scholarly journals A novel approach for selecting potent peptide inhibitors of the SARS-CoV2-Mpro protease

2021 ◽  
Author(s):  
Alexander Pisarchik
Keyword(s):  
High Throughput ◽  
Peptide Library ◽  
Peptide Inhibitors ◽  
Carrier Protein ◽  
Selective Inhibitors ◽  
Cytotoxic Protein ◽  
Novel Approach ◽  
Wide Range ◽  
Protein Selection

Abstract Here, we describe a new high throughput selection technology for identifying exceedingly specific and effective peptide inhibitors. This technology incorporates the co-expression of a cytotoxic protein and a library of peptide variants inserted directly into a loop of a carrier protein. Selection is based on the cytotoxicity neutralization by a member of a peptide library binding to and inhibiting the cytotoxic protein. Our technology provides the flexibility of screening both cyclic and linear peptides. Herein, we demonstrate the power of this technology by developing selective inhibitors of the main coronavirus protease (Mpro) in a matter of weeks by screening libraries of cyclic and linear peptides. This technology opens up an opportunity to develop inhibitors for a wide range of previously undruggable targets.

Isoform-Selective PI3K Inhibitors for Various Diseases

2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina
Keyword(s):  
Intracellular Signaling ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Type I ◽  
Selective Inhibitors ◽  
Pi3k Inhibitors ◽  
Wide Range ◽  
Lipid Kinases ◽  
Isoform Selectivity

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.

scholarly journals Responsive and Personalized Web Layouts with Integer Programming

2021 ◽  
Vol 5 (EICS) ◽  
pp. 1-23
Author(s):  
Markku Laine ◽  
Yu Zhang ◽  
Simo Santala ◽  
Jussi P. P. Jokinen ◽  
Antti Oulasvirta
Keyword(s):  
Integer Programming ◽  
Web Design ◽  
Web Pages ◽  
Web Page Design ◽  
Automated Generation ◽  
Novel Approach ◽  
Wide Range ◽  
Responsive Design ◽  
Responsive Web Design ◽  
Page Design

Over the past decade, responsive web design (RWD) has become the de facto standard for adapting web pages to a wide range of devices used for browsing. While RWD has improved the usability of web pages, it is not without drawbacks and limitations: designers and developers must manually design the web layouts for multiple screen sizes and implement associated adaptation rules, and its "one responsive design fits all" approach lacks support for personalization. This paper presents a novel approach for automated generation of responsive and personalized web layouts. Given an existing web page design and preferences related to design objectives, our integer programming -based optimizer generates a consistent set of web designs. Where relevant data is available, these can be further automatically personalized for the user and browsing device. The paper includes presentation of techniques for runtime adaptation of the designs generated into a fully responsive grid layout for web browsing. Results from our ratings-based online studies with end users (N = 86) and designers (N = 64) show that the proposed approach can automatically create high-quality responsive web layouts for a variety of real-world websites.

scholarly journals From Multiplex Serology to Serolomics—A Novel Approach to the Antibody Response against the SARS-CoV-2 Proteome

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 749
Author(s):  
Julia Butt ◽  
Rajagopal Murugan ◽  
Theresa Hippchen ◽  
Sylvia Olberg ◽  
Monique van Straaten ◽  
...  
Keyword(s):  
Antibody Response ◽  
High Throughput ◽  
Large Population ◽  
High Sensitivity ◽  
Population Based ◽  
Antibody Responses ◽  
Hek293 Cells ◽  
Novel Approach ◽  
Assay Performance ◽  
Multiplex Serology

The emerging SARS-CoV-2 pandemic entails an urgent need for specific and sensitive high-throughput serological assays to assess SARS-CoV-2 epidemiology. We, therefore, aimed at developing a fluorescent-bead based SARS-CoV-2 multiplex serology assay for detection of antibody responses to the SARS-CoV-2 proteome. Proteins of the SARS-CoV-2 proteome and protein N of SARS-CoV-1 and common cold Coronaviruses (ccCoVs) were recombinantly expressed in E. coli or HEK293 cells. Assay performance was assessed in a COVID-19 case cohort (n = 48 hospitalized patients from Heidelberg) as well as n = 85 age- and sex-matched pre-pandemic controls from the ESTHER study. Assay validation included comparison with home-made immunofluorescence and commercial enzyme-linked immunosorbent (ELISA) assays. A sensitivity of 100% (95% CI: 86–100%) was achieved in COVID-19 patients 14 days post symptom onset with dual sero-positivity to SARS-CoV-2 N and the receptor-binding domain of the spike protein. The specificity obtained with this algorithm was 100% (95% CI: 96–100%). Antibody responses to ccCoVs N were abundantly high and did not correlate with those to SARS-CoV-2 N. Inclusion of additional SARS-CoV-2 proteins as well as separate assessment of immunoglobulin (Ig) classes M, A, and G allowed for explorative analyses regarding disease progression and course of antibody response. This newly developed SARS-CoV-2 multiplex serology assay achieved high sensitivity and specificity to determine SARS-CoV-2 sero-positivity. Its high throughput ability allows epidemiologic SARS-CoV-2 research in large population-based studies. Inclusion of additional pathogens into the panel as well as separate assessment of Ig isotypes will furthermore allow addressing research questions beyond SARS-CoV-2 sero-prevalence.

