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Discovery, development, and future application of senolytics: theories and predictions.

ABSTRACT: Senescent cells accumulate with aging and at etiological sites of multiple diseases, including those accounting for most morbidity, mortality, and health costs. Senescent cells do not replicate, can release factors that cause tissue dysfunction, and yet remain viable. The discovery of senolytic drugs, agents that selectively eliminate senescent cells, created a new route for alleviating age-related dysfunction and diseases. As anticipated for agents targeting fundamental aging mechanisms that are 'root cause' contributors to multiple disorders, potential applications of senolytics are protean. We review the discovery of senolytics, strategies for translation into clinical application, and promising early signals from clinical trials.

SUBMITTER: Wissler Gerdes EO

PROVIDER: S-EPMC7302972 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Recent advances in the discovery of senolytics.

Project description:The demonstration in model organisms that cellular senescence drives aging and age-related diseases has led to widespread efforts to identify compounds able to selectively kill senescent cells, termed senolytics. Approaches used to identify senolytics include bioinformatic analysis of senescent cell anti-apoptotic pathways (SCAPs) for drug development and screening of drugs libraries on different senescent cell types in culture. Alternatively, cytotoxic compounds can be made specific to senescent cells through a prodrug strategy such as linking the compound to a galactose moiety where toxicity is activated by lysosomal β-galactosidase. Identified senolytics can then be optimized through medicinal chemistry or linking to E3 targeting moieties to facilitate proteolysis of their targets. This review will provide an overview of approaches to identify senolytics and an update of the classes of senolytics identified to date.

| S-EPMC8687661 | biostudies-literature

The evolution of genomic imprinting: theories, predictions and empirical tests.

Project description:The epigenetic phenomenon of genomic imprinting has motivated the development of numerous theories for its evolutionary origins and genomic distribution. In this review, we examine the three theories that have best withstood theoretical and empirical scrutiny. These are: Haig and colleagues' kinship theory; Day and Bonduriansky's sexual antagonism theory; and Wolf and Hager's maternal-offspring coadaptation theory. These theories have fundamentally different perspectives on the adaptive significance of imprinting. The kinship theory views imprinting as a mechanism to change gene dosage, with imprinting evolving because of the differential effect that gene dosage has on the fitness of matrilineal and patrilineal relatives. The sexual antagonism and maternal-offspring coadaptation theories view genomic imprinting as a mechanism to modify the resemblance of an individual to its two parents, with imprinting evolving to increase the probability of expressing the fitter of the two alleles at a locus. In an effort to stimulate further empirical work on the topic, we carefully detail the logic and assumptions of all three theories, clarify the specific predictions of each and suggest tests to discriminate between these alternative theories for why particular genes are imprinted.

| S-EPMC4105453 | biostudies-other

The Parenthood and Happiness Link: Testing Predictions from Five Theories.

Project description:This research studied the relationship between parenthood and life satisfaction in Switzerland. We tested predictions derived from set-point theory, the economic model of parenthood, the approaches that underscore work-family conflict and the psychological rewards from parenthood, and the 'taste for children' theory. We used Swiss Household Panel data (2000-2018) to analyse how life satisfaction changed during parenthood (fixed-effects regression) separately for a first child and a second child, mothers and fathers, and various socio-demographic groups. Our results showed that having a second child, which is common in Switzerland, correlates negatively with mothers' life satisfaction. The observed patterns are consistent with the idea that mothers' life satisfaction trajectories reflect work-family conflict. We found partial support for the set-point and the 'taste for children' theories. Our results did not support the approaches that emphasize the importance of psychological rewards from parenthood.

| S-EPMC7113361 | biostudies-literature

Testing formal predictions of neuroscientific theories of ADHD with a cognitive model-based approach.

Project description:Neuroscientific theories of attention-deficit/hyperactivity disorder (ADHD) alternately posit that cognitive aberrations in the disorder are due to acute attentional lapses, slowed neural processing, or reduced signal-to-noise ratios. However, they make similar predictions about behavioral summary statistics (response times [RTs] and accuracy), hindering the field's ability to produce strong and specific tests of these theories. The current study uses the linear ballistic accumulator (LBA; Brown & Heathcote, 2008), a mathematical model of choice RT tasks, to distinguish between competing theory predictions. Children with ADHD (n = 80) and age-matched controls (n = 32) completed a numerosity discrimination paradigm at 2 levels of difficulty, and RT data were fit to the LBA model to test theoretical predictions. Individuals with ADHD displayed slowed processing of evidence for correct responses (signal) relative to their peers but comparable processing of evidence for error responses (noise) and between-trial variability in processing (performance lapses). The findings are inconsistent with accounts that posit an increased incidence of attentional lapses in the disorder and provide partial support for those that posit slowed neural processing and lower signal-to-noise ratios. Results also highlight the utility of well-developed cognitive models for distinguishing between the predictions of etiological theories of psychopathology. (PsycINFO Database Record

| S-EPMC6091877 | biostudies-literature

Benchmarking AlphaFold-enabled molecular docking predictions for antibiotic discovery

Project description: Not available

| S-BSST863 | biostudies-other

Development of a protein-ligand extended connectivity (PLEC) fingerprint and its application for binding affinity predictions.

