Featured
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Article
| Open AccessIdentification of a family of species-selective complex I inhibitors as potential anthelmintics
Soil-transmitted helminths (STHs) are major pathogens. Here the authors screen 480 structural families of natural products to find compounds that kill Caenorhabditis elegans specifically when they require rhodoquinone (RQ)-dependent metabolism: they identify several classes of compounds and show some compounds kill adult STHs.
- Taylor Davie
- , Xènia Serrat
- & Andrew G. Fraser
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Article
| Open AccessA dual diffusion model enables 3D molecule generation and lead optimization based on target pockets
Structure-based generative chemistry is crucial in computer-aided drug discovery. Here, authors propose PMDM, a conditional generative model for 3D molecule generation tailored to specific targets. Extensive experiments demonstrate that PMDM can effectively generate rational bioactive molecules
- Lei Huang
- , Tingyang Xu
- & Hengtong Zhang
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Perspective
| Open AccessCellular reprogramming as a tool to model human aging in a dish
The development of human cellular models of aging that surpass the limitations of animal models of aging is urgent. Here, the authors explore the opportunities and limitations of cellular reprogramming to create reliable aging in vitro models and their potential for the discovery of anti-aging compounds.
- Patricia R. Pitrez
- , Luis M. Monteiro
- & Lino Ferreira
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Article
| Open AccessLearning representations for image-based profiling of perturbations
Assessing cell phenotypes in image-based assays requires solid computational methods for transforming images into quantitative data. Here, the authors present a strategy for learning representations of treatment effects from high-throughput imaging, following a causal interpretation.
- Nikita Moshkov
- , Michael Bornholdt
- & Juan C. Caicedo
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Article
| Open AccessCepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery
Cepharanthine is a secondary metabolite isolated from Stephania with a variety of medicinal properties. Here, the authors assembled three Stephania genomes, propose cepharanthine biosynthetic pathway, and assess the antiviral potential of cepharanthine-related metabolites.
- Liang Leng
- , Zhichao Xu
- & Shilin Chen
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Article
| Open AccessDrug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor
There is a need for effective antiviral drugs against RSV infection. Conducting an RSV repurposing screen using the ReFRAME library Sake et al. identify lonafarnib as an RSV fusion protein inhibitor, characterize its binding site within the viral protein and show its antiviral effects in a mouse model.
- Svenja M. Sake
- , Xiaoyu Zhang
- & Thomas Pietschmann
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Article
| Open AccessDynamicBind: predicting ligand-specific protein-ligand complex structure with a deep equivariant generative model
Proteins often function by changing conformations upon ligand binding. Efficient structural modelling of these interactions, crucial for drug discovery, is limited: here the authors address this with DynamicBind, a diffusion-based deep generative model.
- Wei Lu
- , Jixian Zhang
- & Shuangjia Zheng
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Article
| Open AccessHigh-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
Using an unbiased phenotypic cell-based high-throughput screen, the authors identify and characterize a small molecule, BCH-HSP-C01, that restores aberrant protein trafficking in neuronal models of adapter protein complex 4 deficiency.
- Afshin Saffari
- , Barbara Brechmann
- & Mustafa Sahin
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Article
| Open AccessSelective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines
Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.
- Gisele Nishiguchi
- , Lauren G. Mascibroda
- & Zoran Rankovic
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Article
| Open AccessMultiplexed multicolor antiviral assay amenable for high-throughput research
Antiviral approaches against entire genera or families of viruses need to be constantly developed and innovated. Focusing on several distantly-related orthoflaviviruses, the authors develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once.
- Li-Hsin Li
- , Winston Chiu
- & Kai Dallmeier
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Article
| Open AccessMolecular basis of human trace amine-associated receptor 1 activation
hTA1 is a drug target for several neuropsychiatric disorders. Using cryo-EM and pharmacological assays, the authors illuminate hTA1’s similarity to neurotransmitter receptors and discover that the antipsychotic asenapine potently activates the receptor.
- Gregory Zilberg
- , Alexandra K. Parpounas
- & Daniel Wacker
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Article
| Open AccessMapping combinatorial drug effects to DNA damage response kinase inhibitors
DNA damage is a key component of many cancer therapies. Here, the authors utilised a dose-response combination screen of ATR, ATM and DNA-PK inhibitors, and identified combination treatments that achieves high combinatorial efficacy and synergy.
- Hanrui Zhang
- , Julian Kreis
- & Yuanfang Guan
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Article
| Open AccessComplexEye: a multi-lens array microscope for high-throughput embedded immune cell migration analysis
Video microscopy is key in studying cell migration, but accomplishing this in a high-throughput manner is still challenging. Here, the authors present an array microscope that can track the movements of thousands of individual cells simultaneously, and that can be used for drug screening studies.
