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Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development
Alternative splicing is a process during gene expression that increases the diversity of proteins encoded by a single gene. Here, the authors perform RNA-sequencing on cardiac cells from mice and show that extensive changes in gene expression and alternative splicing occur during the first month after birth.
- Jimena Giudice
- , Zheng Xia
- & Thomas A. Cooper
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| Open AccessExperimental orthotopic transplantation of a tissue-engineered oesophagus in rats
Patients with oesophageal diseases may require surgical removal and replacement of the oesophagus. Here the authors seed mesenchymal stromal cells on a decellularized rat oesophagus and show that this bioengineered tissue construct restores swallowing function after transplantation into rats.
- Sebastian Sjöqvist
- , Philipp Jungebluth
- & Paolo Macchiarini
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Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1
The transcription factor NR5A1 has so far mainly been known for regulating the biosynthesis of steroids. Here the authors discover that NR5A1 also has a role in energy metabolism, demonstrating that NR5A1 regulates several key enzymes involved in the breakdown of glucose.
- Takashi Baba
- , Hiroyuki Otake
- & Ken-Ichirou Morohashi
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| Open AccessUltra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen
The potential of extracellular vesicles (EVs) as cancer biomarkers is substantial. Here, Yoshioka et al. describe a sensitive technique to analyse EVs directly from blood samples of patients with colorectal cancer, highlighting a liquid biopsy technique with cancer-detection possibilities.
- Yusuke Yoshioka
- , Nobuyoshi Kosaka
- & Takahiro Ochiya
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Methionine restriction extends lifespan of Drosophila melanogaster under conditions of low amino-acid status
Dietary restriction of the amino acid methionine extends the lifespan of rodents. Here the authors systematically test diets with varying amino-acid content and show that methionine restriction extends the lifespan of yeast and flies only when the content of other amino acids in the diet is also low.
- Byung Cheon Lee
- , Alaattin Kaya
- & Vadim N. Gladyshev
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CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation
The prohibitin complex promotes cell survival by regulating mitochondrial morphogenesis. Wang et al.identify a long non-coding RNA that regulates this complex in cardiomyocytes by acting as a sponge to downregulate a prohibitin-targetting miRNA, protecting cells from apoptosis in anoxic conditions.
- Kun Wang
- , Bo Long
- & Pei-Feng Li
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| Open AccessCaloric restriction reduces age-related and all-cause mortality in rhesus monkeys
Caloric restriction extends the lifespan of various organisms but whether it works in monkeys is controversial. Here, Colman et al.report that caloric restriction reduces all-cause mortality of rhesus macaques, and perform a weight comparison that aims to reconcile their findings with contradictory results from a similar study.
- Ricki J. Colman
- , T. Mark Beasley
- & Rozalyn M. Anderson
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Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen
Semen-derived peptides can form amyloid fibrils that boost HIV infection in vitro, but the existence of such fibrils in semen remained to be demonstrated. Here, the authors show that human semen contains amyloid fibrils, which can bind HIV particles and increase their infectiveness.
- Shariq M. Usmani
- , Onofrio Zirafi
- & Jan Münch
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Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling
The IRE1α-XBP1 signalling pathway is part of the ER stress response but has also been linked to glucose and lipid metabolism. Here the authors show that IRE1α in the liver acts as a nutrient-sensor, regulating the metabolic adaptation to fasting and a ketogenic diet by inducing PPARα expression.
- Mengle Shao
- , Bo Shan
- & Yong Liu
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Selective inhibition of BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle
A major problem in the treatment of bone tumours and metastases is the vicious cycle between bone tumours and resorption. Here, the authors show that treatment with the BET bromodomain inhibitor JQ1 inhibits osteoblast and osteoclast differentiation, and bone tumour development.
- François Lamoureux
- , Marc Baud’huin
- & Benjamin Ory
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Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction
The adipokine endotrophin promotes tumour inflammation and angiogenesis, but its effects on adipose tissue are unclear. Here, Sun et al.show that endotrophin promotes adipose tissue inflammation and fibrosis, and that injections of an anti-endotrophin antibody improve metabolic parameters of mice on a high-fat diet.
- Kai Sun
- , Jiyoung Park
- & Philipp E. Scherer
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| Open AccessBlockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome
Ionizing radiation damages small intestinal crypt cells, including epithelial stem cells and their progeny. Here the authors show that radiation-induced crypt cell death is amplified by the release of cellular RNA from apoptotic epithelial cells, which then triggers pro-apoptotic TLR3 signalling on neighbouring cells.
