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| Open AccessTranscriptomic profiling of skeletal muscle adaptations to exercise and inactivity
The pathways that underlie the effects of exercise on metabolism remain incompletely described. Here, the authors perform a meta-analysis of transcriptomic data from 66 published datasets of human skeletal muscle. They identify pathways selectively activated by inactivity, aerobic or resistance exercise, and characterize NR4A3 as one of the genes responsive to inactivity.
- Nicolas J. Pillon
- , Brendan M. Gabriel
- & Juleen R. Zierath
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Article
| Open AccessSingle AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice
Replacing mutant genes with wildtype copies using adeno-associated virus (AAV) has been explored for the treatment of inherited retinopathies, but the low cargo limit restricts its use. Here the authors describe a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end joining.
- Koji M. Nishiguchi
- , Kosuke Fujita
- & Toru Nakazawa
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Article
| Open AccessEndothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype
Vascular senescence is closely associated with individual ageing, while its causative role remains unclear. Here Barinda et al. generate endothelial cell-specific progeroind mice, and reveal that endothelial cell senescence directly induces metabolic disorders through senescence-messaging secretomes.
- Agian Jeffilano Barinda
- , Koji Ikeda
- & Noriaki Emoto
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Article
| Open AccessNon-invasive characterization of human bone marrow stimulation and reconstitution by cell-free messenger RNA sequencing
Circulating cell-free mRNA holds great promise as a non-invasive diagnostic biomarker. Here the authors show that cell-free mRNA captures transcripts from the bone marrow and can be used to non-invasively monitor dynamic changes in bone marrow physiology.
- Arkaitz Ibarra
- , Jiali Zhuang
- & Michael Nerenberg
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Article
| Open AccessSestrins are evolutionarily conserved mediators of exercise benefits
Exercise improves metabolic health and physical condition, particularly important for health in aged individuals. Here, the authors identify that Sestrins, proteins induced by exercise, are key mediators of the metabolic adaptation to exercise and increase endurance through the AKT and PGC1a axes.
- Myungjin Kim
- , Alyson Sujkowski
- & Jun Hee Lee
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Article
| Open AccessO-GlcNAc transferase inhibits visceral fat lipolysis and promotes diet-induced obesity
Post-translational O-linked β-N acetylglucosamine (O-GlcNAc) modification acts as a nutrient-sensing mechanism. Here the authors report that O-GlcNAc transferase inhibits adipose tissue lipolysis via O-GlcNAcylation of the lipid droplet protein perilipin 1 and thus promotes diet-induced obesity.
- Yunfan Yang
- , Minnie Fu
- & Xiaoyong Yang
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Article
| Open AccessAn independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment
In breast cancer, the immune infiltration of the tumour associates with clinical outcome. Here, the authors infer immune context based on gene expression data and identify a new independent subtype linked to pro-tumorigenic immune infiltration.
- Xavier Tekpli
- , Tonje Lien
- & Vessela N. Kristensen
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Article
| Open AccessThe long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia
LncRNAs at the HOX gene locus are increased in expression in NPM1 mutant acute myeloid leukemia. In this study, the authors show that one such lncRNA, HOX3B-AS3, has a role in regulating gene transcription and protein synthesis in leukemia cells.
- Dimitrios Papaioannou
- , Andreas Petri
- & Ramiro Garzon
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Article
| Open AccessModulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo
The ERK signalling pathway is activated in many cancers, however ERK1 and ERK2 are difficult to target pharmacologically. Here, the authors identify a small molecule inhibitor that binds covalently to the D-recruitment site of ERK and induces cell death and reduces tumour growth in mice.
- Tamer S. Kaoud
- , William H. Johnson
- & Kevin N. Dalby
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Article
| Open AccessMetabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty
Risk of age-related chronic disorders and decrease in resilience is associated with ageing. Here the authors analyse the human blood metabolome and identify metabolites associated with frailty.
- Nicholas J. W. Rattray
- , Drupad K. Trivedi
- & Royston Goodacre
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Article
| Open AccessEngineered amphiphilic peptides enable delivery of proteins and CRISPR-associated nucleases to airway epithelia
Delivering biological cargo to airway epithelial cells is very challenging. Here, the authors use engineered amphiphilic peptides to shuttle proteins and CRISPR RNPs into airway cells in vivo.
