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Article
| Open AccessLabel-free biosensor assay decodes the dynamics of Toll-like receptor signaling
Toll-like receptors are key mediators of immune responses, but gaps remain in understanding their signalling. Here, the authors introduce an optical biosensor assay to detect real-time TLR activation and signalling dynamics, uncovering signalling signatures that may aid future drug design.
- Janine Holze
- , Felicitas Lauber
- & Günther Weindl
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Comment
| Open AccessSplitting the chains: ultra-basal insulin analog uncovers a redox mechanism of hormone clearance
Reporting in Nature Communications, Kjeldsen and colleagues describe a redox mechanism of insulin clearance based on separation of A- and B chains. Exploiting an ultra-long-acting analog protected from classical clearance pathways, the study highlights principles of protein stability in pharmacology.
- Michael A. Weiss
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Article
| Open AccessSplit-design approach enhances the therapeutic efficacy of ligand-based CAR-T cells against multiple B-cell malignancies
A switchable CAR-T cell platform comprises a universal receptor expressed on T cells and tumor-targeting adapter molecules. Here the authors propose an APRIL- and BAFF-based switchable CAR strategy for ligand-mediated CAR-T-cell activation, showing anti-tumor activity in models of B-cell malignancies.
- Shuhong Li
- , Licai Shi
- & Yu J. Cao
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Article
| Open AccessStructural insights into the agonist selectivity of the adenosine A3 receptor
Adenosine A3 receptor (A3R) plays important roles in neurons, heart, and immune cells, and is often overexpressed in tumors. Oshima et al. identify tRNA-derived i6A as an A3R-selective ligand and use cryo-EM to reveal A3R’s selectivity and activation mechanisms.
- Hidetaka S. Oshima
- , Akiko Ogawa
- & Osamu Nureki
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Article
| Open AccessIn silico formulation optimization and particle engineering of pharmaceutical products using a generative artificial intelligence structure synthesis method
Pharmaceutical drug dosage forms are traditionally determined through extensive physical experimentation. Here, the authors present a generative AI method that creates digital drug products from images, matching and improving critical quality attributes such as particle size and drug loading.
- Timothy Hornick
- , Chen Mao
- & Shawn Zhang
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Article
| Open AccessCYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles
CYP5122A1 is a sterol C4-methyl oxidase that catalyzes the sequential oxidation of lanosterol, is essential for both Leishmania donovani promastigotes in culture and intracellular amastigotes in infected mice, and provides a new target for antileishmanial drug discovery.
- Yiru Jin
- , Somrita Basu
- & Michael Zhuo Wang
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Article
| Open AccessRisk-stratified treatment for drug-susceptible pulmonary tuberculosis
Authors perform an analysis of the patient data and risk factors to evaluate unfavorable outcomes and adverse events in adults with pulmonary tuberculosis treated with a 4-month rifapentine based regimen. Low rifapentine exposure was the most clinically significant risk factor for treatment failure and tuberculosis relapse.
- Vincent K. Chang
- , Marjorie Z. Imperial
- & Elizabeth Guy
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Article
| Open AccessStructural insights into epitope-paratope interactions of a monoclonal antibody targeting CEACAM5-expressing tumors
Cryo-electron microscopy was used to determine the high-resolution structure of the antigen-binding fragment of tusamitamab bound to the A3-B3 domains of CEACAM5. The conformational constraints discovered in this study may inform the rational design of new CEACAM5-targeting therapies.
- Anand Kumar
- , Francis Duffieux
- & Alexey Rak
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Article
| Open AccessSingle-cell landscape of innate and acquired drug resistance in acute myeloid leukemia
The molecular mechanisms underlying drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML) remain to be explored. Here, the use of bulk and single cell multi-omics and ex vivo drug profiling for 21 rrAML patients reveals mechanisms of resistance to the Bcl-2 inhibitor venetoclax and treatment vulnerabilities.
- Rebekka Wegmann
- , Ximena Bonilla
- & Alexandre P. A. Theocharides
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Article
| Open AccessTamGen: drug design with target-aware molecule generation through a chemical language model
Generative AI holds promise for creating novel compounds. Here, authors introduce TamGen, a GPT-like model designed to generate molecules tailored to specific target proteins. TamGen identified 14 potent compounds against the Tuberculosis ClpP protease, showing its potential for drug discovery.
