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Article
| Open AccessCis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia
Preeclampsia is the leading cause of maternal and fetal mortality worldwide. Here, the authors show that cis P-tau is a central circulating etiologic driver in preeclampsia and that the stereo-specific antibody targeting cis P-tau holds promise for early diagnosis and treatment of the disease.
- Sukanta Jash
- , Sayani Banerjee
- & Surendra Sharma
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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 AccessStructural basis of lipid-droplet localization of 17-beta-hydroxysteroid dehydrogenase 13
Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Here, the authors report crystal structures of HSD17B13 and its complexes with two series of inhibitors.
- Shenping Liu
- , Ruth F. Sommese
- & Michelle F. Clasquin
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Article
| Open AccessCholesterol removal improves performance of a model biomimetic system to co-deliver a photothermal agent and a STING agonist for cancer immunotherapy
Strategies for biological membrane engineering have been proposed to enhance their anti-clearance efficiency and improve their clinical translation potential. Here the authors design nanoparticles coated with low-cholesterol membranes from T cells overexpressing PD1, showing reduced clearance in the blood and improved anti-tumor efficacy when loaded with a STING agonist and a photothermal agent.
- Lin Li
- , Mengxing Zhang
- & Ling Zhang
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Review Article
| Open AccessChallenges in developing Geroscience trials
Geroscience is becoming a major hope for preventing age-related diseases and loss of function by targeting biological mechanisms of aging. This article reports a discussion of a research Task Force on the challenges posed by the clinical research in Geroscience so that future gerotherapeutic clinical trials can be conducted successfully.
- Yves Rolland
- , Felipe Sierra
- & Alex Zhavoronkov
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Article
| Open AccessCD98hc is a target for brain delivery of biotherapeutics
New delivery platforms are needed to allow broader application of biotherapeutics for CNS diseases. Here, the authors show enhanced CNS delivery with a transport vehicle engineered to bind CD98hc, a highly expressed target at the blood-brain barrier.
- Kylie S. Chew
- , Robert C. Wells
- & Mihalis S. Kariolis
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Article
| Open AccessLenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation
Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.
- Satoshi Yamanaka
- , Hirotake Furihata
- & Tatsuya Sawasaki
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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 AccessOptical blood-brain-tumor barrier modulation expands therapeutic options for glioblastoma treatment
Relevant preclinical models and effective drug delivery strategies are important to advance glioblastoma (GBM) therapy. Here, the authors characterise genetically engineered mouse models that recapitulate two important GBM subtypes, and use them to show that picosecond laser stimulation of vascular-targeting gold nanoparticles can modulate blood-brain-tumour barrier permeability and expand therapeutic options for GBM.
- Qi Cai
- , Xiaoqing Li
- & Zhenpeng Qin
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Article
| Open AccessStructural basis of agonist specificity of α1A-adrenergic receptor
α1-adrenergic receptors (α1- AR) play critical roles in the cardiovascular and nervous systems. Here, the authors report molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by the agonist A61603.
- Minfei Su
- , Jinan Wang
- & Xin-Yun Huang
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Article
| Open AccessComplementarity-determining region clustering may cause CAR-T cell dysfunction
The challenge of designing chimeric antigen receptor (CAR)-T cells for cancer therapy is not limited to finding targetable cellular proteins, but also in optimising the effector properties. Here authors show that single-chain variable fragment targeting moieties could unpredictably prompt spontaneous CAR-T cell activation via CAR clustering, which argues for empirical screening for tonic signalling.
- Tina Sarén
- , Giulia Saronio
- & Magnus Essand
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Article
| Open AccessSimultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics
Untargeted metabolomics enables simultaneous measurement of xenobiotic fate and effects in biological systems. This is demonstrated through discovering extensive biotransformation maps, measuring systemic exposures over time, and directly associating endogenous biochemical responses to internal dose.
