Commercial Library Research Articles

MACE - An Open Access Data Repository of Mass Spectra for Chemical Ecology.

MACE is an open access collection of electron impact (EI) mass spectra for coupled gas chromatography-mass spectrometry (GC/MS) that serves as an add-on database, comprising curated spectra not present in widely available commercial mass spectral libraries, such as the NIST or WILEY databases. The spectra are stored as text files that allow easy integration into individual GC/MS systems. The article describes the concept of MACE, the data structure, how to contribute, and its usage. MACE is designed as a community effort and will require contributions from the community to be successful.

A Novel Strategy for Regulating mRNA's Degradation via Interfering the AUF1's Binding to mRNA.

The study on the mechanism and kinetics of mRNA degradation provides a new vision for chemical intervention on protein expression. The AU enrichment element (ARE) in mRNA 3′-UTR can be recognized and bound by the ARE binding protein (AU-rich Element factor (AUF1) to recruit RNase for degradation. In the present study, we proposed a novel strategy for expression regulation that interferes with the AUF1-RNA binding. A small-molecule compound, JNJ-7706621, was found to bind AUF1 protein and inhibit mRNA degradation by screening the commercial compound library. We discovered that JNJ-7706621 could inhibit the expression of AUF1 targeted gene IL8, an essential pro-inflammatory factor, by interfering with the mRNA homeostatic state. These studies provide innovative drug design strategies to regulate mRNA homeostasis.

Hesperadin suppresses pancreatic cancer through ATF4/GADD45A axis at nanomolar concentrations

Pancreatic cancer (PC) is a fatal disease with poor survival and limited therapeutic strategies. In this study, we identified Hesperadin as a potent anti-cancer compound against PC, from a high-throughput screening of a commercial chemical library associated with cell death. Hesperadin induced potent growth inhibition in PC cell lines and patient-derived tumor organoids in a dose- and time-dependent manner, with IC50 values in the nanomolar range. Cellular studies showed that Hesperadin caused mitochondria damage in PC cells, resulting in reactive oxygen species production, ER stress and apoptotic cell death. Transcriptomic analysis using RNA-sequencing data identified GADD45A as a potential target of Hesperadin. Mechanistic studies showed that Hesperadin could increase GADD45A expression in PC cells via ATF4, leading to apoptosis. Moreover, immunohistochemical staining of 92 PC patient samples demonstrated the correlation between ATF4 and GADD45A expression. PC xenograft studies demonstrated that Hesperadin could effectively inhibit the growth of PC cells in vivo. Together, these findings suggest that Hesperadin is a novel drug candidate for PC.

Discovery of Chitin Deacetylase Inhibitors through Structure-Based Virtual Screening and Biological Assays.

Chitin deacetylase (CDA) inhibitors were developed as novel antifungal agents because CDA participates in critical fungal physiological and metabolic processes and increases virulence in soilborne fungal pathogens. However, few CDA inhibitors have been reported. In this study, 150 candidate CDA inhibitors were selected from the commercial Chemdiv compound library through structure-based virtual screening. The top-ranked 25 compounds were further evaluated for biological activity. The compound J075-4187 had an IC50 of 4.24 ± 0.16 μM for AnCDA. Molecular docking calculations predicted that compound J075-4187 binds to the amino acid residues, including active sites (H101, D48). Furthermore, compound J075-4187 inhibited food spoilage fungi and plant pathogenic fungi, with minimum inhibitory concentration (MIC) at 260 μg/ml and minimum fungicidal concentration (MFC) at 520 μg/ml. Therefore, compound J075-4187 is a good candidate for use in developing antifungal agents for fungi control.

Gender and Catalog

The present papers aims at analyzing the actions of the publishing industry in connection with the transposition of Latin American and Caribbean literature written by women from printed to digital format. It presents some results obtained from searches and it detects and analyzes the strategies implemented by the main commercial platforms, digital libraries and bookstores in transposing literary works by women. Likewise, it describes the mechanisms negatively impacting on their representation in the general catalog of Latin American and Caribbean literature. The irruption of works in the public domain and best-selling works by female writers from the region is also discussed.