- Kehan Wu
- , Yingce Xia
- & Tie-Yan Liu
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Article
| Open AccessTranscriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-related drug targets for cardiometabolic diseases
Here, the authors identify genes and drug targets that show immune cell-specific and activation time point-specific effects on type 2 diabetes and coronary heart disease and find strong immune-to-metabolic disease connections.
- Xueyan Wu
- , Hui Ying
- & Jieli Lu
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Article
| Open AccessPredicting transcriptional responses to novel chemical perturbations using deep generative model for drug discovery
Understanding transcriptional responses to chemical perturbations is crucial for drug discovery. Here, authors present PRnet, a deep generative model that predicts gene responses to novel chemical perturbations, enabling in-silico drug screening and the identification of candidate compounds for various diseases.
- Xiaoning Qi
- , Lianhe Zhao
- & Yi Zhao
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Article
| Open AccessAlligamycin A, an antifungal β-lactone spiroketal macrolide from Streptomyces iranensis
From the rapamycin-producer Streptomyces iranensis, authors report on the discovery of the antifungal candidate alligamycin A, which exhibited strong activities against several drug-resistant Aspergillus and Talaromyces.
- Zhijie Yang
- , Yijun Qiao
- & Ling Ding
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Article
| Open AccessPCLAF-DREAM drives alveolar cell plasticity for lung regeneration
Cell plasticity, changes in cell fate, is involved in tissue regeneration. Here, Kim et al. show that PCLAF-DREAM-driven alveolar cell plasticity is crucial for lung regeneration and targetable as a preventative strategy for lung fibrosis.
- Bongjun Kim
- , Yuanjian Huang
- & Jae-Il Park
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Article
| Open AccessStructuring lipid nanoparticles, DNA, and protein corona into stealth bionanoarchitectures for in vivo gene delivery
Encapsulation of large-size DNA molecules into lipid nanoparticles (LNPs) remains challenging. Here, the authors engineer PEGylated LNPs with DNA and plasma proteins to improve the delivery of large DNA molecules, enhancing the gene therapy potential.
- Serena Renzi
- , Luca Digiacomo
- & Giulio Caracciolo
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| Open AccesssChemNET: a deep learning framework for predicting small molecules targeting microRNA function
Here the authors developed and experimentally validated sChemNET, a deep learning framework to predict small molecules affecting microRNA function based on chemical structure and sequence data. sChemNET predicts bioactive small molecules on the basis of sparse chemical datasets.
- Diego Galeano
- , Imrat
- & Afshin Beheshti
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Article
| Open AccessAnnonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice
Obesity is a significant health risk, and current treatments are inadequate. This study reveals that AA005, an annonaceous acetogenin mimic, targets mitochondrial HADHA in adipose tissue to boost thermogenesis via the UCP1 pathway, providing a promising new strategy for obesity treatment.
- Bing Han
- , Zhan-Ming Li
- & Li-Shun Wang
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Article
| Open AccessBenchmarking machine learning methods for synthetic lethality prediction in cancer
A comprehensive benchmarking of existing synthetic lethality (SL) prediction methods is lacking. Here, the authors compare 12 recently developed machine learning methods for SL prediction, assess their performance, and provide guidance on the selection of the most suitable method.
- Yimiao Feng
- , Yahui Long
- & Jie Zheng
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Article
| Open AccessSingle molecule tracking based drug screening
EGFR is a primary target molecule in drug exploration for cancer therapeutics. Here, the authors show a demonstration of single-molecule tracking-based drug screening for EGFR, proving the selectivity for tyrosine kinase inhibitors and potential to find drugs with previously untargeted mechanisms.
- Daisuke Watanabe
- , Michio Hiroshima
- & Masahiro Ueda
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Article
| Open AccessSpatial transcriptomics of a parasitic flatworm provides a molecular map of drug targets and drug resistance genes
Fasciola hepatica is a complex multicellular pathogen and the causative agent of fascioliasis, a zoonotic disease that compromises liver function. Using spatial transcriptomics, the authors uncover the tissue-specific gene expression of F. hepatica and identify genes with expression in the surface layer for drug-target discovery.