- Tara J. Bowen
- , Andrew D. Southam
- & Mark R. Viant
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Article
| Open AccessMacrocyclization of linear molecules by deep learning to facilitate macrocyclic drug candidates discovery
Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds with improved pharmacological properties. Here, the authors propose a deep learning based macrocyclization method to generate diverse macrocycles from a given acyclic molecule.
- Yanyan Diao
- , Dandan Liu
- & Honglin Li
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Article
| Open AccessMAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas
The MAPK pathway is a key driver of pediatric low-grade gliomas (pLGG); however, response to MAPK inhibitors (MAPKi) in pLGG patients is not consistent. Here, the authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi and apply them to bulk and single-cell sequencing datasets from pLGG patients and preclinical models.
- Romain Sigaud
- , Thomas K. Albert
- & Till Milde
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Article
| Open AccessDNA framework-engineered chimeras platform enables selectively targeted protein degradation
The lack of a universal platform for PROTAC development remains a major bottleneck. Here, the authors report modular DNA framework-based PROTACs (DbTACs) that enable precise control of the linker length and selective degradation of diverse targets in different cellular compartments using various warheads.
- Li Zhou
- , Bin Yu
- & Yi Ma
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Article
| Open AccessIdentification of a small-molecule inhibitor that selectively blocks DNA-binding by Trypanosoma brucei replication protein A1
The authors identify a small molecule inhibitor targeting the ssDNA-binding function of T. brucei Replication Protein A1 without affecting the host ortholog. They confirm the key residue in TbRPA1 involved in the species-specific selectivity of the chemical probe.
- Aditi Mukherjee
- , Zakir Hossain
- & Hee-Sook Kim
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Article
| Open AccessA preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
In vitro secondary pharmacology assays are used to predict the clinical adverse event risks of new drugs. Here, the authors describe a new database, identify the most predictive assays for estimating risk, and propose candidate mechanisms to explain clinically observed risk profiles.
- Jeffrey J. Sutherland
- , Dimitar Yonchev
- & Laszlo Urban
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Article
| Open AccessTargeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction
Dynamin-related protein 1 (Drp1) mediates physiological and pathological mitochondrial fission, and the latter can be selectively blocked by a peptide inhibitor. Here, the authors identify a small molecule that mimics the benefits of this peptide inhibitor in cells and a mouse model of endotoxemia.
- Luis Rios
- , Suman Pokhrel
- & Daria Mochly-Rosen
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Article
| Open AccessMultiplexed RNA profiling by regenerative catalysis enables blood-based subtyping of brain tumors
Current methods to subtype brain tumors rely on invasive biopsies. Here, the authors develop a digital platform to regeneratively convert and catalytically enhance signals from rare circulating RNAs for blood-based characterization of brain tumors.
- Yan Zhang
- , Chi Yan Wong
- & Huilin Shao
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Article
| Open AccessA renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury
KIM1 is dramatically upregulated in acute kidney injury (AKI) and but how KIM1 affects AKI remains unknown. Here, the authors report that renal specific Kim1 knockout relieves AKI, unveil a YY1-KIM1-DR5 axis in the progression of AKI, and suggest potential therapeutic strategies against AKI.
- Chen Yang
- , Huidie Xu
- & Ling Zheng
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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 AccessLateral membrane organization as target of an antimicrobial peptidomimetic compound
The mechanism of action of the antibacterial tripeptide AMC-109 is unclear. Here, Melcrová et al. show that AMC-109 self-assembles into stable aggregates with a cationic surface, and then individual peptides insert into the bacterial membrane and disrupt membrane nanodomains, thus affecting membrane function without forming pores.
- Adéla Melcrová
- , Sourav Maity
- & Wouter H. Roos
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Article
| Open AccessInduction of lysosomal exocytosis and biogenesis via TRPML1 activation for the treatment of uranium-induced nephrotoxicity
The roles of lysosomes in uranium (U) decorporation and detoxification remain to be elucidated. Here, the authors demonstrate that TRPML1 activation is an attractive therapeutic strategy to induce lysosomal exocytosis and biogenesis for the treatment of U-induced nephrotoxicity.