- Naoki Takemura
- , Takumi Kawasaki
- & Satoshi Uematsu
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Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice
Ionizing radiation damages the gastrointestinal system, but the cell types involved in intestinal damage and repair are controversial. Here the authors use bone marrow transplantation models and various irradiation regimes to rule out a role of bone marrow-derived cells in acute gastrointestinal injury and recovery in mice.
- Brian J. Leibowitz
- , Liang Wei
- & Jian Yu
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A highly efficient cocaine-detoxifying enzyme obtained by computational design
The enzyme butyrylcholinesterase (BChE) can metabolize cocaine, albeit at relatively low speeds. Here the authors use computational methods to define mutations that increase BChE-mediated cocaine hydrolysis, achieving a catalytic activity comparable to that of one of the fastest naturally occurring enzyme.
- Fang Zheng
- , Liu Xue
- & Chang-Guo Zhan
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Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity
Glucocorticoid levels in the body are controlled by an intricate feedback system acting on the hypothalamus. Here the authors provide molecular insight into this process, identifying TrkB signalling in cholecystokinin-GABAergic neurons as a key component of hypothalamic glucocorticoid signalling.
- Mirjam Geibel
- , Sylvia Badurek
- & Liliana Minichiello
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| Open AccessThe serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling
Hepatic insulin resistance is a hallmark of diabetes, but its aetiology is incompletely understood. Here, Uchimura and colleagues show that the serine protease prostasin cleaves Toll-like receptor 4 (TLR4) and regulates hepatic insulin sensitivity by modulating TLR4-mediated signalling.
- Kohei Uchimura
- , Manabu Hayata
- & Kenichiro Kitamura
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| Open AccessHACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress
HACE1 is an E3 ubiquitin ligase known to regulate various cell biological processes. Here, Zhang et al.identify HACE1 as a protective factor in the heart, demonstrating that HACE1 inhibits the development of heart failure in response to haemodynamic stress by regulating protein degradation pathways.
- Liyong Zhang
- , Xin Chen
- & Peter P. Liu
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The use of silk-based devices for fracture fixation
Current bone fracture repair options include metallic and resorbable systems, both of which suffer from various issues and limitations. Here, the authors demonstrate resorbable and biocompatible silk bone screws, via in vivotesting.
- Gabriel S. Perrone
- , Gary G. Leisk
- & David L. Kaplan
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Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity
Malfunction of the blood brain barrier (BBB) is implicated in disorders of the central nervous system. Here, Yao et al.show that astrocytic laminin maintains the integrity of the BBB by binding to integrin α2 receptors on BBB pericytes, thereby preventing their differentiation.
- Yao Yao
- , Zu-Lin Chen
- & Sidney Strickland
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3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium
Tools for cardiac physiological mapping are important for basic and clinical cardiac research. Here the authors use 3D printing to create a thin, elastic silicone sheath that fits tightly around the entire epicardium and contains sensors to measure a variety of physiological parameters of the beating heart ex vivo.
- Lizhi Xu
- , Sarah R. Gutbrod
- & John A. Rogers
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A cortical–spinal prosthesis for targeted limb movement in paralysed primate avatars
Brain–machine interfaces are being investigated for recovery of motor function after paralysis. Shanechi et al.present a neural prosthesis that decodes premotor neuronal activity in an alert monkey to activate spinal neurons and muscles that produce target-directed movements in a sedated monkey or avatar.
- Maryam M. Shanechi
- , Rollin C. Hu
- & Ziv M. Williams
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Notch2 activation ameliorates nephrosis
The Notch signalling pathway is normally inactive in adult kidneys, but reactivated in kidney diseases. Here the authors show that activation of Notch2 receptors protects renal podocytes from apoptosis, which contrasts with the known detrimental effects of Notch1 signalling on the progression of kidney disease.
- Eriko Tanaka
- , Katsuhiko Asanuma
- & Yasuhiko Tomino
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| Open AccessIRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling
The transcription factor interferon regulatory factor 8 (IRF8) is known to regulate differentiation and function of immune cells. Here the authors show that IRF8 is upregulated in the hypertrophic heart in humans and mice, where it suppresses cardiac remodelling by inhibiting calcineurin signalling.
- Ding-Sheng Jiang
- , Xiang Wei
- & Hongliang Li
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| Open AccessEstimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa
Reduction in malaria transmission has changed the age pattern of malaria incidence. This study brings insights into the changes in age distributions of clinical malaria across Africa, with importance for improving within-population targeting of malaria control interventions.
- Jamie T. Griffin
- , Neil M. Ferguson
- & Azra C. Ghani
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| Open AccessA rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages
Gene expression is highly variable between tissues, and changes during development and with age. Here, the authors provide a comprehensive RNA-Seq analysis of the rat transcriptome, spanning eleven organs, four developmental stages and both sexes.
