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| Open AccessGenome-wide functional screening of drug-resistance genes in Plasmodium falciparum
Plasmodium falciparum malaria is treated using artemisinin combination therapy (ACT), in which artemisinin is supplied along with partner drugs such as mefloquine, piperaquine, and lumefantrine. However, resistance has been reported in endemic regions. To identifying new effector genes involved in resistance, Iwanaga et al. develop a large scale transgenic screen with genomic libraries of resistance strains. Using this approach they provide evidence that transcriptional upregulation of pfmdr7 contributes to mefloquine resistance in a clinical isolate.
- Shiroh Iwanaga
- , Rie Kubota
- & Chairat Uthaipibull
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Article
| Open AccessConnecting omics signatures and revealing biological mechanisms with iLINCS
There are only a few platforms that integrate multiple omics data types, bioinformatics tools, and interfaces for integrative analyses and visualization that do not require programming skills. Here the authors present an integrative web-based platform for analysis of omics data and signatures of cellular perturbations.
- Marcin Pilarczyk
- , Mehdi Fazel-Najafabadi
- & Mario Medvedovic
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Article
| Open AccessRare loss of function variants in the hepatokine gene INHBE protect from abdominal obesity
Abdominal fat has been shown to increase cardiometabolic disease risk. In this study, the authors report that loss-of-function variants in the gene INHBE associate with lower BMI-adjusted waist-to-hip ratio, a surrogate measure of abdominal fat.
- Aimee M. Deaton
- , Aditi Dubey
- & Paul Nioi
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Article
| Open AccessTargeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
Antibodies targeting sclerostin can ameliorate postmenopausal osteoporosis but present some cardiovascular risk. Here the authors show that the cardiovascular and skeletal effects of sclerostin are mediated by different loops, suggesting ways to preserve the positive effects on bone formation while avoiding the negative cardiovascular consequences.
- Yuanyuan Yu
- , Luyao Wang
- & Ge Zhang
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Article
| Open AccessTargeting dual-specificity tyrosine phosphorylation-regulated kinase 2 with a highly selective inhibitor for the treatment of prostate cancer
The kinase DYRK2 is a known oncogene but its role in prostate cancer is unexplored. Here, the authors identify DYRK2 as a target for prostate cancer with a role in invasion and they discover a specific DYRK2 inhibitor that has good pharmacokinetics and efficacy in vivo.
- Kai Yuan
- , Zhaoxing Li
- & Peng Yang
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Article
| Open AccessADAMTS4-specific MR probe to assess aortic aneurysms in vivo using synthetic peptide libraries
New biomarkers are required to improve the assessment of aortic wall integrity and risk of rupture. Here the authors report the development of an imaging probe for ADAMTS4, which they test in an abdominal aortic aneurysm mouse model and show in vivo prediction of aneurysm and rupture.
- Jan O. Kaufmann
- , Julia Brangsch
- & Marcus R. Makowski
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Article
| Open AccessAIMP2-DX2 provides therapeutic interface to control KRAS-driven tumorigenesis
Direct targeting of oncogenic KRAS activity is a challenge. Here the authors report that a splice variant of AIMP2, AIMP2-DX2, enhances KRAS stability by blocking ubiquitin-mediated degradation of KRAS via the E3 ligase, Smurf2, and identify a chemical that can hinder AIMP2-DX2 from interacting with KRAS.
- Dae Gyu Kim
- , Yongseok Choi
- & Sunghoon Kim
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Article
| Open AccessIdentification of oleoylethanolamide as an endogenous ligand for HIF-3α
Whether hypoxia-inducible factors (HIFs) can be directly regulated by endogenous small molecules is a long-standing question. Here authors identified the metabolite oleoylethanolamide as a HIF-3α ligand and further revealed its mechanism of action.
- Xiaotong Diao
- , Fei Ye
- & Dalei Wu
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Article
| Open AccessAtaluren binds to multiple protein synthesis apparatus sites and competitively inhibits release factor-dependent termination
Ataluren is the only nonsense suppressor drug currently approved for clinical use. Here, the authors determine where ataluren binds to the ribosome and how it inhibits termination at nonsense codons.