- Dengqin Zhong
- , Ruiyun Wang
- & Honghong Chen
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Article
| Open AccessMultiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function
ApoE is known to be important for lipid nanoparticle function. Here, the authors shows that efficacious coronal ApoE originates from high-density lipoprotein (HDL) particles and, enhances hepatic delivery, making HDL a superior biomarker for lipid nanoparticle potency.
- Kai Liu
- , Ralf Nilsson
- & Alan Sabirsh
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Article
| Open AccessRapid planning and analysis of high-throughput experiment arrays for reaction discovery
High-throughput experimentation is an increasingly important tool in reaction discovery, while there remains a need for software solutions to navigate data-rich experiments. Here the authors report phactor™, a software that facilitates the performance and analysis of high-throughput experimentation in a chemical laboratory.
- Babak Mahjour
- , Rui Zhang
- & Tim Cernak
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Article
| Open AccessA rapid cell-free expression and screening platform for antibody discovery
Antibody discovery is bottlenecked by the individual expression and evaluation of antigen specific hits. Here, the authors build an antibody screening workflow leveraging cell-free protein synthesis that enables expression and evaluation of hundreds of antibody fragments in less than 24 h.
- Andrew C. Hunt
- , Bastian Vögeli
- & Michael C. Jewett
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Article
| Open AccessSUMOylation of Rho-associated protein kinase 2 induces goblet cell metaplasia in allergic airways
Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.
- Dan Tan
- , Meiping Lu
- & Ximei Wu
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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 AccessDprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid
Pretomanid and delamanid are pro-drugs used for the treatment of tuberculosis, but their precise mechanisms of action are unclear. Here, the authors identify an enzyme required for the synthesis of the mycobacterial cell wall as a molecular target of the activated drugs.
- Katherine A. Abrahams
- , Sarah M. Batt
- & Gurdyal S. Besra
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Article
| Open AccessNon-covalent inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo
Only praziquantel is available for treating schistosomiasis, a disease affecting >200 million people. Here, the authors identify compounds active against schistosome infections meeting the criteria for lead progression indicated by WHO with better activity against juvenile worms than praziquantel.
- Valentina Z. Petukhova
- , Sammy Y. Aboagye
- & Pavel A. Petukhov
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Article
| Open AccessUSP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice
The redox status of a cell is regulated through a number of mechanisms, chief among these is the KEAP1-mediated ubiquitination and degradation of NRF2. Here the authors show that KEAP1 itself is ubiquitinated and degraded in a process that is opposed by the ubiquitin-specific protease USP25.
- Changzhou Cai
- , Huailu Ma
- & Jiewei Wang
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Article
| Open AccessStructural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody
α1A-adrenergic receptor (α1AAR) regulates smooth muscle contraction and cognitive functions. Here, authors provide structural insight into α1AAR activation and binding modes of the orthosteric ligands and an extracellular allosteric nanobody.
- Yosuke Toyoda
- , Angqi Zhu
- & Xiangyu Liu
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Article
| Open AccessMultivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2
There are currently two types of antiviral drugs – neutralizing antibodies and small molecule inhibitors. Here, the authors report the development of bicyclic peptides that combine the advantages of both and show their antiviral capacity against SARS-CoV-2 in vitro as well as in small animal models.
- Katherine U. Gaynor
- , Marina Vaysburd
- & Leo C. James
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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 AccessBiomedical knowledge graph learning for drug repurposing by extending guilt-by-association to multiple layers
Computational drug repurposing models that leverage biomedical knowledge graphs to associate drugs to diseases, are biased to genes. Here, the authors present DREAMwalk, which extends guilt-by-association for multi-layer knowledge graph learning using a semantic information-guided random walk.
- Dongmin Bang
- , Sangsoo Lim
- & Sun Kim
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Article
| Open AccessChemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid
Lipoic acid is a food supplement and approved neuropathy drug but lacks known molecular targets. Here, Lechner et al. employ chemoproteomic target deconvolution to demonstrate that (R)- but not (S)-lipoic acid stereoselectively inhibits histone deacetylases at physiologically achievable doses.