scholarly journals Density Guarantee on Finding Multiple Subgraphs and Subtensors

2021 ◽  
Vol 15 (5) ◽  
pp. 1-32
Author(s):  
Quang-huy Duong ◽  
Heri Ramampiaro ◽  
Kjetil Nørvåg ◽  
Thu-lan Dam
Keyword(s):  
Lower Bound ◽  
State Of The Art ◽  
The State ◽  
The Other ◽  
Exact Methods ◽  
Practical Solution ◽  
Novel Approach ◽  
Wide Range ◽  
Real World Datasets ◽  
Tensor Data

Dense subregion (subgraph & subtensor) detection is a well-studied area, with a wide range of applications, and numerous efficient approaches and algorithms have been proposed. Approximation approaches are commonly used for detecting dense subregions due to the complexity of the exact methods. Existing algorithms are generally efficient for dense subtensor and subgraph detection, and can perform well in many applications. However, most of the existing works utilize the state-or-the-art greedy 2-approximation algorithm to capably provide solutions with a loose theoretical density guarantee. The main drawback of most of these algorithms is that they can estimate only one subtensor, or subgraph, at a time, with a low guarantee on its density. While some methods can, on the other hand, estimate multiple subtensors, they can give a guarantee on the density with respect to the input tensor for the first estimated subsensor only. We address these drawbacks by providing both theoretical and practical solution for estimating multiple dense subtensors in tensor data and giving a higher lower bound of the density. In particular, we guarantee and prove a higher bound of the lower-bound density of the estimated subgraph and subtensors. We also propose a novel approach to show that there are multiple dense subtensors with a guarantee on its density that is greater than the lower bound used in the state-of-the-art algorithms. We evaluate our approach with extensive experiments on several real-world datasets, which demonstrates its efficiency and feasibility.

scholarly journals Integrated impedance sensing of liquid sample plug flow enables automated high throughput NMR spectroscopy

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Omar Nassar ◽  
Mazin Jouda ◽  
Michael Rapp ◽  
Dario Mager ◽  
Jan G. Korvink ◽  
...  
Keyword(s):  
Nmr Spectroscopy ◽  
High Throughput ◽  
Plug Flow ◽  
Microfluidic System ◽  
High Resolution Spectroscopy ◽  
Dead Volume ◽  
Absolute Difference ◽  
Immiscible Fluid ◽  
Flow Sensors ◽  
Novel Approach

AbstractA novel approach for automated high throughput NMR spectroscopy with improved mass-sensitivity is accomplished by integrating microfluidic technologies and micro-NMR resonators. A flow system is utilized to transport a sample of interest from outside the NMR magnet through the NMR detector, circumventing the relatively vast dead volume in the supplying tube by loading a series of individual sample plugs separated by an immiscible fluid. This dual-phase flow demands a real-time robust sensing system to track the sample position and velocities and synchronize the NMR acquisition. In this contribution, we describe an NMR probe head that possesses a microfluidic system featuring: (i) a micro saddle coil for NMR spectroscopy and (ii) a pair of interdigitated capacitive sensors flanking the NMR detector for continuous position and velocity monitoring of the plugs with respect to the NMR detector. The system was successfully tested for automating flow-based measurement in a 500 MHz NMR system, enabling high resolution spectroscopy and NMR sensitivity of 2.18 nmol s1/2 with the flow sensors in operation. The flow sensors featured sensitivity to an absolute difference of 0.2 in relative permittivity, enabling distinction between most common solvents. It was demonstrated that a fully automated NMR measurement of nine individual 120 μL samples could be done within 3.6 min or effectively 15.3 s per sample.

scholarly journals An Advanced Educational Tool for Digital Forensic Engineering

2016 ◽  
Vol 11 (03) ◽  
pp. 15 ◽  
Author(s):  
Primož Cigoj ◽  
Borka Jerman Blažič
Keyword(s):  
Digital Forensics ◽  
Real Life ◽  
University Education ◽  
Educational Tool ◽  
Digital Tool ◽  
College And University ◽  
Novel Approach ◽  
Wide Range ◽  
E Learning ◽  
Forensic Engineering

This paper presents a novel approach to education in the area of digital forensics based on a multi-platform cloud-computer infrastructure and an innovative computer based tool. The tool is installed and available through the cloud-based infrastructure of the Dynamic Forensic Education Alliance. Cloud computing provides an efficient mechanism for a wide range of services that offer real-life environments for teaching and training cybersecurity and digital forensics. The cloud-based infrastructure, the virtualized environment and the developed educational tool enable the construction of a dynamic e-learning environment making the training very close to reality and to real-life situations. The paper presents the Dynamic Forensic Digital tool named EduFors and describes the different levels of college and university education where the tool is introduced and used in the training of future investigators of cybercrime events.

scholarly journals A novel approach for rapid high-throughput selection of recombinant functional rat monoclonal antibodies

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Qin Chen ◽  
Shengping Qiu ◽  
Huanhuan Li ◽  
Chaolong Lin ◽  
Yong Luo ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
High Throughput ◽  
Novel Approach ◽  
Selection Of
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