- Shijie Huang
- , Arpan Bhattacharya
- & Barry S. Cooperman
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Article
| Open AccessDual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis
Osteoarthritic (OA) is characterized by progressive destruction of joint cartilage. Here, the authors show that microRNA-17 plays a dual role in maintaining cartilage homeostasis and in the prevention of osteoarthritis, by targeting hypoxia-inducible factor-1α as well as multiple matrix-degrading enzymes.
- Yun Zhang
- , Shuaijun Li
- & Lei Cui
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Article
| Open AccessActivation and allosteric regulation of the orphan GPR88-Gi1 signaling complex
GPR88 is an orphan GPCR and regulates diverse brain functions. Here, the authors report two structures of the human GPR88-Gi complex, showing an allosteric ligand directly involved in the interaction interface between the receptor and G-protein, and a density which may represent an endogenous ligand of GPR88.
- Geng Chen
- , Jun Xu
- & Yang Du
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Article
| Open AccessCFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway
Currently, there is no therapy for patients with cystic fibrosis caused by nonsense mutations. Here the authors show that CFTR mRNAs with nonsense codons are predominantly degraded by the SMG6-mediated branch of the NMD pathway, providing potential therapeutic strategies for the devastating disease.
- Edward J. Sanderlin
- , Melissa M. Keenan
- & Lulu Huang
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Article
| Open AccessCinA mediates multidrug tolerance in Mycobacterium tuberculosis
Drug tolerance complicates the treatment of tuberculosis. Here, Kreutzfeldt et al. show that the protein CinA mediates drug tolerance in Mycobacterium tuberculosis by cleaving NAD-drug adducts, suggesting CinA as a potential target to shorten tuberculosis treatment by potentiating the efficacy of currently used antibiotics.
- Kaj M. Kreutzfeldt
- , Robert S. Jansen
- & Sabine Ehrt
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Article
| Open AccessDistinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors
How resistance to different classes of AKT inhibitors can emerge is unclear. Here, the authors show that resistance to allosteric inhibitors is mainly due to mutation of AKT1 while the ATP competitive resistance is driven by activation of PIM kinases in prostate cancer models.
- Kristin M. Zimmerman Savill
- , Brian B. Lee
- & Kui Lin
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Article
| Open AccessAn anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA
Here, Zhao et al. characterize the anti-viral effect of the compound APL-16-5, which is originally derived from the plant endophytic fungus Aspergillus, on Influenza A virus infection in vitro and in vivo. They find that APL-16-5 binds to the E3 ligase TRIM25 and viral polymerase subunit PA and therewith mediates ubiquitination of PA and subsequent proteasome-mediated degradation.’
- Jianyuan Zhao
- , Jing Wang
- & Shan Cen
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Article
| Open AccessKnowledge graph-based recommendation framework identifies drivers of resistance in EGFR mutant non-small cell lung cancer
Resistance to EGFR inhibitors presents a major obstacle in treating non-small cell lung cancer. Here, the authors develop a recommender system ranking genes based on trade-offs between diverse types of evidence linking them to potential mechanisms of EGFRi resistance.
- Anna Gogleva
- , Dimitris Polychronopoulos
- & Krishna C. Bulusu
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Article
| Open AccessA proximity biotinylation-based approach to identify protein-E3 ligase interactions induced by PROTACs and molecular glues
PROTACs and molecular glues target E3 ubiquitin ligases to substrate proteins. Here, the authors develop a proximity biotinylation-based method to identify drug-induced E3 ligase-substrate interactions, enabling the assessment of the target spectrum of PROTACs and molecular glues in cells.
- Satoshi Yamanaka
- , Yuto Horiuchi
- & Tatsuya Sawasaki
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Article
| Open AccessSliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket – targeting P-pocket by fragment screening
Here the authors observe a transient P-pocket created when HIV reverse transcriptase slides over DNA substrate, identify fragments targeting this pocket, and develop a cryo-EM platform for lead optimization.