- Ying Yu
- , James C. Fuscoe
- & Charles Wang
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Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy
N-methyl-D-aspartate receptors (NMDARs) are key regulators of neuronal excitability in the brain and NMDAR mutations are implicated in epilepsy. Here, the authors identify a NMDAR subunit mutation in a child with epileptic encephalopathy, and show that this mutation increases the activity of NMDAR channels.
- Hongjie Yuan
- , Kasper B. Hansen
- & Stephen F. Traynelis
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| Open AccessCritical roles of nardilysin in the maintenance of body temperature homoeostasis
The precise regulation of mammalian body temperature is important for survival. Here the authors show that the peptidase nardilysin represses the transcription factor PGC-1α, and identify nardilysin as a regulator of basal body temperature, cold-induced thermogenesis and body insulation.
- Yoshinori Hiraoka
- , Tatsuhiko Matsuoka
- & Eiichiro Nishi
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Autotransporters but not pAA are critical for rabbit colonization by Shiga toxin-producing Escherichia coli O104:H4
An outbreak of diarrhoea and haemolytic uraemic syndrome in Germany in 2011 was caused by a Shiga toxin-producing enteroaggregative E. coli, which carried the aggregative adherence plasmid pAA. Here, the authors show that autotransporters, but not pAA, are required for intestinal colonization in an infant rabbit model.
- Diana Munera
- , Jennifer M. Ritchie
- & Matthew K. Waldor
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Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection
Antibiotics alter the intestinal microbiota and facilitate colonization of pathogens such as Clostridium difficile. Here, the authors show that antibiotic-induced shifts in the mouse gut microbiome are correlated with changes in levels of certain metabolites that C. difficilecan use for germination and growth.
- Casey M. Theriot
- , Mark J. Koenigsknecht
- & Vincent B. Young
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A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation
Inflammatory processes in atherosclerotic lesions promote disease progression and plaque rupture. Here the authors load the drug statin into nanoparticles made of recombinant high-density lipoprotein and show that these accumulate in atherosclerotic plaques and reduce plaque inflammation in mice.
- Raphaël Duivenvoorden
- , Jun Tang
- & Willem J. M. Mulder
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| Open AccessDrawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing
Adeno-associated viruses (AAV) are promising gene transfer vectors for human gene therapy. Here, the authors report a high-throughput, sequencing-based method for characterizing amino acid function in AAV capsids and highlight the potential of this method for improving capsid design.
- Kei Adachi
- , Tatsuji Enoki
- & Hiroyuki Nakai
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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease
Alterations in hepatocyte metabolism can lead to disorders such as non-alcoholic steatohepatitis (NASH). Here the authors create a comprehensive model of hepatocyte metabolism and use it to identify metabolic pathways altered in disease, revealing that serine levels are reduced in patients with NASH.
- Adil Mardinoglu
- , Rasmus Agren
- & Jens Nielsen
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slanDCs selectively accumulate in carcinoma-draining lymph nodes and marginate metastatic cells
slanDCs represent a population of dendritic cells whose role in cancer immune surveillance is not known. Here, the authors reveal that in cancer patients, slanDCs accumulate in the metastatic tumour-draining lymph nodes but not primary carcinoma sites, suggesting their involvement in nodal immune responses to cancer cells.
- William Vermi
- , Alessandra Micheletti
- & Marco A. Cassatella
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Indoleamides are active against drug-resistant Mycobacterium tuberculosis
New classes of antitubercular drugs are in constant demand as drug-resistant strains of Mycobacterium tuberculosis become more prevalent. Here, the authors characterize a class of drugs that are active against various M. tuberculosisstrains, including those resistant to currently used antituberculars.
- Shichun Lun
- , Haidan Guo
- & William R. Bishai
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The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis
Gene expression in the vascular endothelium is sensitive to shear forces exerted by the circulation. Here the authors identify miR-712 as a mechanosensitive microRNA expressed in endothelial cells and show that miR-712 inhibits pro-atherogenic processes by downregulating tissue inhibitor of metalloproteinase 3.
- Dong Ju Son
- , Sandeep Kumar
- & Hanjoong Jo
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Activation of TREK-1 by morphine results in analgesia without adverse side effects
Opioid analgesic drugs act at opioid receptors to exert analgesic effects, but they also exert adverse side effects. In this study, the authors show that the TREK-1 potassium channel is responsible for mediating the analgesic effects of morphine but not the adverse side effects.
- Maïly Devilliers
- , Jérôme Busserolles
- & Alain Eschalier
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The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension
Variants of the gene encoding the RhoGAP GRAF3 are associated with hypertension; however, the molecular basis for this association is unclear. Here, Bai et al.show that GRAF3 is strongly and specifically expressed in vascular smooth muscle cells, where it regulates blood pressure by inhibiting the GTPase RhoA.