- Zülal Cibir
- , Jacqueline Hassel
- & Matthias Gunzer
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Article
| Open AccessHigh-throughput target trial emulation for Alzheimer’s disease drug repurposing with real-world data
Target trial emulation (TTE) simulates randomized controlled trials using real world data (RWD). Here, authors show the effectiveness of different TTE strategies to identify drug candidates that could be potentially repurposed to Alzheimer’s disease using two large scale RWD warehouses.
- Chengxi Zang
- , Hao Zhang
- & Fei Wang
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Article
| Open AccessA naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging
Ameliorating or preventing signatures of aging in humans using natural compounds is an exciting area of research. Here the authors isolate a previously unknown phytochemical from carrots which activates defence mechanisms against oxidative stress and extends lifespan in worms, and improves glucose metabolism, promotes exercise capacity, and protects from frailty at higher age in mice.
- Carolin Thomas
- , Reto Erni
- & Michael Ristow
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Article
| Open AccessDocking for EP4R antagonists active against inflammatory pain
Non-addictive treatments for pain are much needed. Here, the authors identify in vivo active leads for inflammatory pain using large library docking against the EP4 prostaglandin receptor.
- Stefan Gahbauer
- , Chelsea DeLeon
- & Brian K. Shoichet
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Article
| Open AccessA multi-reservoir extruder for time-resolved serial protein crystallography and compound screening at X-ray free-electron lasers
Protein serial crystallography at X-ray free-electron lasers (XFELs) is a powerful technique for structure determination. Here, authors present a device for sample delivery designed to abate challenges to non-specialists allowing for compound screening.
- Maximilian Wranik
- , Michal W. Kepa
- & Jörg Standfuss
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Article
| Open AccessCurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose–response curves
Dose-response curves are ubiquitous in pharmacology and biology, yet potency and effect size are often estimated even when there is no response. Here, authors present a statistical framework to assess curve significance and demonstrate how this aids drug mode of action analysis in large public datasets.
- Florian P. Bayer
- , Manuel Gander
- & Matthew The
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Article
| Open AccessExplainable machine learning for profiling the immunological synapse and functional characterization of therapeutic antibodies
Therapeutic antibodies are crucial in treating severe diseases. Here, the authors introduce scifAI, an open-source explainable AI framework for analyzing imaging flow cytometry data, enabling rapid screening of therapeutic antibody candidates.
- Sayedali Shetab Boushehri
- , Katharina Essig
- & Fabian Schmich
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Article
| Open AccessDiscovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening
Modulation of the myosin molecular motor has emerged as a potential therapeutic target for both heart disease and heart failure. Here, the authors use AI-based virtual high throughput screening to identify compounds that acts as a cardiac-specific myosin modulators.
- Priyanka Parijat
- , Seetharamaiah Attili
- & Thomas Kampourakis
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Article
| Open AccessA semiconductor 96-microplate platform for electrical-imaging based high-throughput phenotypic screening
Cell-based phenotypic assays link in vitro discovery to disease pathology. Here, the authors report a semiconductor-based microplate platform to perform high-throughput, high-dimensional “electrical imaging” for label-free assessment of live cell morphology and function.
- Shalaka Chitale
- , Wenxuan Wu
- & Jeffrey Abbott
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Article
| Open AccessA knowledge-guided pre-training framework for improving molecular representation learning
Accurate property prediction relies on effective molecular representation. Here, the authors introduce KPGT, a knowledge-guided self-supervised framework that improves molecular representation, leading to superior predictions of molecular properties and advancing AI-driven drug discovery.
- Han Li
- , Ruotian Zhang
- & Jianyang Zeng
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Article
| Open AccessSmall molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing
Regulatory miRNAs have significant therapeutic potential. Here the authors developed a screen to identify small molecule drugs that modulate miRNome profiles in human neurons and validated cardiac glycosides as inducers of the neuroprotective miR-132.
- Lien D. Nguyen
- , Zhiyun Wei
- & Anna M. Krichevsky
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Article
| Open AccessCLOOME: contrastive learning unlocks bioimaging databases for queries with chemical structures
Artificial intelligence can assist in obtaining knowledge from bioimaging data, but need human annotation. Here the authors use multimodal contrastive learning to link chemical structures and cell phenotypes, which can lead to foundation models for microscopy images.
- Ana Sanchez-Fernandez
- , Elisabeth Rumetshofer
- & Günter Klambauer
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Article
| Open AccessRecognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides
Identification of molecules that induce novel interactions between proteins has been limited by the complexity of rationally designing interactions. The authors report a method to discover molecular glue-like “trimerizers” based on α-helically constrained peptides that can co-opt the surfaces of E3 ubiquitin ligases to bind therapeutically important proteins.