- Sateesh Krishnamurthy
- , Christine Wohlford-Lenane
- & Paul B. McCray Jr.
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Article
| Open AccessPhosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion
Elevated inorganic phosphate levels promote excessive parathyroid hormone secretion, which contributes to the aetiology of secondary hyperparathyroidism. Here, the authors show that phosphate directly inhibits the calcium-sensing receptor, the main regulator of parathyroid hormone secretion.
- Patricia P. Centeno
- , Amanda Herberger
- & Donald T. Ward
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Article
| Open AccessSustained elevation of MG53 in the bloodstream increases tissue regenerative capacity without compromising metabolic function
MG53 is a protein that regulates the cell membrane repair process, and it’s been suggested that it might play a role in diabetes. Here, the authors demonstrate that circulating MG53 functions as a myokine to facilitate tissue injury-repair and regeneration without impacting glucose handling.
- Zehua Bian
- , Qiang Wang
- & Jianjie Ma
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Article
| Open AccessAlterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas
Infant gliomas behave differently to their childhood or adult counterparts. Here, the authors perform a large-scale genetic analysis of these tumours, revealing genetic alterations which may offer therapeutic opportunities.
- Ana S. Guerreiro Stucklin
- , Scott Ryall
- & Cynthia Hawkins
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Article
| Open AccessRBM3 promotes neurogenesis in a niche-dependent manner via IMP2-IGF2 signaling pathway after hypoxic-ischemic brain injury
Therapeutic hypothermia is a potent tool in the treatment of neonatal hypoxic-ischemic (HI) injury, yet the underlying mechanisms remain unclear. Here, authors demonstrate how the RNA-binding motif protein RBM3, which is induced by mild cooling while global translation rate is slowed down, contributes substantially to neuroregeneration after adult HI injury, specifically in the subventricular zone and subgranular zone.
- Xinzhou Zhu
- , Jingyi Yan
- & Sven Wellmann
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Article
| Open AccessActivating newborn neurons suppresses depression and anxiety-like behaviors
It is unclear if there is a causal link between increased neurogenesis and altered affective behaviors in major depressive disorders. Here, the authors show that selectively suppressing the excitability of newborn neurons, without altering neurogenesis, abolishes the antidepressant effects of fluoxetine.
- Elif Tunc-Ozcan
- , Chian-Yu Peng
- & John A. Kessler
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Article
| Open AccessStandard screening methods underreport AAV-mediated transduction and gene editing
Conventional methods to detect AAV vector transduction can miss transient or low levels of reporter expression. Here the authors use editing-reporter mice and discover numerous sites of AAV targeting along with better prediction of the gene editing footprint.
- Jonathan F. Lang
- , Sushila A. Toulmin
- & Beverly L. Davidson
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Article
| Open AccessMolecular retargeting of antibodies converts immune defense against oncolytic viruses into cancer immunotherapy
The efficacy of oncolytic adenoviruses is limited by strong immune responses being induced against the oncolytic virus itself. Here, the authors generate a bispecific molecule capable of redirecting the adenovirus-specific antibodies to tumour cells and show this induces immune mediated cancer growth inhibition and enhances the therapeutic efficacy of viral oncolysis.
- Julia Niemann
- , Norman Woller
- & Florian Kühnel
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Article
| Open AccessUpper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling
Upper tract urothelial carcinoma (UTUC) is an aggressive cancer and largely uncharacterised cancer. Here, Faltas and colleagues report its distinctive molecular and immune landscape compared to urothelial carcinoma of the bladder and explore the role of FGFR3 signaling in UTUC biology.
- Brian D. Robinson
- , Panagiotis J. Vlachostergios
- & Bishoy M. Faltas
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Article
| Open AccessMolecular tuning of farnesoid X receptor partial agonism
The ligand-activated transcription factor farnesoid X receptor (FXR) acts as a cellular sensor for bile acids and is of interest as a drug target. Here the authors employ X-ray crystallography and NMR to characterize the molecular determinants of FXR agonists, antagonists and a partial agonist that drive FXR activation and antagonism.