- Svenja Gramberg
- , Oliver Puckelwaldt
- & Simone Haeberlein
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| Open AccessExpanding drug targets for 112 chronic diseases using a machine learning-assisted genetic priority score
Here, the authors introduce ML-GPS, a machine learning framework that prioritizes drug targets for 112 chronic diseases and integrates genetic associations with predicted phenotypes.
- Robert Chen
- , Áine Duffy
- & Ron Do
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| Open AccessDesign of a Cereblon construct for crystallographic and biophysical studies of protein degraders
Structure-based drug discovery of cereblon (CRBN)-recruiting protein degraders has been to date challenging due to limitations with current constructs for recombinant protein expression. In this work, the authors design and validate a truncated CRBN construct, CRBNmidi, that enables crystallization and biophysical characterization of CRBN-binding ligands and degraders.
- Alena Kroupova
- , Valentina A. Spiteri
- & Alessio Ciulli
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Article
| Open AccessCardiovascular and renal effects of apelin in chronic kidney disease: a randomised, double-blind, placebo-controlled, crossover study
Despite treatment, patients with chronic kidney disease remain at high risk of kidney failure and cardiovascular disease. Here, the authors show that apelin offers potential cardiorenal protection for this high-risk patient group.
- Fiona A. Chapman
- , Vanessa Melville
- & Neeraj Dhaun
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Article
| Open AccessPrinciples of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2
KLHDC2 is a promising E3 ligase for targeted protein degradation (TPD). In this study, the authors demonstrate that heterobifunctional degraders induce cooperative ternary complexes with KLHDC2 and BRD3. They highlight exit vector, neo-substrate, E3 ligase selectivity, and prodrug choice can effectively leverage C-degron E3s for TPD.
- Daniel C. Scott
- , Suresh Dharuman
- & Brenda A. Schulman
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Article
| Open AccessCYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect
Targeted protein degradation (TPD) can be employed to eliminate disease-causing proteins. Here, the authors present CYpHER, a TPD tool that uses molecules engineered for intracellular target release with drug recycling via transferrin receptor. CYpHER induces depletion of extracellular targets in vitro and in xenograft tumours.
- Zachary R. Crook
- , Gregory P. Sevilla
- & Natalie W. Nairn
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Article
| Open AccessStructural basis for antibiotic transport and inhibition in PepT2
The uptake and elimination of beta-lactam antibiotics are facilitated by the proton-coupled peptide transporters. Here authors present cryo-EM structures of PepT2 in complex with the cefadroxil, amoxicillin and cloxacillin to reveal a mechanism of beta-lactam antibiotic recognition
- Joanne L. Parker
- , Justin C. Deme
- & Simon Newstead
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Article
| Open AccessStructural basis of μ-opioid receptor targeting by a nanobody antagonist
The µ-opioid receptor is a key clinical target. Here, the authors describe nanobody NbE, a selective and high affinity antagonist, which is downsized to small cyclic peptides. The work enables unique receptor targeting based on nanobody interaction.
- Jun Yu
- , Amit Kumar
- & Miriam Stoeber
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Article
| Open AccessTwo-dimensional coordination risedronate-manganese nanobelts as adjuvant for cancer radiotherapy and immunotherapy
Radiation therapy (RT) can induce immunogenic cell death and elicit anti-tumor immune responses. Here the authors report the design and characterization of a risedronate-manganese-based nanosystem for in situ vaccination, amplifying RT-mediated anti-tumor immunity in preclinical models.
- Zhusheng Huang
- , Shiqian Huang
- & Lianhui Wang
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Article
| Open AccessDevelopment of folate receptor targeting chimeras for cancer selective degradation of extracellular proteins
Selective protein degradation in disease-relevant cells or tissues has seen limited success. Hence, the authors develop Folate Receptor Targeting Chimeras (FRTACs) to specifically target proteins in cancer cells, aiming to reduce on-target, off-tumor toxicity.