- Olena S. Tokareva
- , Kunhua Li
- & John H. McGee
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Article
| Open AccessCyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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Article
| Open AccessDevelopment of cyclopeptide inhibitors of cGAS targeting protein-DNA interaction and phase separation
Cyclic GMP-AMP synthase (cGAS) is critical in modulating cellular inflammation. Here, the authors report a class of cyclopeptide inhibitors of cGAS targeting protein DNA interaction and phase separation.
- Xiaoquan Wang
- , Youqiao Wang
- & Junmin Quan
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Article
| Open AccessFirst fully-automated AI/ML virtual screening cascade implemented at a drug discovery centre in Africa
Streamlined data-driven drug discovery remains challenging, especially in resource-limited settings. Here, the authors present ZairaChem, an AI/ML tool that streamlines QSAR/QSPR modelling, implemented for the first time at the H3D Centre in South Africa.
- Gemma Turon
- , Jason Hlozek
- & Miquel Duran-Frigola
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Article
| Open AccessHigh-throughput screening of BAM inhibitors in native membrane environment
The bacterial insertase BAM is a key target for novel antibiotics that are urgently needed. Here, we describe the implementation of an assay that allows screening for BAM inhibitors in the native membrane in high-throughput format.
- Parthasarathi Rath
- , Adrian Hermann
- & Sebastian Hiller
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Article
| Open AccessSulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used but their risks for early neurodevelopment remain controversial. Here, the authors showed in zebrafish larvae that sulindac induces GABAergic neuron apoptosis through autophagy activation that leads to hyperactive behavior.
- Wenwei Sun
- , Meimei Wang
- & Zhibin Huang
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Article
| Open AccessPharmacological perturbation of the phase-separating protein SMNDC1
SMNDC1 is a splicing factor that binds arginine methylation with its Tudor domain. Here, the authors study the protein’s phase-separating behavior and develop small-molecule Tudor domain inhibitors that perturb SMNDC1 function.
- Lennart Enders
- , Marton Siklos
- & Stefan Kubicek
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Article
| Open AccessSequence-based drug design as a concept in computational drug design
Conventional structure-based drug design pipeline is a complex, human-engineered process with multiple independently optimized steps. Here, the authors report a sequence-to-drug concept that discovers drug-like small molecule modulators directly from protein sequences.
- Lifan Chen
- , Zisheng Fan
- & Mingyue Zheng
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Article
| Open AccessLiver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion
Nonalcoholic steatohepatitis (NASH) starts with lipid droplet accumulation in the liver that eventually causes inflammation and fibrosis. Here, authors use lipophagy activators to limit the accumulation of lipids in the liver and show that this can prevent disease progression in a mouse model of nonalcoholic steatohepatitis.
- Yoshito Minami
- , Atsushi Hoshino
- & Satoaki Matoba
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Article
| Open AccessA landscape of response to drug combinations in non-small cell lung cancer
Combination of drugs within cancer treatment is a popular way to overcome resistance and increase efficacy. Here, the authors analyse over 5000 targeted agent combinations in non-small cell lung cancer to identify potentially effective drug strategies.
- Nishanth Ulhas Nair
- , Patricia Greninger
- & Cyril H. Benes
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Article
| Open AccessHybrid-DIA: intelligent data acquisition integrates targeted and discovery proteomics to analyze phospho-signaling in single spheroids
Standard mass spectrometry analyses often miss key targets required for phospho-signalling reconstruction. Here, authors present an intelligent data acquisition strategy that combines discovery and targeted analysis in one run and apply it to maximize the information from single spheroids drug screenings.
- Ana Martínez-Val
- , Kyle Fort
- & Jesper V. Olsen
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Article
| Open AccessMachine learning optimization of candidate antibody yields highly diverse sub-nanomolar affinity antibody libraries
Therapeutic antibody discovery is time and cost-intensive. Here, the authors develop a machine learning-driven method enabling accelerated design of large and diverse single-chain variable fragments with high binding efficiency, especially at high levels of diversity.
- Lin Li
- , Esther Gupta
- & Matthew E. Walsh
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Article
| Open AccessDiscovery of senolytics using machine learning
Cellular senescence is involved in many disease processes but few senolytic compounds are currently known. Here, the authors report the discovery of three senolytics using machine learning models trained solely on published data, with large reductions in drug screening costs.