- Severin Lechner
- , Raphael R. Steimbach
- & Bernhard Kuster
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Article
| Open AccessMechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design
Myosin A (PfMyoA) is essential for the pathogenesis of Plasmodium falciparum, the causative agent of malaria. Here we decipher the mechanism by which a small molecule inhibitor (KNX-002) of PfMyoA impedes its motor activity.
- Dihia Moussaoui
- , James P. Robblee
- & Anne Houdusse
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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 AccessDirected natural evolution generates a next-generation oncolytic virus with a high potency and safety profile
Compromised killing effects of oncolytic viruses due to attenuation of virulence remains a challenge. Here, the authors use a directed natural evolution approach to increase the oncolytic effect of the oncolytic virus M1 attributed to mutations in the E2 and nsP3 genes.
- Li Guo
- , Cheng Hu
- & Yuan Lin
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Article
| Open AccessEmpowering drug off-target discovery with metabolic and structural analysis
The authors present a workflow integrating metabolic perturbations with protein structural analysis to identify drug off-targets, demonstrating how combining machine learning methods with mechanistic analyses can benefit off-target identification.
- Sourav Chowdhury
- , Daniel C. Zielinski
- & Eugene I. Shakhnovich
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Article
| Open AccessPregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions
The increase in detoxification gene expression is a common transcriptome marker for longevity interventions. Here, the authors show that nomilin extends lifespan and healthspan in animals through activation of PXR regulated detoxification functions.
- Shengjie Fan
- , Yingxuan Yan
- & Cheng Huang
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Article
| Open AccessDurable contraception in the female domestic cat using viral-vectored delivery of a feline anti-Müllerian hormone transgene
This study demonstrates the safety and long-term efficacy of a single-dose, injectable contraceptive in female domestic cats. Treated females remained contracepted for over two years, and did not ovulate or produce kittens when paired with males.
- Lindsey M. Vansandt
- , Marie-Charlotte Meinsohn
- & David Pépin
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Article
| Open AccessDevelopment of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding
Despite the therapeutic interest in targeting CDK2, developing a selective CDK2 inhibitor has been challenging. Here, the authors describe a potent and selective CDK2 inhibitor that binds an allosteric pocket, preventing activating protein partners from binding and showing potential as a contraceptive.
- Erik B. Faber
- , Luxin Sun
- & Gunda I. Georg
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Article
| Open AccessStructural mapping of Nav1.7 antagonists
Voltage-gated sodium (Nav) channels are targeted by various clinically applied and investigational drugs. Here cryo-EM structures of Nav1.7 bound to 7 compounds with diverse chemical skeletons reveal the structural basis of action of these drugs and provide a 3D structural map for drug binding sites on Nav channels.
- Qiurong Wu
- , Jian Huang
- & Nieng Yan
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Article
| Open AccessTherapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice
The WNT/b-catenin pathway is essential for bloodbrain barrier (BBB) and blood-retina barrier (BRB) function. A bioengineered FZD4-selective WNT surrogate demonstrated systemic efficacy during BRB and ischemic stroke BBB dysfunction in mice.
- Jie Ding
- , Sung-Jin Lee
- & Calvin J. Kuo
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Matters Arising
| Open AccessReply to: The G protein preference of orexin receptors is currently an unresolved issue
- Jie Yin
- , Yanyong Kang
- & Daniel M. Rosenbaum
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Article
| Open AccessAntibody blockade of Jagged1 attenuates choroidal neovascularization
Current treatment for neovascular age-related macular degeneration (nAMD) does not help all patients. Here, the authors show that using antibodies to block Jagged1 reduces disease burden in a model of nAMD, which could enable new treatment options.
- Torleif Tollefsrud Gjølberg
- , Jonas Aakre Wik
- & Eirik Sundlisæter