Project description:MotivationFingerprints (FPs) are the most common small molecule representation in cheminformatics. There are a wide variety of FPs, and the Extended Connectivity Fingerprint (ECFP) is one of the best-suited for general applications. Despite the overall FP abundance, only a few FPs represent the 3D structure of the molecule, and hardly any encode protein-ligand interactions.ResultsHere, we present a Protein-Ligand Extended Connectivity (PLEC) FP that implicitly encodes protein-ligand interactions by pairing the ECFP environments from the ligand and the protein. PLEC FPs were used to construct different machine learning models tailored for predicting protein-ligand affinities (pKi∕d). Even the simplest linear model built on the PLEC FP achieved Rp = 0.817 on the Protein Databank (PDB) bind v2016 'core set', demonstrating its descriptive power.Availability and implementationThe PLEC FP has been implemented in the Open Drug Discovery Toolkit (https://github.com/oddt/oddt).Supplementary informationSupplementary data are available at Bioinformatics online.

| S-EPMC6477977 | biostudies-literature

Evaluating the Lettuce Metatranscriptome with MinION Sequencing for Future Spaceflight Food Production Application.

Project description:Healthy plants are vital for successful, long-duration missions in space, as they provide the crew with life support, food production, and psychological benefits. The microorganisms that associate with plant tissues play a critical role in improving plant growth, health, and production. To that end, it is necessary to develop methodologies that investigate the metabolic activities of the plant’s microbiome in orbit to enable rapid responses regarding the care of plants in space. In this study, we developed a protocol to characterize the endophytic and epiphytic microbial metatranscriptome of red romaine lettuce, a key salad crop that was grown under International Space Station (ISS)-like conditions. Microbial transcripts enriched from host-microbe total RNA were sequenced using the Oxford Nanopore MinION sequencing platform. Results showed that this enrichment approach was highly reproducible and effective for rapid on-site detection of microbial transcriptional activity. Taxonomic analysis based on 16S and 18S rRNA transcripts identified that the top five most abundant phyla in the lettuce microbiome were Firmicutes, Proteobacteria, Actinobacteria, Bacteroidetes, and Ascomycota. The metatranscriptomic analysis identified the expression of genes involved in many metabolic pathways, including carbohydrate metabolism, energy metabolism, and signal transduction. Network analyses of the expression data show that, within the signal transduction pathway of the fungal community, the Mitogen-Activated Protein Kinase signaling pathway was tightly regulated across all samples and could be a potential driver for fungal proliferation. Our results demonstrated the feasibility of using MinION-based metatranscriptomics of enriched microbial RNA as a method for rapid, on-site monitoring of the transcriptional activity of crop microbiomes, thereby helping to facilitate and maintain plant health for on-orbit space food production.

2021-06-20 | GSE152914 | GEO

Application of Q2MM to predictions in stereoselective synthesis.

Project description:Quantum-Guided Molecular Mechanics (Q2MM) can be used to derive transition state force fields (TSFFs) that allow the fast and accurate predictions of stereoselectivity for a wide range of catalytic enantioselective reactions. The basic ideas behind the derivation of TSFFs using Q2MM are discussed and the steps involved in obtaining a TSFF using the Q2MM code, publically available at github.com/q2mm, are shown. The applicability for a range of reactions, including several non-standard applications of Q2MM, is demonstrated. Future developments of the method are also discussed.

| S-EPMC6069518 | biostudies-literature

Creepy cats and strange high houses: Support for configural processing in testing predictions of nine uncanny valley theories.

Project description:In 1970, Masahiro Mori proposed the uncanny valley (UV), a region in a human-likeness continuum where an entity risks eliciting a cold, eerie, repellent feeling. Recent studies have shown that this feeling can be elicited by entities modeled not only on humans but also nonhuman animals. The perceptual and cognitive mechanisms underlying the UV effect are not well understood, although many theories have been proposed to explain them. To test the predictions of nine classes of theories, a within-subjects experiment was conducted with 136 participants. The theories' predictions were compared with ratings of 10 classes of stimuli on eeriness and coldness indices. One type of theory, configural processing, predicted eight out of nine significant effects. Atypicality, in its extended form, in which the uncanny valley effect is amplified by the stimulus appearing more human, also predicted eight. Threat avoidance predicted seven; atypicality, perceptual mismatch, and mismatch+ predicted six; category+, novelty avoidance, mate selection, and psychopathy avoidance predicted five; and category uncertainty predicted three. Empathy's main prediction was not supported. Given that the number of significant effects predicted depends partly on our choice of hypotheses, a detailed consideration of each result is advised. We do, however, note the methodological value of examining many competing theories in the same experiment.

| S-EPMC8024776 | biostudies-literature

Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation.

Project description:This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.

| S-EPMC4809625 | biostudies-literature

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