scholarly journals Hijacking Transposable Elements for Saturation Mutagenesis in Fungi

2021 ◽  
Vol 2 ◽  
Author(s):  
Sanne Schrevens ◽  
Dominique Sanglard
Keyword(s):  
Transposable Elements ◽  
Target Identification ◽  
Molecular Genetic ◽  
Fungal Species ◽  
Saturation Mutagenesis ◽  
Transposon Insertion ◽  
Drug Target Identification ◽  
Recent Developments ◽  
Compensatory Mutations ◽  
Almost All

Transposable elements are present in almost all known genomes, these endogenous transposons have recently been referred to as the mobilome. They are now increasingly used in research in order to make extensive mutant libraries in different organisms. Fungi are an essential part of our lives on earth, they influence the availability of our food and they live inside our own bodies both as commensals and pathogenic organisms. Only few fungal species have been studied extensively, mainly due to the lack of appropriate molecular genetic tools. The use of transposon insertion libraries can however help to rapidly advance our knowledge of (conditional) essential genes, compensatory mutations and drug target identification in fungi. Here we give an overview of some recent developments in the use of different transposons for saturation mutagenesis in different fungi.

Drug Target Identification in Tissues by Thermal Proteome Profiling

2021 ◽  
Vol 62 (1) ◽  
Author(s):  
André Mateus ◽  
Nils Kurzawa ◽  
Jessica Perrin ◽  
Giovanna Bergamini ◽  
Mikhail M. Savitski
Keyword(s):  
Drug Target ◽  
Target Identification ◽  
Annual Review ◽  
Publication Date ◽  
Proteome Profiling ◽  
Biological Phenomena ◽  
Target Deconvolution ◽  
Drug Target Identification ◽  
Recent Developments ◽  
Fundamental Biology

Drug target deconvolution can accelerate the drug discovery process by identifying a drug's targets (facilitating medicinal chemistry efforts) and off-targets (anticipating toxicity effects or adverse drug reactions). Multiple mass spectrometry–based approaches have been developed for this purpose, but thermal proteome profiling (TPP) remains to date the only one that does not require compound modification and can be used to identify intracellular targets in living cells. TPP is based on the principle that the thermal stability of a protein can be affected by its interactions. Recent developments of this approach have expanded its applications beyond drugs and cell cultures to studying protein-drug interactions and biological phenomena in tissues. These developments open up the possibility of studying drug treatment or mechanisms of disease in a holistic fashion, which can result in the design of better drugs and lead to a better understanding of fundamental biology. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Development of a target identification approach using native mass spectrometry

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Miaomiao Liu ◽  
Wesley C. Van Voorhis ◽  
Ronald J. Quinn
Keyword(s):  
Mass Spectrometry ◽  
Protein Interactions ◽  
Target Identification ◽  
Native Mass Spectrometry ◽  
Pharmaceutical Drugs ◽  
Ligand Complex ◽  
Experimental Conditions ◽  
Protein Mixture ◽  
Native Ms ◽  
Drug Target Identification

AbstractA key step in the development of new pharmaceutical drugs is the identification of the molecular target and distinguishing this from all other gene products that respond indirectly to the drug. Target identification remains a crucial process and a current bottleneck for advancing hits through the discovery pipeline. Here we report a method, that takes advantage of the specific detection of protein–ligand complexes by native mass spectrometry (MS) to probe the protein partner of a ligand in an untargeted method. The key advantage is that it uses unmodified small molecules for binding and, thereby, it does not require labelled ligands and is not limited by the chemistry required to tag the molecule. We demonstrate the use of native MS to identify known ligand–protein interactions in a protein mixture under various experimental conditions. A protein–ligand complex was successfully detected between parthenolide and thioredoxin (PfTrx) in a five-protein mixture, as well as when parthenolide was mixed in a bacterial cell lysate spiked with PfTrx. We provide preliminary data that native MS could be used to identify binding targets for any small molecule.

scholarly journals Recent Developments in Diagnosis and Care for Girls in Turner Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Carolyn Bondy
Keyword(s):  
Turner Syndrome ◽  
Brain Size ◽  
Molecular Genetic ◽  
Oocyte Donation ◽  
Breath Holding ◽  
Chromosomal Anomalies ◽  
The Past ◽  
Molecular Tests ◽  
Effective Counseling ◽  
Recent Developments