- Daniel Merk
- , Sridhar Sreeramulu
- & Harald Schwalbe
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Article
| Open AccessDOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation
Histone 3 lysine 79 is mono (me1), di (me2), or tri (me3) methylated by the methyltransferase DOT1L. Here the authors reveal a group of enhancers defined by H3K79me2/3 which regulates enhancer-promoter interactions and other key enhancer features in MLL-AF4 leukemia cells.
- Laura Godfrey
- , Nicholas T. Crump
- & Thomas A. Milne
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Article
| Open AccessReduced subcutaneous adipogenesis in human hypertrophic obesity is linked to senescent precursor cells
Adipose tissue hypertrophy in obesity is associated with insulin resistance and other metabolic complications. Here, the authors analyze subcutaneous adipose tissue from patients with hypertrophic obesity and insulin resistance and find that adipocyte progenitor cells show features of senescence and have poor differentiation capacity.
- Birgit Gustafson
- , Annika Nerstedt
- & Ulf Smith
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Article
| Open AccessTranslatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells
The ribosomal protein RPL10 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). Here, the authors show that it promotes proliferation of T-ALL cells by upregulating the serine biosynthesis enzyme phosphoserine phosphatase which in turn modulates serine and glycine metabolism.
- Kim R. Kampen
- , Laura Fancello
- & Kim De Keersmaecker
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Article
| Open AccessFibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B
Fibroadipogenic precursor cells (FAPs) contribute to fibrosis and adipogenic replacement in muscular dystrophies. Here, the authors show that FAPs contribute to adipogenic loss in mouse models of limb girdle muscular dystrophy 2B via a mechanism dependent on expression of Annexin A2, and that this process can be prevented by its pharmacologic inhibition in mice.
- Marshall W. Hogarth
- , Aurelia Defour
- & Jyoti K. Jaiswal
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Article
| Open AccessImpaired cellular energy metabolism in cord blood macrophages contributes to abortive response toward inflammatory threats
Neonatal immune responses are known to differ to those of an adult immune response. Here Dreschers and colleagues, compare macrophage populations derived from cord blood or adult peripheral blood and show a metabolic impairment of glycolysis in macrophages derived from cord blood which may impair response to infective scenarios such as sepsis.
- Stephan Dreschers
- , Kim Ohl
- & Klaus Tenbrock
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Article
| Open AccessHepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα
Dysregulation of PPARα dependent fatty acid oxidation promotes hepatic steatosis. Here the authors show that GPS2 inhibits PPARα activity and that ablation of GPS2 ameliorates hepatic steatosis in mice.
- Ning Liang
- , Anastasius Damdimopoulos
- & Rongrong Fan
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Article
| Open AccessDefective homologous recombination DNA repair as therapeutic target in advanced chordoma
Chordomas are rare bone tumors with limited therapeutic options. Here, the authors identify molecular alterations associated with defective homologous recombination DNA repair in advanced chordomas and report prolonged response in a patient treated with a PARP inhibitor, which later acquired resistance due to a newly gained PARP1 mutation.
- Stefan Gröschel
- , Daniel Hübschmann
- & Stefan Fröhling
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Article
| Open AccessHepatic arginase 2 (Arg2) is sufficient to convey the therapeutic metabolic effects of fasting
Fasting is known for its beneficial effects on obesity and diabetes-related health complications. Here Zhang et al. show that fasting induces expression of arginase-2 (Arg2) in the liver, and that hepatic Arg2, by suppressing the expression of the regulator of G-protein signalling 16, recapitulates the positive effects of fasting in obesity and diabetes.
- Yiming Zhang
- , Cassandra B. Higgins
- & Brian J. DeBosch
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Article
| Open AccessMechanical stretch induces hair regeneration through the alternative activation of macrophages
Mechanical stimulation is known to affect cell proliferation, differentiation, and regeneration. Here, the authors demonstrate that stretching mouse skin recruits macrophages and polarizes them into M2 cells that facilitate hair regeneration through the release of growth factors, including HGF and IGF-1
- Szu-Ying Chu
- , Chih-Hung Chou
- & Oscar K. Lee
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Article
| Open AccessUSP8 maintains embryonic stem cell stemness via deubiquitination of EPG5
Autophagy is implicated in self-renewal of stem cells, including embryonic stem cells (ES cells). Here the authors demonstrate EPG5 is highly expressed in ES cells, and its deubiquitylation by USP8 stimulates its interaction with LC3 to promote autophagy and maintenance of stemness.