Particle and Particle Agglomerate Size Monitoring by Scanning Probe Microscope

In the present study, the use of a scanning probe microscope is described for monitoring the sizes of nanoparticles. Monitoring is the process of acquiring and analysing the set of overlapping images. The main analysis steps are image segmentation, determination of nanoparticles allocation and their sizes, determination of the overlap of images with one another, and exclusion of repeating measurements for the formation of the correct particle-size sampling. The thorough examination of commercial scanning probe microscopes, software, and image processing libraries showed that their capabilities are limited for image segmentation and determination of sizes in complex structured images. A method based on the surface curvature computation is proposed for the image segmentation (allocation of particles) and determination of particle sizes. The curvature is estimated using the surface area approximation with respect to the circumference. It is proposed to use sample displacement sensors as an aid for image stitching.

Covalent Fragment Screening Identifies Rgl2 RalGEF Cysteine for Targeted Covalent Inhibition of Ral GTPase Activation.

Ral GTPases belong to the RAS superfamily, and they are directly activated by K-RAS. The RalGEF pathway is one of the three major K-RAS signaling pathways. Ral GTPases do not possess a cysteine nucleophile to develop a covalent inhibitor following the strategy that led to a K-RAS G12C therapeutic agent. However, several cysteine amino acids exist on the surface of guanine exchange factors that activate Ral GTPases, such as Rgl2. Here, we screen a library of cysteine electrophile fragments to determine if covalent bond formation at one of the Rgl2 surface cysteines could inhibit Ral GTPase activation. We found several chloroacetamide and acrylamide fragments that inhibited Ral GTPase exchange by Rgl2. Site-directed mutagenesis showed that covalent bond formation at Cys-284, but not other cysteines, leads to inhibition of Ral activation by Rgl2. Follow-up time- and concentration-dependent studies of derivatives identified by substructure search of commercial libraries further confirmed Cys-284 as the reaction site and identified the indoline fragments as the most promising series for further development. Cys-284 is located outside of the Ral ⋅ Rgl2 interface on a loop that has several residues that come in direct contact with Ral GTPases. Our allosteric covalent fragment inhibitors provide a starting point for the development of small-molecule covalent inhibitors to probe Ral GTPases in animal models.

Comprehensive analysis of commercial fragment libraries.

Screening of fragment libraries is a valuable approach to the drug discovery process. The quality of the library is one of the keys to success, and more particularly the design or choice of a library has to meet the specificities of the research program. In this study, we made an inventory of the commercial fragment libraries and we established a methodology which allows any library to be positioned in relation to the complete offer currently on the market, by addressing the following questions: does this chemical library look like another chemical library? What is the coverage of the current chemical space by this chemical library? What are the characteristic structural features of the fragments of this chemical library? We based our analysis on 2D and 3D chemical descriptors, framework class generation and the generative topographic map. We identified 59 270 scaffolds, which can be searched in a dedicated web site (https://gtmfrag.drugdesign.unistra.fr) and developed a model which accounts for fragment diversity while being easy to interpret (download at 10.5281/zenodo.5534434).

SpeedyGenesXL: an Automated, High-Throughput Platform for the Preparation of Bespoke Ultralarge Variant Libraries for Directed Evolution.

Directed evolution of proteins is a highly effective strategy for tailoring biocatalysts to a particular application, and is capable of engineering improvements such as kcat, thermostability and organic solvent tolerance. It is recognized that large and systematic libraries are required to navigate a protein's vast and rugged sequence landscape effectively, yet their preparation is nontrivial and commercial libraries are extremely costly. To address this, we have developed SpeedyGenesXL, an automated, high-throughput platform for the production of wild-type genes, Boolean OR, combinatorial, or combinatorial-OR-type libraries based on the SpeedyGenes methodology. Together this offers a flexible platform for library synthesis, capable of generating many different bespoke, diverse libraries simultaneously.

Machine learnt patterns in rhodium-catalysed asymmetric Michael addition using chiral diene ligands

Interpretable featurisation allows Quantitative Structure-Property Relationships (QSPR) between chiral diene ligand structures and product stereoselectivities in rhodium-catalysed asymmetric Michael additions (RhCASA). The machine learning approach developed herein is simple to implement yet provides instructive insights and useful predictions (q2/R2 0.7–0.8). These simple interpretable features are found to give comparable predictive ability to both commercial (Dragon) and molecular signature descriptor library approaches. Strong insights into the specific areas of the chiral diene ligand that engender improved RhCASA process enantioselectivity are achieved. These were more interpretable, to synthetic chemists, than existing ML approaches, greatly facilitating design of new chiral diene-ligands.