- Vanessa Smer-Barreto
- , Andrea Quintanilla
- & Diego A. Oyarzún
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Article
| Open AccessIdentification of indocyanine green as a STT3B inhibitor against mushroom α-amanitin cytotoxicity
There is currently no specific antidote for death cap mushroom poisoning treatment. Here, the authors identify STT3B as a druggable target and show that indocyanine green is a STT3B inhibitor that can block α-amanitin toxicity in cell lines, liver organoids and mice.
- Bei Wang
- , Arabella H. Wan
- & Qiao-Ping Wang
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Article
| Open AccessCollateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance
Collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities for antimicrobial drug discovery. Here, Liu et al. screen large chemical libraries across 29 drug-resistant E. coli strains to identify multiple CS interactions, including natural products with potent CS activities against cephalosporin-resistant strains.
- Dennis Y. Liu
- , Laura Phillips
- & Roger G. Linington
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Article
| Open AccessImproving the generalizability of protein-ligand binding predictions with AI-Bind
State-of-the-art machine learning models in drug discovery fail to reliably predict the binding properties of poorly annotated proteins and small molecules. Here, the authors present AI-Bind, a machine learning pipeline to improve generalizability and interpretability of binding predictions.
- Ayan Chatterjee
- , Robin Walters
- & Giulia Menichetti
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Article
| Open AccessSafe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening
Authors propose their splenic mimetic filtration method, microsphiltration, and utilise this approach in a drug-screen, to identify compounds that induce a stiffening effect on Plasmodium falciparum-infected erythrocytes. They proceed to assess safety and tolerability of one identified compound in a phase I clinical trial.
- Mario Carucci
- , Julien Duez
- & Pierre Buffet
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Article
| Open AccessGenipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage
In this work, the authors identify Genipin as a small iridoid able to prevent alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.
- Rita Rosado-Ramos
- , Gonçalo M. Poças
- & Cláudia N. Santos
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Article
| Open AccessSingle-molecule fingerprinting of protein-drug interaction using a funneled biological nanopore
Efficient screening of protein-drug interactions (PDIs) has been impeded by the limitations of current biophysical approaches. Here, the authors present a funneled YaxAB nanopore sensor which allows label-free, single-molecule detection of proteins and PDIs.
- Ki-Baek Jeong
- , Minju Ryu
- & Seung-Wook Chi
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Article
| Open AccessTrio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers
Dual-pharmacophore DNA-Encoded Libraries (DELs) can generate large libraries, but linker optimisation is challenging. Here, the authors report a trio-pharmacophore DEL (T-DEL) for both de novo fragment identification and linker optimization of known fragment pairs.
- Meiying Cui
- , Dzung Nguyen
- & Yixin Zhang
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Article
| Open Access1,2,4,5-Tetrazine-tethered probes for fluorogenically imaging superoxide in live cells with ultrahigh specificity
Specific detection of cellular superoxide is challenging. Here, the authors designed 1,2,4,5-tetrazine based fluorogenic probes for specific and sensitive imaging of superoxide, and applied them in high throughput screening of modulators of oxidative stress.
- Xuefeng Jiang
- , Min Li
- & Xin Li
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Article
| Open AccessReference compounds for characterizing cellular injury in high-content cellular morphology assays
Cellular nuisance compounds are a burden in chemical biology and drug screening. Here the authors profile prototypical cytotoxic and nuisance compounds using the cell painting assay to systematically characterise cellular morphologies associated with compound-dependent cellular injury and nuisance activity.
- Jayme L. Dahlin
- , Bruce K. Hua
- & Bridget K. Wagner
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Article
| Open AccessNorepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Sympathetic neurons are affected in familial dysautonomia, a rare disease associated with a mutation in ELP1, but the mechanisms are not fully understood. Here the authors show, using neurons derived from participants with familial dysauotnomia, that spontaneous sympathetic neuron hyperactivity is observed and is associated with norepinephrine transporter deficits.
- Hsueh-Fu Wu
- , Wenxin Yu
- & Nadja Zeltner
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Article
| Open AccessMaprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells
ER stress is associated with various neurodegenerative diseases. This study found that FDA approved drug, maprotiline, inhibits histamine receptor H1-mediated ER stress and provides significant neuroprotection in mouse glaucoma model.
- Wei Chen
- , Pingting Liu
- & Yang Hu
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Article
| Open AccessHigh-throughput small molecule screen identifies inhibitors of microsporidia invasion and proliferation in C. elegans
Microsporidia are fungal-related intracellular parasites that infect animals and humans. Here, Murareanu et al. develop a high-throughput screening method using the nematode C. elegans as a host, and identify several compounds that inhibit microsporidia infection through different mechanisms.
- Brandon M. Murareanu
- , Noelle V. Antao
- & Aaron W. Reinke