- Haifeng Gu
- , Xingxing Shi
- & Tongbiao Zhao
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Article
| Open AccessDiagnosis of fusion genes using targeted RNA sequencing
Rapid and accurate detection of fusion genes is important in cancer diagnostics. Here, the authors demonstrate that targeted RNA sequencing provides fast, sensitive and quantitative gene fusion detection and overcomes the limitations of approaches currently in clinical use.
- Erin E. Heyer
- , Ira W. Deveson
- & James Blackburn
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Article
| Open AccessThe deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors
Deubiquitinases have been shown to be involved in double strand break repair pathways. Here the authors reveal that USP15 deybiquitinase plays a role in homologues recombination repair by targeting BARD1 and affecting cells response to PARP inhibitors.
- Yihan Peng
- , Qingchao Liao
- & Huadong Pei
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Article
| Open AccessCRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations
CRISPR-Cas9 has been rapidly adopted to generate cell line models of disease. Here the authors show, while attempting to establish a congenital erythropoietic porphyria model, unexpected chromosome truncations generated by a p53-dependent mechanism.
- Grégoire Cullot
- , Julian Boutin
- & Aurélie Bedel
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Article
| Open AccessG-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma
ATRX deficiency is linked to genomic stability in cancer cells. Here, the authors show that ATRX inactivation induces G-quadruplex formation, leading to genome-wide DNA damage, and the use of G-quadruplex stabilisers can be exploited therapeutically in ATRX deficient gliomas.
- Yuxiang Wang
- , Jie Yang
- & Jason T. Huse
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Article
| Open AccessEngineered transfer RNAs for suppression of premature termination codons
Premature termination codon suppression therapy could be used to treat a range of genetic disorders. Here the authors present a high-throughput cell-based assay to identify anticodon engineered tRNAs with high suppression activity.
- John D. Lueck
- , Jae Seok Yoon
- & Christopher A. Ahern
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Article
| Open AccessImprovement of antibody functionality by structure-guided paratope engraftment
Quaternary contacts mediated by an extended heavy-chain framework region 3 (FR3) have been shown to improve binding to HIV envelope and virus neutralization for a few antibodies. Here, Liu et al. engraft such an FR3 loop onto several potent broadly neutralizing antibodies, resulting in improved neutralization activity and pharmacokinetics.
- Qingbo Liu
- , Yen-Ting Lai
- & Paolo Lusso
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Article
| Open AccessDeregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer
Loss of PIK3R1 in ovarian cancer is a common event, which provides opportunities for therapeutic intervention. Here, the authors show that the STAT3 and AKT signaling pathways are activated upon PIK3R1 loss and that, in mice, inhibitors of these pathways could block tumorigenesis.
- Xinran Li
- , Victor C. Y. Mak
- & Lydia W. T. Cheung
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Article
| Open AccessFolliculin regulates mTORC1/2 and WNT pathways in early human pluripotency
The pathways involved in exit from pluripotency in human embryonic stem cells are poorly understood. Here, the authors performed a CRISPR-based screen to identify genes that promote exit from naïve pluripotency and find a role for folliculin (FLCN) by regulating the mTOR and Wnt pathways.
- J. Mathieu
- , D. Detraux
- & H. Ruohola-Baker
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Article
| Open AccessAAV2.7m8 is a powerful viral vector for inner ear gene therapy
Adeno-associated virus is used in gene therapy in mouse models of hearing loss. Here the authors compare vectors and find AAV2.7m8 can infect cells in the inner ear with high efficiency.
- Kevin Isgrig
- , Devin S. McDougald
- & Wade W. Chien
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Article
| Open AccessPodocyte GSK3 is an evolutionarily conserved critical regulator of kidney function
Glycogen Synthase Kinase 3 (GSK3) has conserved functions across species but its role in the kidney is unclear. Here, the authors show that in the kidney podocyte cell of mice and related nephrocyte in Drosophila that GSK3 is a master regulator of function both during development and in maturity.