The past decade produced important advances in molecular genetic techniques potentially supplanting the traditional cytogenetic diagnosis of Turner syndrome (TS). Rapidly evolving genomic technology is used to screen 1st trimester pregnancies for sex chromosomal anomalies including TS, and genomic approaches are suggested for the postnatal diagnosis of TS. Understanding the interpretation and limitations of new molecular tests is essential for clinicians to provide effective counseling to parents or patients impacted by these tests. Recent studies have advanced the concept that X chromosome genomic imprinting influences expression of the Turner phenotype and contributes to gender differences in brain size and coronary disease. Progress in cardiovascular MRI over the past decade has dramatically changed our view of the scope and criticality of congenital heart disease in TS. Cardiac MRI is far more effective than transthoracic echocardiography in detecting aortic valve abnormalities, descending aortic aneurysm, and partial anomalous pulmonary venous return; recent technical advances allow adequate imaging in girls as young as seven without breath holding or sedation. Finally, important developments in the area of gynecological management of girls and young women with TS are reviewed, including prognostic factors that predict spontaneous puberty and potential fertility and recent practice guidelines aimed at reducing cardiovascular risk for oocyte donation pregnancies in TS.

scholarly journals Drug Target Identification with Machine Learning: How to Choose Negative Examples

2021 ◽  
Vol 22 (10) ◽  
pp. 5118
Author(s):  
Matthieu Najm ◽  
Chloé-Agathe Azencott ◽  
Benoit Playe ◽  
Véronique Stoven
Keyword(s):  
Machine Learning ◽  
Drug Target ◽  
Target Identification ◽  
Target Prediction ◽  
False Positives ◽  
Machine Learning Algorithms ◽  
Statistical Bias ◽  
Protein Targets ◽  
Drug Target Identification ◽  
Approved Drugs

Identification of the protein targets of hit molecules is essential in the drug discovery process. Target prediction with machine learning algorithms can help accelerate this search, limiting the number of required experiments. However, Drug-Target Interactions databases used for training present high statistical bias, leading to a high number of false positives, thus increasing time and cost of experimental validation campaigns. To minimize the number of false positives among predicted targets, we propose a new scheme for choosing negative examples, so that each protein and each drug appears an equal number of times in positive and negative examples. We artificially reproduce the process of target identification for three specific drugs, and more globally for 200 approved drugs. For the detailed three drug examples, and for the larger set of 200 drugs, training with the proposed scheme for the choice of negative examples improved target prediction results: the average number of false positives among the top ranked predicted targets decreased, and overall, the rank of the true targets was improved.Our method corrects databases’ statistical bias and reduces the number of false positive predictions, and therefore the number of useless experiments potentially undertaken.

scholarly journals Microbiological analysis of commonly used toothpaste samples in Bangladesh

2019 ◽  
Vol 8 (1) ◽  
pp. 38-40
Author(s):  
Mousumi Talukder ◽  
Ifra Tun Nur
Keyword(s):  
Microbiological Quality ◽  
Enteric Bacteria ◽  
Fungal Species ◽  
Microbiological Analysis ◽  
Bacillus Spp ◽  
Viable Bacteria ◽  
Dental Diseases ◽  
Almost All ◽  
Staphylococcus Spp ◽  
Great Public Health

Present study attempted to identify and enumerate microorganisms spoiling commonly used toothpaste samples. Among 7 brand of toothpaste, almost all were found to be rigorously contaminated with total viable bacteria within a range of 103 – 105 cfu/g. Proliferation of fungal species was observed up to 105 cfu/g. Prevalence of Staphylococcus spp., Pseudomonas spp. and Bacillus spp. was observed within a range of 103-105 cfu/g while Vibrio spp. were completely absent. Among the enteric bacteria, Escherichia coli and Klebsiella spp. was found in all the samples tested. Such findings highlighted a great public health risk associated with dental diseases among the users and thereby specified the importance to introduce a proper guideline in maintaining good microbiological quality for such daily usage healthcare products. Stamford Journal of Microbiology, Vol.8(1) 2018: 38-40

scholarly journals INTERDISCIPLINARY ART PRACTICES IN INDIA

2016 ◽  
Vol 4 (8) ◽  
pp. 168-175
Author(s):  
Rafi Saba ◽  
Furqan Ahmad
Keyword(s):  
Information Technology ◽  
Science Technology ◽  
Art Practices ◽  
Recent Developments ◽  
Almost All ◽  
Changing World