Promotion of a book in the publishing Internet discourse

The relevance of this research is substantiated by sustained interest in the study of discourse applicable to various social institutions. Publishing discourse appeared in the limelight of the linguists not that long ago. The activity of publishers as a discursive practice intersects with the activity of commercial organizations and libraries. The communication of publishers with other actors in the process of book distribution is also carried via Internet. The goal of this research lies in examination of the means of book promotion in the online publishing discourse. The study leans on the material of the three websites of the English-language publishers. Analysis is conducted on the verbal text and audio-visual communication channels between the publishers and the audience. The analysis of practical material demonstrates that the publisher’s abstract implements the informational and evaluation functions. The additional sources of information on the publisher imply the citations from peer reviews, information about the author, various polycode texts (images and videos), as well as hypertext links to other commercial resources. The leading role in implementation of the informational-advertising functional is assigned to lexicon. Namely the nouns and adjectives affect the appellative-emotional functions. Perlocutive effect of the publisher’s abstract is enhanced by inclusion of citation text, both from the promoted work and reputable sources (newspapers and journals). Citations from peer reviews are usually presented fragmentary, and contain only complimentary statements, which form the attractive image of the book. The conducted research contributes to the development of marketing linguistics, the study of publisher’s paratext, publishing activity as discursive practice, and has prospects for further research in the area of marketing strategies aimed at promotion of books of various formats and genres on the offline and online platforms.

Towards discovery of inhibitors of the undecaprenyl-pyrophosphate phosphatase BacA by virtual high-throughput screening

Increasing resistance to common antibiotics is becoming a major challenge that requires the development of new antibacterial agents. Peptidoglycan is an essential heteropolymer of the bacterial envelope that ensures the integrity and shape of all bacteria and is also an important target for antibiotics. The biosynthesis of peptidoglycan depends on a lipid carrier, undecaprenyl phosphate. As a byproduct of peptidoglycan polymerization, the lipid carrier is released as undecaprenyl pyrophosphate, which must be recycled to allow new polymerization cycles. To this end, it undergoes a dephosphorylation process catalyzed by the membrane phosphatase BacA, which is specific and highly conserved in bacteria. In the present study, we identified small molecules displaying inhibitory potency towards BacA. We began by preparing a commercial compound library, followed by high-throughput virtual screening by ensemble docking using the 3D structure of BacA and molecular dynamics snapshots to account for the flexibility of the protein. Of 83 compounds computationally selected and tested in a biochemical assay, one sulfamoylthiophene molecule showed significant inhibition of the undecaprenyl pyrophosphate dephosphorylation activity catalyzed by BacA. Subsequently, an additional 33 scaffold analogs were selected and acquired, of which 6 compounds exhibited BacA inhibition. The IC50 values of these compounds ranged from 42 to 366 μM. In addition, significant antibacterial activity against Escherichia coli was observed in TolC/PAP2-depleted strains. We believe that the overall strategy followed in this study and the identified class of inhibitors provide a solid foundation for the further development of potent BacA-targeted inhibitors and the discovery of novel antibacterial compounds.

Professional publishing and Lithuanian books in the first two-thirds of the 19th century in Lithuania: The case of the Zawadzki firm

Successfully profiting from textbook publishing as the typographer at Vilnius University, Józef Zawadzki (1781‒1838) established one of the most important and most successful book publishing, production, and distribution companies of the 19th and the first half of the 20th century in the territories of former Polish-Lithuanian Commonwealt. The Zawadzki firm represented the new category of professional publishers. Over the first seventy years of the firm’s existence at the firm’s expense were published 122 Lithuanian books, as well as printed about 50 Lithuanian publications at their authors finances. The attitude of the members of Zawadzki family regarding the publishing of Lithuanian books essentially changed. While the Józef Zawadzki was indifferent towards them, in the middle of the 19th century Adam Zawadzki (1814‒1875) outcompeted other professional book publishers and distributors, and monopolized the publishing of Lithuanian books in the Samogitian Diocese, becoming not only the most important publisher of Lithuanian books, but also their printer and distributor. The successful realization of Adam Zawadzki’s business plans was partly due to his longstanding contacts with the most active figures of Lithuanian written culture, with whom he maintained a new form of cooperation based on authorial royalties, partly due effectively distribution of published matter, using first stationary bookstore in the periphery, located in the west of Lithuania (which served as a retail and wholesale trade enterprise), various ways of non-stationary book trade, services of a commercial library and advertising. Owing to Adam’s efforts, the Zawadzki firm made a significant contribution uniting main forces of authors and publishers of Lithuanian books in 19th century Lithuania, renewing the repertoire of Lithuanian books, as well as giving Lithuanian book publishing, production and distribution features characteristic for a modern business. A model of dealing with censorship through illegal publishing, developed with the publication Apej brostwą błaiwistes arba nusiturieima, was used throughout all the forty years of the press ban and helped raising several generations of literate Lithuanians and bringing Lithuania and Lithuania Minor closer together.

Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.

Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/β-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.

μATR-FTIR Spectral Libraries of Plastic Particles (FLOPP and FLOPP-e) for the Analysis of Microplastics

Raman spectral libraries specific to microplastics demonstrated improved spectral matching results when weathered plastics and a variety of particle colors and morphologies were included. Here, we explore if this is true for Fourier transform infrared (FTIR) spectroscopy as well. We present two novel databases specific to microplastics using attenuated total reflection (μATR-FTIR): (1) an FTIR library of plastic particles (FLOPP), containing 186 spectra from common plastic items, across 14 polymer types and (2) an FTIR library of plastic particles sourced from the environment (FLOPP-e), containing 195 spectra across 15 polymer types. Both libraries include particles from a variety of sources, morphologies, and colors. We demonstrate the applicability of these libraries for microplastics research by comparing spectral match results from two microplastic datasets. For this, we use different combinations of libraries including: commercially available reference libraries, an open-access polymer library, and FLOPP and FLOPP-e. Among tests, the greatest mean HQI result was achieved when the greatest number of libraries was included. This work demonstrates that spectral libraries specific to plastic particles found in the environment improve the accuracy of spectral matching and are best used in combination with commercial libraries containing chemical components that are commonly found within plastics and other anthropogenic particles. Multivariate principal component analyses of FLOPP and FLOPP-e spectra confirmed differences among polymer types and higher variation in principal component scores among weathered particles, but no patterns were observed among particle colors or morphologies. These results demonstrate that ATR-FTIR analyses are sensitive to weathering of plastics but not to particle color and morphology.

Efficient Exploration of Chemical Space with Docking and Deep Learning.

With the advent of make-on-demand commercial libraries, the number of purchasable compounds available for virtual screening and assay has grown explosively in recent years, with several libraries eclipsing one billion compounds. Today's screening libraries are larger and more diverse, enabling the discovery of more-potent hit compounds and unlocking new areas of chemical space, represented by new core scaffolds. Applying physics-based in silico screening methods in an exhaustive manner, where every molecule in the library must be enumerated and evaluated independently, is increasingly cost-prohibitive. Here, we introduce a protocol for machine learning-enhanced molecular docking based on active learning to dramatically increase throughput over traditional docking. We leverage a novel selection protocol that strikes a balance between two objectives: (1) identifying the best scoring compounds and (2) exploring a large region of chemical space, demonstrating superior performance compared to a purely greedy approach. Together with automated redocking of the top compounds, this method captures almost all the high scoring scaffolds in the library found by exhaustive docking. This protocol is applied to our recent virtual screening campaigns against the D4 and AMPC targets that produced dozens of highly potent, novel inhibitors, and a blind test against the MT1 target. Our protocol recovers more than 80% of the experimentally confirmed hits with a 14-fold reduction in compute cost, and more than 90% of the hit scaffolds in the top 5% of model predictions, preserving the diversity of the experimentally confirmed hit compounds.

Kaempferol 3-O-gentiobioside, an ALK5 inhibitor, affects the proliferation, migration, and invasion of tumor cells via blockade of the TGF-β/ALK5/Smad signaling pathway.

Overactivation of TGF-β/ALK5/Smad signaling pathway has been observed in the advanced stage of various human malignancies. As a key component of TGF-β/ALK5/Smad signaling pathway transduction, TGF-β type I receptor (also known as ALK5) has emerged as a promising therapeutic target for cancer treatment. In this study, to discover a novel ALK5 inhibitor, a commercial natural products library was screened using docking-based virtual screening, followed by luciferase reporter assay. A flavonoid glycoside kaempferol 3-O-gentiobioside (KPF 3-O-G) was identified as a potent ALK5 inhibitor through directly bound to the ATP-site of ALK5, resulting in the inhibitory effects on phosphorylation and translocation of Smad2 and expression of Smad4. Additionally, we found that KPF 3-O-G reduced cell proliferation and inhibited TGF-β-induced cell migration and invasion. Moreover, western blotting and immunofluorescent analysis showed that KPF 3-O-G significantly reversed the TGF-β-induced EMT biomarkers, including upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and snail. In vivo study showed that KPF 3-O-G administration reduced tumor growth in human ovarian cancer xenograft mouse model, without obvious toxic effect. This study provided novel insight into the anticancer effects of KPF-3-O-G and indicated that KPF-3-O-G might be developed as potential therapeutics for cancer treatment after further validation.