- Xue Bai
- , Kaitlin C. Lenhart
- & Joan M. Taylor
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| Open AccessMicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice
The micro-RNA miR-33 is encoded by an intron of the gene encoding sterol regulatory-binding protein 2 (SREBP-2) and controls cholesterol homoeostasis. Here, Horie et al.identify SREBP-1 as a target of miR-33 and show that deletion of miR-33 promotes diet-induced obesity and liver steatosis in mice.
- Takahiro Horie
- , Tomohiro Nishino
- & Koh Ono
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| Open AccessA truncated Wnt7a retains full biological activity in skeletal muscle
Wnt7a regulates various aspects of skeletal muscle function. Here, the authors show that a truncated Wnt7a protein lacking the palmitoylation domain retains its biological activity in skeletal muscle, suggesting that simplified Wnt7a proteins may be viable as Wnt-based therapeutics.
- Julia von Maltzahn
- , Radoslav Zinoviev
- & Michael A. Rudnicki
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| Open AccessProtective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation
Induction of protective immunity mediated by CD8+ T cells has been a long sought goal in vaccinology. Here, Ewer et al. report induction of protective efficacy against Plasmodium falciparummalaria in a phase IIa prime-boost vaccine trial where efficacy correlates strongly with induced CD8 T-cell responses.
- Katie J. Ewer
- , Geraldine A. O’Hara
- & Adrian V. S. Hill
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| Open AccessTRAF1 is a critical regulator of cerebral ischaemia–reperfusion injury and neuronal death
TRAF1 is an intracellular signalling molecule that has diverse biological functions. In this study, the authors show that TRAF1 is expressed in mice soon after they have suffered a stroke and that increased TRAF1 expression increases susceptibility to ischaemia-induced apoptosis and brain injury.
- Yan-Yun Lu
- , Zuo-Zhi Li
- & Hongliang Li
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| Open AccessRhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription
The formation of blood and lymph vessels after injury requires precise temporal coordination. Here, the authors show that the small GTPase RhoB induces angiogenesis but inhibits lymphangiogenesis in response to dermal wounding by activating different sets of genes in blood vessels and lymphatic endothelial cells.
- Damien Gerald
- , Irit Adini
- & Laura E. Benjamin
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| Open AccessA closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice
Designer gene circuits allow the controlled expression of proteins in response to specific stimuli. Here, Rössger et al.use synthetic biology approaches to create a fatty-acid biosensor that controls the production of a satiety hormone and use it to control diet-induced obesity in mice.
- Katrin Rössger
- , Ghislaine Charpin-El-Hamri
- & Martin Fussenegger
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Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology
Myofibroblasts drive fibrogenesis in the liver but their cellular origins remain unclear. Here Mederacke et al. use the Lratgene to label hepatic stellate cells (HSCs) in transgenic mice and reveal HSCs as the major source of myofibroblasts in models of toxic, biliary and fatty liver fibrosis.
- Ingmar Mederacke
- , Christine C. Hsu
- & Robert F. Schwabe
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| Open AccessPlatelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A
Haemophilia is a genetic bleeding disorder associated with a deficiency in the coagulation factor VIII. Here, the authors use gene therapy to achieve stable overexpression of factor VIII in platelets of dogs with haemophilia A, preventing the occurrence of severe bleeding episodes for over 2.5 years.
- Lily M. Du
- , Paquita Nurden
- & David A. Wilcox
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Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
The enzyme NEU1 negatively regulates lysosomal exocytosis in various cell types. Annunziata et al.show that mice deficient in NEU1 display Alzheimer’s disease-like pathology and that direct brain administration of NEU1 reduces pathology in an Alzheimer’s disease mouse model.
- Ida Annunziata
- , Annette Patterson
- & Alessandra d’Azzo
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| Open AccessChondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury
The glycosaminoglycan chondroitin sulphate inhibits axon growth. Here the authors show that mice deficient in chondroitin sulphate biosynthesis have increased levels of heparan sulphate, which is more efficient than chondroitinase in supporting recovery from spinal cord injury.
- Kosei Takeuchi
- , Nozomu Yoshioka
- & Michihiro Igarashi
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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression
Methylphenidate, the active compound in Ritalin, is used to treat attention and hyperactivity disorders, but it is also taken for recreational use. Calipari et al.show that high-dose methylphenidate leads to enhanced dopaminergic responses to amphetamines, and enhanced amphetamine-seeking behaviour in rats.
- Erin S. Calipari
- , Mark J. Ferris
- & Sara R. Jones