- Yaxian Zhou
- , Chunrong Li
- & Weiping Tang
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Comment
| Open AccessStrengthening and expanding capacities in clinical trials: advancing pandemic prevention, preparedness and response in Africa
Enhancing the clinical trial capabilities within Africa is essential to augment the continent’s pandemic prevention, preparedness and response efforts. Here, we describe the critical challenges of clinical trials in Africa and draw upon the lessons learnt from the
Con sortium forC OVID-19Va ccineC linicalT rials (CONCVACT) experience, such as the importance of regional collaboration, capacity building and establishing standardized protocols.- Nicaise Ndembi
- , Tadesse T. Mekonen
- & John Nkengasong
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Article
| Open AccessTRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA
Here, Xin Pan and colleagues found that activation of thyroid hormone receptor-β is necessary for alveolar epithelial cell differentiation during lung repair and regeneration, and confirmed a specific agonist and molecular targets for fibrosis therapy.
- Xin Pan
- , Lan Wang
- & Guoying Yu
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Article
| Open AccessTargeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity
Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Here the authors show that elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local bone GC activation, is associated with bone loss and obesity mice.
- Chuanxin Zhong
- , Nanxi Li
- & Ge Zhang
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Article
| Open AccessReversible covalent c-Jun N-terminal kinase inhibitors targeting a specific cysteine by precision-guided Michael-acceptor warheads
Bálint et al utilized cyclohexenone and cyclopentenone based reversible covalent warheads to produce specific composite c-Jun N-terminal kinase inhibitors to demonstrate the modular nature of Michael acceptor based cyclic warhead designs.
- Dániel Bálint
- , Ádám Levente Póti
- & Attila Reményi
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Article
| Open AccessMolecular and functional landscape of malignant serous effusions for precision oncology
Personalized treatment for cancer patients relies on the deep characterization of tumor cells from patient biopsies. In this study, functional multi-omics profiling of a pan-cancer cohort of malignant serous effusions (MSE) finds strong coherence between MSE and matched solid tumors, underlining the feasibility and utility of multi-modal MSE-based precision oncology.
- Rebekka Wegmann
- , Lorenz Bankel
- & Berend Snijder
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Article
| Open AccessStructural basis of thiamine transport and drug recognition by SLC19A3
Here, the structure of SLC19A3, an essential human transport protein for vitamin B1, has been determined in different conformations and bound to its substrate and different drug molecules. The researchers provide deep molecular insights into the transport cycle and drug interactions of this critical protein.
- Florian Gabriel
- , Lea Spriestersbach
- & Christian Löw
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Article
| Open AccessSol-moiety: Discovery of a water-soluble prodrug technology for enhanced oral bioavailability of insoluble therapeutics
Current water-soluble prodrug technologies typically result in a lack of overall improvement in oral bioavailability relative to standard formulation strategies. Here, the authors report water soluble promoiety (Sol-moiety) technology that shows improved oral bioavailability over existing water-soluble prodrug technologies and the ability to switch from intravenous to oral administration.
- Arvin B. Karbasi
- , Jaden D. Barfuss
- & Mark Smith
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Article
| Open AccessStructure elucidation of a human melanocortin-4 receptor specific orthosteric nanobody agonist
Melanocortin-4 receptor (MC4R) is key in controlling hunger. Here, authors discover the MC4R-specific, potent agonist nanobody pN162. The pN162-MC4R-Gs-Nb35 structure shows its distinct binding mode compared to peptide agonists.
- Thomas Fontaine
- , Andreas Busch
- & Christel Menet
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Article
| Open AccessThe urotensin II receptor triggers an early meningeal response and a delayed macrophage-dependent vasospasm after subarachnoid hemorrhage in male mice
“In subarachnoid hemorrhage (SAH), therapies are limited and clinical outcomes remain disappointing. The authors show a contribution of the urotensin II system in microvascular changes, vasospasm, neuroinflammation and cognitive deficits post-SAH, primarily through meningeal cells and border-associated macrophages
- Martin Pedard
- , Lucie Prevost
- & Hélène Castel
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Article
| Open AccessStructural insights into the human P2X1 receptor and ligand interactions
The P2X1 receptor is a promising target for the development of a non-hormonal male contraceptive. Here, researchers determined the atomic structure of the P2X1 receptor, revealing opportunities for developing drugs to target this receptor.