Today in this fastest changing world of science, technology, inventions and information technology, every field is connected to one another in some way. Science technology and innovations are affecting almost all the facets of life and disciplines of knowledge hence art is not the exception. Today art is not limited to the paint and canvases instead it has different aspects. This study was conducted, referring to the changes in the art practices and examines some recent developments in contemporary Indian Arts. Interdisciplinary means combining, connecting or involving two or more academic, scientific, or artistic disciplines. It represents the fusion of two or more professions, technologies, departments, or the like.

scholarly journals The issue of nosocomial infection caused by Klebsiella pneumoniae blaNDM-type

2020 ◽  
Vol 15 (2) ◽  
pp. 124-133
Author(s):  
Olga Mironenko ◽  
◽  
Victoria Selnitseva ◽  
Lidia Soprun ◽  
Elena Shmushkevich ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Nosocomial Infection ◽  
Molecular Genetic ◽  
Mechanisms Of Resistance ◽  
Infectious Process ◽  
Saint Petersburg ◽  
Microbiological Study ◽  
Wide Range ◽  
Almost All ◽  
Emergence Of Resistance

The article presents information about circulating isolates Klebsiella pneumoniae in a hospital megapolis with properties of hypervirulence and simultaneous multiresistance. The resulting K. pneumonia isolates are of particular importance due to the emergence of resistance to almost all β-lactams due to the presence of carbapenemase metal-β-lactamase. Furthermore, the isolated strains producing carbapenemases possess mechanisms of resistance to a wide range of antimicrobial preparations, and the types of infectious process caused by carbapenemazo-producing enterobacteries are characterized by a high lethality level. Microbiological, biochemical, biophysical, molecular-genetic, biological, bioinformational and statistical methods of research were used in the work. A prospective method was used to identify the source of the infections. In the first stage, a microbiological study was carried out on biomaterials obtained from patients treated in a hospital in Saint Petersburg. After a microbiological study, 52 isolates of K. pneumoniae were obtained, 53.8 % of isolates had a hypermucoid phenotype and 98 % had carbapenemases:blaNDM type — 49 (92 %), blaNDM+OXA-48-like — 3 (8 %). Isolates with two new phenotypes have been isolated (no. 2511 and no. 2512). Isolates of no. 2512 LD50 had 10*2 BAC/ml, and plasmids such as Incfib(Mar), Inchi1b, and Incr were also found, with Incr-A plasmid emitted encoding resistance to fluoroquinolone: aac(6’)-Ib-cr and to β-lactam antibiotics: blaTEM-1B. The described data confirm the opinions of the researchers about the possible formation of a new “super pathogen” — instantaneously hypervirulent and plural resistant strain of K. pneumoniae.

scholarly journals A New Big-Data Paradigm for Target Identification and Drug Discovery

2017 ◽  
Author(s):  
Neel S. Madhukar ◽  
Prashant K. Khade ◽  
Linda Huang ◽  
Kaitlyn Gayvert ◽  
Giuseppe Galletti ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Clinical Application ◽  
Small Molecule ◽  
Target Identification ◽  
Clinical Development ◽  
Data Types ◽  
Public Data ◽  
Drug Target Identification ◽  
Approved Drugs

AbstractDrug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using only public data BANDIT achieved an accuracy of approximately 90% over 2000 different small molecules – substantially better than any other published target identification platform. We applied BANDIT to a library of small molecules with no known targets and generated ∼4,000 novel molecule-target predictions. From this set we identified and experimentally validated a set of novel microtubule inhibitors, including three with activity on cancer cells resistant to clinically used anti-microtubule therapies. We next applied BANDIT to ONC201 – an active anti- cancer small molecule in clinical development – whose target has remained elusive since its discovery in 2009. BANDIT identified dopamine receptor 2 as the unexpected target of ONC201, a prediction that we experimentally validated. Not only does this open the door for clinical trials focused on target-based selection of patient populations, but it also represents a novel way to target GPCRs in cancer. Additionally, BANDIT identified previously undocumented connections between approved drugs with disparate indications, shedding light onto previously unexplained clinical observations and suggesting new uses of marketed drugs. Overall, BANDIT represents an efficient and highly accurate platform that can be used as a resource to accelerate drug discovery and direct the clinical application of small molecule therapeutics with improved precision.

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