- Abhimanyu K. Singh
- , Sergio E. Martinez
- & Kalyan Das
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Article
| Open AccessLight-mediated discovery of surfaceome nanoscale organization and intercellular receptor interaction networks
The spatial organization of cell surface receptors is critical for cell signaling and drug action. Here, the authors develop an optoproteomic method for mapping surface protein interactions, revealing cellular responses to antibodies, drugs and viral particles as well as immunosynapse signaling events.
- Maik Müller
- , Fabienne Gräbnitz
- & Bernd Wollscheid
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Article
| Open AccessNetwork medicine for disease module identification and drug repurposing with the NeDRex platform
There is an unmet need for adaptable tools allowing biomedical researchers to employ network-based drug repurposing approaches for their individual use cases. Here, the authors close this gap with NeDRex, an integrative and interactive platform.
- Sepideh Sadegh
- , James Skelton
- & Tim Kacprowski
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Article
| Open AccessA unified drug–target interaction prediction framework based on knowledge graph and recommendation system
Prediction of drug-target interactions (DTI) plays a vital role in drug development through applications in various areas, such as virtual screening for lead discovery, drug repurposing and identification of potential drug side effects. Here, the authors develop a unified framework for DTI prediction by combining a knowledge graph and a recommendation system.
- Qing Ye
- , Chang-Yu Hsieh
- & Tingjun Hou
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Article
| Open AccessThe chemotherapeutic CX-5461 primarily targets TOP2B and exhibits selective activity in high-risk neuroblastoma
CX-5461 recently progressed through phase I clinical trial as a first-inhuman inhibitor of RNA-POL I. Here, the authors demonstrate that CX-5461 synergizes with topoisomerase I inhibitors to inhibit neuroblastoma cells and that its primary target in this disease is topoisomerase II beta and not RNA-POL I.
- Min Pan
- , William C. Wright
- & Paul Geeleher
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Article
| Open AccessThe serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation
Mechanisms triggering hypertrophic scar formation remain poorly understood. Here the authors perform scRNA-seq on mature human hypertrophic scars and developing scars in mice to identify the serine proteases dipeptidyl-peptidase 4 and urokinase as key molecules in this process.
- Vera Vorstandlechner
- , Maria Laggner
- & Michael Mildner
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Article
| Open AccessChemical proteomic profiling reveals protein interactors of the alarmones diadenosine triphosphate and tetraphosphate
Diadenosine polyphosphates (ApAs) are involved in cellular stress signaling but only a few molecular targets have been characterized so far. Here, the authors develop ApnA-based photoaffinity-labeling probes and use them to identify Ap3A and Ap4A binding proteins in human cell lysates.
- Lena Krüger
- , Christoph J. Albrecht
- & Andreas Marx
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| Open AccessMultifaceted mechanisms mediating cystine starvation-induced ferroptosis
The cyst(e)ine/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis is the most frequently targeted pathway to trigger the ferroptosis cascade and suppress tumor growth. Two recent studies present additional mechanisms underlying cystine starvation-induced ferroptosis apart from impaired GSH synthesis.
- Zhennan Shi
- , Nathchar Naowarojna
- & Yilong Zou
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Article
| Open AccessA deep learning approach to identify gene targets of a therapeutic for human splicing disorders
Drugs that modify RNA splicing are promising treatments for many genetic diseases. Here the authors show that deep learning strategies can predict drug targets, strongly supporting the use of in silico approaches to expand the therapeutic potential of drugs that modulate RNA splicing.
- Dadi Gao
- , Elisabetta Morini
- & Susan A. Slaugenhaupt
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Article
| Open AccessSmall-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues
Although Hippo signaling restricts regeneration in many mammalian organs, the pharmaceutical tools available to modulate the pathway have been limited. Here, the authors report a small molecule that may inhibit a key element in the Hippo cascade and may activate regenerative responses in several mammalian tissues.
- Nathaniel Kastan
- , Ksenia Gnedeva
- & A. J. Hudspeth
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Article
| Open AccessNaturally-occurring spinosyn A and its derivatives function as argininosuccinate synthase activator and tumor inhibitor
Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.
