, and NK cells. These data are in agreement with previous studies (Busfield et al. ASH 2013 abs3598). Following incubation with JNJ-63709178, potent activation of CD4+ and CD8+ T cells was observed at sub-nanomolar levels, with EC50values of 0.07 nM and 0.1 nM, respectively. Higher CD123 expression and T-cell activation correlated strongly with profound depletion of basophils and pDCs, as well as partial depletion of eosinophils and monocytes. Consistent with low CD123 expression, T cells and NK cells did not show substantial dose-dependent depletion. In contrast to CD123 expression levels, B cells and neutrophils showed partial depletion, despite low CD123 expression, while mDCs did not show dose-dependent depletion, despite higher CD123 levels. The activation of T cells and cytotoxic effect on CD123-positive cells was observed only with JNJ-63709178. The control compound CNTO 7008 (nullxCD3) had no effect on T-cell activation or any of the investigated cell populations. Conclusions These findings highlight the potential pharmacodynamic markers of JNJ-63709178 (CD123xCD3) bispecific treatment and provide a better understanding of its mechanism of action and a rationale for receptor expression monitoring during ongoing clinical trials. Disclosures Babich: Janssen: Employment. Li:Janssen: Employment. Gaudet:Janssen Pharmaceuticals R&D: Employment, Other: Stock options, Patents & Royalties: pending, not yet issued. Huang:Janssen Research & Development, LLC: Employment, Other: I am an employee of Janssen and a stock owner . Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment. Salvati:Janssen Pharmaceuticals R&D: Employment, Other: stock options, Patents & Royalties: patent. Kalota:Janssen Pharmaceuticals R&D: Employment, Other: stock.
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LaFave, Lindsay M., Wendy Béguelin, Richard Koche, et al. "BAP1 Loss Results in EZH2-Dependent Transformation in Myelodysplastic Syndromes." Blood 126, no. 23 (2015): 713. http://dx.doi.org/10.1182/blood.v126.23.713.713.
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Abstract Recurrent somatic loss-of-function mutations in ASXL1 (Addition of sex combs-like 1) are common genetic events in a spectrum of myeloid malignancies and these alterations demarcate patients with poor outcome. ASXL1 forms a chromatin regulatory complex with the ubiquitin hydrolase BAP1 (BRCA1 associated protein-1), a protein that has been found to be transcriptionally repressed in MDS patients. These data are consistent with BAP1 having tumor suppressive activity in MDS; however, the mechanism by which disruption of the ASXL1-BAP1 axis leads to transformation is not well understood. We conditionally deleted Bap1 in the murine hematopoietic system utilizing Mx1-Cre (hereafter referred to as Bap1 KO). One hundred percent of mice with confirmed Bap1 deletion developed a fully penetrant MDS-like disease characterized by leukocytosis, anemia, and splenomegaly. Bap1 KO mice have an expansion of the granulocyte macrophage progenitor compartment (GMP; Lin- c-Kit+ Sca1- CD34+ Fcϒ+). Given the role of BAP1 in epigenetic regulation, we investigated the effect of Bap1 loss on chromatin state and transcriptional output. We first assessed epigenetic changes in Bap1 KO mice by performing histone mass spectometry in control and Bap1 KO hematopoietic stem and progenitor cells (HSPCs, c-Kit+ enriched). Bap1 loss increased H3K27me2/3 at the expense of H3K27me0/1. We confirmed that H3K27me3 was increased in Bap1 KO bone marrow cells by completing H3K27me3 ChIP-Sequencing in HSPCs. Enumeration of H3K27me3 peaks in Bap1 KO versus control cells indicated an increase in H3K27me3 domains (Figure A). We next overlaid RNA-Sequencing from GMP sorted Bap1 KO bone marrow cells with genes marked by H3K27me3, as indicated by ChIP-Sequencing. We found that Bap1 loss resulted in a global decrease in gene expression (68% downregulated, 657/968 genes, p-adj <0.01) and that increased H3K27me3 identified genes with reduced expression after Bap1 loss (NES=-1.39, FDR<0.001) (Figure A). Gene set enrichment analyses (GSEA) revealed that genes that were altered following depletion of Bap1 corresponded to differentiation, hematopoietic lineage specification, and proliferation pathways. Combined, these data suggest that Bap1 depletion results in increased H3K27me3 and represses gene targets implicated in normal and malignant hematopoiesis. Given the alterations in H3K27me3 in Bap1 KO mice, we investigated whether Bap1- deficient transformation could be rescued by abrogation of PRC2-mediated gene repression. We developed a genetic model with compound deletion of Bap1 and Ezh2, the catalytic component of the PRC2 complex. Co-deletion of Bap1 and Ezh2 resulted in a phenotypic rescue of Bap1 KO associated splenomegaly (spleen weights, Bap1 KO avg. 541.6 mg, Bap1/Ezh2 KO avg. 157.0 mg, p<0.005) (Figure B), leukocytosis (white blood cells counts, Bap1 KO avg. 51 K/uL, Bap1/Ezh2 KO avg. 8 K/uL, p <0.005), anemia (hematocrit, Bap1 KO avg. 28.2%, Bap1/Ezh2 KO avg. 46.0%, p<0.005). Importantly, the increased H3K27me3 levels in Bap1 KO mice were reduced in Bap1/Ezh2 KO mice (Figure B), suggesting that loss of Bap1 leads to Ezh2-dependent malignant transformation. EZH2 small molecule inhibitors have proven effective in EZH2-dependent models of B cell lymphoma. To determine if Ezh2 inhibition was efficacious in the setting of Bap1 loss, we treated a cohort of Bap1 KO mice with either vehicle (NaCMC) or 500 mg/kg EPZ011989, an EZH2 inhibitor with in vivo activity. Treatment of Bap1 KO mice for 16 days resulted in significant reduction of splenomegaly (spleen weights, vehicle avg. 522.0, EPZ011989 treated avg. 216.2, p<0.005) (Figure C) and anemia (white blood cell counts, vehicle avg. 61.7 K/uL, EPZ011989 treated avg. 14.5 K/uL, p <0.005), consistent with the phenotype of our genetic Bap1/Ezh2 compound deletion model. These data suggest that decreased BAP1 expression could serve as a biomarker for sensitivity to EZH2 inhibition. Figure 1. Figure 1. Disclosures Knutson: Epizyme, Inc: Employment. Campbell:Epizyme, Inc: Employment. Keilhack:Epizyme: Employment, Equity Ownership. Melnick:Janssen: Other: Research; ROCHE: Other: Research; Genentech: Speakers Bureau; Celgene: Consultancy; Eli Lilly: Consultancy; Epizyme: Consultancy. Armstrong:Epizyme, Inc: Consultancy. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.