- J. A. Hurcombe
- , P. Hartley
- & R. J. M. Coward
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Article
| Open AccessSensitivity to splicing modulation of BCL2 family genes defines cancer therapeutic strategies for splicing modulators
Small molecule modulators of RNA splicing have therapeutic potential in tumours bearing spliceosome mutations. Here, the authors identify BCL2 genes have differential sensitivities to SF3b-targeting splicing modulators and combination of SF3b-targeting splicing modulators and BCLxL inhibition induces synergistic cytotoxicity in cancer cells.
- Daniel Aird
- , Teng Teng
- & Ping Zhu
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Article
| Open AccessMyopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks
BAG3 is a Hsp70 co-chaperone that is highly expressed in muscles. Here the authors show that several myofibrillar myopathy causing BAG3 mutations are not impaired in Hsp70 binding, but rather impair the ADP-ATP exchange step of the Hsp70 cycle, causing the aggregation of BAG3, Hsp70 and Hsp70 clients and leading to a collapse of protein homeostasis.
- Melanie Meister-Broekema
- , Rebecca Freilich
- & Harm H. Kampinga
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Article
| Open AccessA phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia
The molecular pathway(s) driving antipsychotics (AP) induced hyperphagia remains unclear. A novel C. elegans system is used here to screen for FDA approved drugs that selectively suppresses this response, unraveling potential molecular mediators influencing AP induced hyperphagia in mouse models.
- Anabel Perez-Gomez
- , Maria Carretero
- & Michael Petrascheck
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Article
| Open AccessCytoplasmic LIF reprograms invasive mode to enhance NPC dissemination through modulating YAP1-FAK/PXN signaling
Molecular pathways regulating nasopharyngeal carcinoma (NPC) metastasis are unclear. Here they report higher levels of cytoplasmic leukemia inhibitory factor (cLIF) and LIF receptor (LIFR) to correlate with higher metastasis in NPC patients, and show cLIF to promote NPC metastasis and vascular dissemination via the YAP1-FAK/PXN axis.
- Shu-Chen Liu
- , Tien Hsu
- & Ngan-Ming Tsang
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Comment
| Open AccessMacrophages regulate the clearance of living cells by calreticulin
- Dmitri V. Krysko
- , Kodi S. Ravichandran
- & Peter Vandenabeele
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Article
| Open AccessNeomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies
Activation of PDGFRA by genomic aberrations contributes to tumor progression in several tumor types. Here, the authors perform functional characterization of 16 novel PDGFRA mutations identified from different tumor types and demonstrate that a neomorphic PDGFRA extracellular domain driver mutation is resistant to PDGFRA targeted therapies.
- Carman K. M. Ip
- , Patrick K. S. Ng
- & Gordon B. Mills
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Article
| Open AccessA discrete organoplatinum(II) metallacage as a multimodality theranostic platform for cancer photochemotherapy
It is challenging to design photosensitizers (PS) with high quantum yields generating singlet oxygen due to severe aggregation between the hydrophobic PSs. Here they develop organoplatinum(II) metallatocage-based PS to overcome these challenges and show excellent antitumor effect.
- Guocan Yu
- , Shan Yu
- & Xiaoyuan Chen
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Article
| Open AccessDRUG-seq for miniaturized high-throughput transcriptome profiling in drug discovery
RNA-seq is a powerful tool to investigate how drugs affect the transcriptome but library construction can be costly. Here the authors introduce DRUG-seq, an automated platform for high-throughput transcriptome profiling.
- Chaoyang Ye
- , Daniel J. Ho
- & Ajamete Kaykas
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Article
| Open AccessPrecisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions
Measuring precise protein turnover rates in animals is technically challenging at the proteomic level. Here, Fornasiero and colleagues use isotopic labeling with mass spectrometry and mathematical modeling to accurately determine protein lifetimes in the mouse brain
- Eugenio F. Fornasiero
- , Sunit Mandad
- & Silvio O. Rizzoli