Research on image classification algorithm based on depth residuals shrinkage network in Commercial Image Library

With the advent of the age of multimedia technology and image data, commercial image library services have emerged. We need to use image classification to parse into content that the computer can understand. But when recognizing image features for classification, image data will inevitably produce noise, so in order to make image classification more accurate, we need to remove information that is irrelevant to noise. The Deep Residual Shrinkage Network (DRSN) proposed in this paper can effectively denoise images, and then learn features to classify images. The Deep Residual Shrinkage Network (DRSN) combines the Deep Residual Network (ResNet) and the SENet commonly used in the attention mechanism, and adds a soft threshold function to it. The image data set used in this experiment was downloaded from Panorama Network and Baidu Pictures and then processed. In the experiment, noise was first manually added to the data set, and the deep residual network and the deep residual shrinkage network were used for comparison experiments. It is concluded through experiments that the improved DRSN network has higher accuracy when applied to image classification.

Development of an Accurate Mass Retention Time Database for Untargeted Metabolomic Analysis and Its Application to Plasma and Urine Pediatric Samples.

Liquid-chromatography coupled to high resolution mass spectrometry (LC-HRMS) is currently the method of choice for untargeted metabolomic analysis. The availability of established protocols to achieve a high confidence identification of metabolites is crucial. The aim of this work is to describe the workflow that we have applied to build an Accurate Mass Retention Time (AMRT) database using a commercial metabolite library of standards. LC-HRMS analysis was carried out using a Vanquish Horizon UHPLC system coupled to a Q-Exactive Plus Hybrid Quadrupole-Orbitrap Mass Spectrometer (Thermo Fisher Scientific, Milan, Italy). The fragmentation spectra, obtained with 12 collision energies, were acquired for each metabolite, in both polarities, through flow injection analysis. Several chromatographic conditions were tested to obtain a protocol that yielded stable retention times. The adopted chromatographic protocol included a gradient separation using a reversed phase (Waters Acquity BEH C18) and a HILIC (Waters Acquity BEH Amide) column. An AMRT database of 518 compounds was obtained and tested on real plasma and urine samples analyzed in data-dependent acquisition mode. Our AMRT library allowed a level 1 identification, according to the Metabolomics Standards Initiative, of 132 and 124 metabolites in human pediatric plasma and urine samples, respectively. This library represents a starting point for future metabolomic studies in pediatric settings.

William Edward Daniel Ross’s Transformation into a Popular Fiction Novelist, 1962-1967

William Edward Daniel Ross transformed himself into a popular fiction novelist in mid-life; the years between 1962 and 1967 witnessing his authorial advance from apprentice to journeyman. During this period, he produced at least 85 original novels, which appeared in the United States or the United Kingdom in hardback, paperback, or digest format. By 1966, Ross’s rapid production identified him as a “literary factory” within the trade. As a “professional writer,” he responded to the market needs of publishers, which led him to produce novels in multiple genres, including mysteries, westerns, nurse romances, and gothics. The majority of his novels appeared under pseudonyms, most of them feminine; as Ross recognised, this circumstance obscured his claims to authorship, leading to his early designation as “Canada’s best-known unknown author.” &amp;nbsp;&amp;nbsp; A substantial collection of Ross’s professional papers held at Boston University represents an invaluable resource into this author’s early years as a novelist, and into the trans-Atlantic popular fiction market for which he wrote. In combination with newspaper and magazine articles episodically published about him, this resource reveals an author who, between 1962 and 1967, established himself with publishers as a reliable creator of popular fiction. Ross brokered key business relationships with several hardback publishers producing popular fiction for the commercial lending libraries, as well as half a dozen paperback firms. Ross’s remarkable level of production relied on key “support personnel”: his wife Marilyn Ross facilitated his writing daily while New York-based literary agents Robert Mills and Donald MacCampbell offered strategic guidance.