- Zizheng Zou
- , Xiyuan Hu
- & Zhiyong Luo
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Article
| Open AccessIdentifying therapeutic drug targets using bidirectional effect genes
Prioritising genes as potential drug targets is challenging and often unsuccessful once testing efficacy in humans. Here, the authors propose an approach to identifying drug targets that uses evidence from gain- or loss-of-function mutations associated with bidirectional effects on phenotypes.
- Karol Estrada
- , Steven Froelich
- & Lon R. Cardon
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Article
| Open AccessIdentification of CD318, TSPAN8 and CD66c as target candidates for CAR T cell based immunotherapy of pancreatic adenocarcinoma
There is an unmet clinical need to identify therapeutic options for the treatment of pancreatic cancer (PDAC). Here the authors present a systematic screening approach for the identification of potential PDAC cell surface target candidates for CAR-T cell based immunotherapy, followed by their functional validation in preclinical models.
- Daniel Schäfer
- , Stefan Tomiuk
- & Olaf Hardt
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Article
| Open AccessAccelerating target deconvolution for therapeutic antibody candidates using highly parallelized genome editing
Efficient deconvolution of antibody targets is needed for phenotype-based discovery. Here, the authors investigate a deconvolution approach based on pooled CRISPR Cas9 to achieve 97% deconvolution success rate.
- Jenny Mattsson
- , Ludvig Ekdahl
- & Björn Nilsson
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Article
| Open AccessHistamine H1 receptor deletion in cholinergic neurons induces sensorimotor gating ability deficit and social impairments in mice
Social impairment and anhedonia are common negative symptoms in patients with schizophrenia. Here, the authors show that the histamine H1 receptor in cholinergic neurons in the basal forebrain has a critical role in sensorimotor gating, social behaviour, and anhedonia-like behaviour in mice.
- Li Cheng
- , Cenglin Xu
- & Zhong Chen
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Article
| Open AccessEltrombopag directly inhibits BAX and prevents cell death
The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.
- Adam Z. Spitz
- , Emmanouil Zacharioudakis
- & Evripidis Gavathiotis
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Article
| Open AccessTargeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease
Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.
- Antonio Garcia-Gomez
- , Tianlu Li
- & Esteban Ballestar
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Article
| Open AccessTargeting N-myristoylation for therapy of B-cell lymphomas
N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.
- Erwan Beauchamp
- , Megan C. Yap
- & Luc G. Berthiaume
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Article
| Open AccessRaman-guided subcellular pharmaco-metabolomics for metastatic melanoma cells
Single-cell metabolomics can offer deep insights into the metabolic reprogramming that accompanies disease states. Here, the authors use Raman spectro-microscopy for non-invasive metabolite analysis and identification of druggable metabolic susceptibilities in single live melanoma cells.
- Jiajun Du
- , Yapeng Su
- & Lu Wei
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Article
| Open AccessIRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex
Human enterovirus 71 (EV71) contains an internal ribosome entry site (IRES) that promotes translation of viral RNA. Here the authors show that an antiviral small molecule DMA-135 binds to the EV71 IRES RNA, inducing conformational change and stabilizing a ternary complex to repress translation.
- Jesse Davila-Calderon
- , Neeraj N. Patwardhan
- & Blanton S. Tolbert
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Article
| Open AccessFeline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication
Coronavirus main protease is essential for viral polyprotein processing and replication. Here Vuong et al. report efficient inhibition of SARS-CoV-2 replication by the dipeptide-based protease inhibitor GC376 and its parent GC373, which were originally used to treat feline coronavirus infection.
- Wayne Vuong
- , Muhammad Bashir Khan
- & M. Joanne Lemieux
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Article
| Open AccessIdentification of osteogenic progenitor cell-targeted peptides that augment bone formation
Activation of osteogenic cells is essential for bone regeneration. Here, the authors screen a peptide library and identify 2 compounds that promote osteogenic progenitor cell differentiation in vitro, and show that they increase bone formation and fracture repair in mice.
- Min Jiang
- , Ruiwu Liu
- & Wei Yao
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Article
| Open AccessA machine learning-based chemoproteomic approach to identify drug targets and binding sites in complex proteomes
Proteomics is often used to map protein-drug interactions but identifying a drug’s protein targets along with the binding interfaces has not been achieved yet. Here, the authors integrate limited proteolysis and machine learning for the proteome-wide mapping of drug protein targets and binding sites.