- Felix M. Bennetts
- , Hariprasad Venugopal
- & David M. Thal
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Article
| Open AccessA rapid in vivo pipeline to identify small molecule inhibitors of amyloid aggregation
In this work, Kamal, Knox et al develop a high-throughput system to identify small molecules that disrupt amyloid formation by pre-selecting compounds that suppress molecular interactions within the cuticle of the C. elegans pharynx.
- Muntasir Kamal
- , Jessica Knox
- & Peter J. Roy
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Article
| Open AccessCryo-EM structure of small-molecule agonist bound delta opioid receptor-Gi complex enables discovery of biased compound
The delta opioid receptor (δOR) is key in modulating sensation and emotion with a lower risk of drug dependence. Here, authors report cryo-EM structure of δOR and design probes to explore its signaling bias, with insights for drug discovery.
- Lin Cheng
- , Zhuang Miao
- & Bowen Ke
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Article
| Open AccessComputer-aided drug design to generate a unique antibiotic family
Holo-acyl carrier protein synthase (AcpS) is an enzyme that catalyses the first step in lipid synthesis and is essential for bacterial survival, but no current antibiotics targeting AcpS are known. Here, the authors use computer-aided drug design to develop a structurally unique antibiotic family targeting AcpS.
- Christopher J. Barden
- , Fan Wu
- & Christopher R. McMaster
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Article
| Open AccessIdentification of potent and orally efficacious phosphodiesterase inhibitors in Cryptosporidium parvum-infected immunocompromised male mice
Using phenotypic screening followed by optimization of side activities, the authors here identify pyrazolopyrimidine phosphodiesterase (PDE) inhibitors as anti-cryptosporidial drug leads. Humanizing a Cryptosporidum PDE by CRISPR indicates they target the parasite enzyme.
- Jubilee Ajiboye
- , José E. Teixeira
- & Christopher D. Huston
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Article
| Open AccessOxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models
Ibogaine is a natural substance that interrupts opioid addiction but has cardiac risks. This article introduces novel ibogaine analogs that show reduced cardiac risk and enhanced neuroplasticity and therapeutic-like effects in models of opioid use disorder.
- Václav Havel
- , Andrew C. Kruegel
- & Dalibor Sames
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Article
| Open AccessActivation of parkin by a molecular glue
Parkin is a ubiquitin ligase that protects against early-onset Parkinson’s disease. Here, the authors show a molecular glue that promotes binding of phosphorylated ubiquitin to parkin and rescues the mitophagy defect of mutations in the parkin ubiquitin-like domain.
- Véronique Sauvé
- , Eric Stefan
- & Kalle Gehring
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Article
| Open AccessBWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections
In this work, the authors probe the efficacy of BWC0977, a bacterial topoisomerase inhibitor, in pre-clinical animal models, also demonstrating that BWC0977 is safe and well tolerated in healthy human volunteers, in a phase 1 trial.
- Shahul Hameed P
- , Harish Kotakonda
- & Balasubramanian V
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Article
| Open AccessTargeted transcriptional downregulation of MYC using epigenomic controllers demonstrates antitumor activity in hepatocellular carcinoma models
Development of targeted MYC inhibitors for cancer therapy remains challenging. Here, the authors design an mRNA medicine which downregulates MYC gene transcription via epigenetic modification of MYC regulatory elements, showing significant antitumor activity in preclinical models of hepatocellular carcinoma.
- William Senapedis
- , Kayleigh M. Gallagher
- & Thomas G. McCauley
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Article
| Open AccessData-driven discovery of potent small molecule ice recrystallisation inhibitors
Controlling ice formation is crucial for cryopreservation. Here, authors developed machine learning models to predict ice recrystallisation inhibition by small molecules, showcasing a data-driven approach for cryoprotectant discovery.
- Matthew T. Warren
- , Caroline I. Biggs
- & Gabriele C. Sosso
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Article
| Open AccessEngineered model of heart tissue repair for exploring fibrotic processes and therapeutic interventions
Engineered human models of hearts are needed to study pathology and repair. Here, the authors develop a model which replicates the phased remodelling process. The model is then used to study signalling pathway modulators for their therapeutic potential in a mini-repair model.
- Pengcheng Yang
- , Lihang Zhu
- & Donghui Zhang