- Ilaria Piazza
- , Nigel Beaton
- & Lukas Reiter
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Article
| Open AccessTRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target
Depletion of tribbles pseudokinase 3 (TRIB3) is known to suppress the expression of several tumor-promoting factors, including EGFR. Here, the authors show that TRIB3 interacts with EGFR and regulates its stability and activity, and perturbing EGFR-TRIB3 interaction attenuates NSCLC progression by accelerating EGFR degradation.
- Jiao-jiao Yu
- , Dan-dan Zhou
- & Zhuo-Wei Hu
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Article
| Open AccessExploring the SARS-CoV-2 virus-host-drug interactome for drug repurposing
Information developed to understand the molecular mechanisms of SARS-CoV-2 infection for predicting drug repurposing candidates is time-consuming to integrate and explore. Here, the authors develop an interactive online platform for virus-host interactome exploration and drug (target) identification.
- Sepideh Sadegh
- , Julian Matschinske
- & Jan Baumbach
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Article
| Open AccessJawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol
Biosynthesis of glycosylphosphatidylinositol (GPI) is essential for the integrity of the fungal cell wall. Here, the authors show that the natural product jawsamycin inhibits GPI biosynthesis by targeting a subunit of the fungal UDP-glycosyltransferase, and displays pronounced activity against pathogenic fungi of the order Mucorales.
- Yue Fu
- , David Estoppey
- & Dominic Hoepfner
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Article
| Open AccessAn alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity
PDE3A modulators for cancer therapy cause serious side effects as they inhibit PDE3A phosphodiesterase activity, which is essential for the maturation of oocytes and the formation of platelets. Here, the authors identify a compound, nauclefine, that does not inhibit PDE3A activity but induces apoptosis by enabling a complex formation between PDE3A and SLFN12.
- Youwei Ai
- , Haibing He
- & Xiangbing Qi
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Article
| Open AccessBtk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms
Constitutive Btk signaling drives several B-cell cancers. Here the authors demonstrate key allosteric intramolecular interactions between the SH2 domain and the kinase domain of Btk, and propose an alternative approach for inhibition of both wild-type and tyrosine kinase inhibitor-resistant Btk.
- Daniel P. Duarte
- , Allan J. Lamontanara
- & Oliver Hantschel
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Article
| Open AccessIntegrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes
Benign prostatic hyperplasia (BPH) is one of the most common diseases affecting aging men with limited therapeutic options. In this study, the authors describe the molecular characterization of BPH performing genomic, transcriptomic and epigenetic analysis of 18 BPH cases.
- Deli Liu
- , Jonathan E. Shoag
- & Christopher E. Barbieri
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Article
| Open AccessPan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway
Imidazolopiperazines (IZPs) are a class of compounds under clinical development for malaria, but their mechanism of action is unclear. Here, the authors show that IZPs inhibit the parasite’s secretory pathway, affecting protein trafficking and export.
- Gregory M. LaMonte
- , Frances Rocamora
- & Elizabeth A. Winzeler
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Article
| Open AccessInterference with ERK-dimerization at the nucleocytosolic interface targets pathological ERK1/2 signaling without cardiotoxic side-effects
Drugs targeting dysregulated ERK1/2 signaling can cause severe cardiac side effects, precluding their wide therapeutic application. Here, a new and cardio-safe targeting strategy is presented that interferes with ERK dimerization to prevent pathological ERK1/2 signaling in the heart and cancer.
- Angela Tomasovic
- , Theresa Brand
- & Kristina Lorenz
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Article
| Open AccessPyrazinamide triggers degradation of its target aspartate decarboxylase
It has been shown that the bioactive component of pyrazinamide, pyrazinoic acid (POA), blocks coenzyme A biosynthesis in M. tuberculosis by binding to the aspartate decarboxylase PanD. Here the authors show that pyrazinamide triggers degradation of PanD by stimulating its degradation by the caseinolytic protease Clp.
- Pooja Gopal
- , Jickky Palmae Sarathy
- & Thomas Dick