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| Open AccessRepetitive magnetic stimulation induces plasticity of inhibitory synapses
Repetitive transcranial magnetic stimulation (rTMS) is widely used as a therapeutic tool yet its effect on inhibitory networks in the brain has not been studied. Here, the authors demonstrate that 10Hz rTMS specifically reduces dendritic inhibition onto pyramidal neurons accompanied by remodeling of postsynaptic gephyrin clusters.
- Maximilian Lenz
- , Christos Galanis
- & Andreas Vlachos
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Article
| Open AccessIntestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction
The nuclear farnesoid X receptor (FXR) is activated by bile acids and influences energy metabolism. Here, the authors report a small molecule inhibitor of FXR, glycine-ß-muricholic acid, which inhibits FXR in the intestine and improves metabolic homeostasis by repressing intestinal ceramide synthesis.
- Changtao Jiang
- , Cen Xie
- & Frank J. Gonzalez
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Article
| Open AccessIdentification of an allosteric binding site for RORγt inhibition
Upon the binding of small ligands, nuclear receptors regulate the transcription of genes that are associated with a number of disease mechanisms. Here, the authors report on a novel allosteric ligand binding site on the nuclear receptor RORγt.
- Marcel Scheepstra
- , Seppe Leysen
- & Luc Brunsveld
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Article
| Open AccessEndogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7
Nav1.7 channels are known to regulate pain perception in humans and mice. Here, the authors provide evidence that Nav1.7 deletion leads to transcriptional upregulation of opioid peptides in sensory neurons, and that treatment with the opioid blocker naloxone helps reverse analgesia in mice and human Nav1.7 nulls.
- Michael S. Minett
- , Vanessa Pereira
- & John N. Wood
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Article
| Open AccessAutocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects
GLP-1 is a gut hormone with glucose-lowering activity. Here the authors report the peptide, P5, a variant of the GLP-1 receptor agonist exendin-4, with 'biased' signalling activity, and show that P5 improves glucose homeostasis in diabetic mice by increasing adipose tissue hyperplasia.
- Hongkai Zhang
- , Emmanuel Sturchler
- & Richard A. Lerner
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Article
| Open AccessAn endoscope with integrated transparent bioelectronics and theranostic nanoparticles for colon cancer treatment
Current endoscopes are limited to detection or treatment of colon cancers and growths, or resolution is too low for clinical application. Here the authors present a multimodal endoscope with theranostic nanoparticles that integrates fluorescence-based mapping, electrical impedance, pH and temperature monitoring, RF ablation and localized phototherapy or chemotherapy.
- Hyunjae Lee
- , Youngsik Lee
- & Dae-Hyeong Kim
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The NLRP3 inflammasome is critically involved in the development of bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) is a severe pulmonary complication seen in preterm infants, the molecular mechanisms of which are not clear. Here the authors establish a link between NLRP3 inflammasome activation, leading to production of pro-inflammatory cytokine IL1β, and the development of BPD.
- Jie Liao
- , Vishal S. Kapadia
- & Rashmin C. Savani
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Article
| Open AccessMYC-induced reprogramming of glutamine catabolism supports optimal virus replication
Viruses can reprogram glutamine metabolism of host cells to support bioenergetics demands of viral replication. Here the authors show that adenoviral infection leads to enhanced glutamine metabolism through virus-mediated activation of MYC, which is required for optimal progeny virion generation.
- Minh Thai
- , Shivani K. Thaker
- & Heather R. Christofk
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Article
| Open AccessAntibiotics in neonatal life increase murine susceptibility to experimental psoriasis
Commensal microbes are necessary for proper development of the immune system. Here Zanvit et al. show that neonatal antibiotics treatment causes long-term changes in the gut and skin microbiomes, and exacerbates immune-mediated skin pathology at adult age in mouse experimental models of psoriasis.
- Peter Zanvit
- , Joanne E. Konkel
- & WanJun Chen
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Article
| Open AccessCombining genomic and network characteristics for extended capability in predicting synergistic drugs for cancer
Predicting combinations of chemotherapeutic drugs that act synergistically is challenging. Here the authors take a computational approach to predict synergistic pairs, validate novel pairs using several cancer cell lines, and assess toxicity in a zebrafish xenograft model.
- Yi Sun
- , Zhen Sheng
- & Zhiwei Cao
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Article
| Open AccessCTRP6 is an endogenous complement regulator that can effectively treat induced arthritis
The complement system contributes to chronic inflammatory diseases. Here the authors show that CRTP6 suppresses the alternative complement pathway and reverses rheumatoid arthritis in a mouse model of the disease.
- Masanori A. Murayama
- , Shigeru Kakuta
- & Yoichiro Iwakura
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Article
| Open AccessCatalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice
Inhibiting insulin-degrading enzyme (IDE) has been proposed as a potential therapeutic strategy for the treatment of patients with diabetes. Here, the authors develop a novel IDE inhibitor but find that, surprisingly, IDE inhibition has negative effects on glucose tolerance in mice.
- Rebecca Deprez-Poulain
- , Nathalie Hennuyer
- & Benoit Deprez
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Article
| Open AccessAntagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway
The endothelial secreted protein Del-1 plays a role in limiting inflammation, and its deficiency is associated with pathology in periodontitis and multiple sclerosis. Here the authors show that the negative regulation of Del-1 by IL-17 involves targeting the transcription factor C/EBPß in a GSK-3ß- dependent manner.
- Tomoki Maekawa
- , Kavita Hosur
- & George Hajishengallis
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Article
| Open AccessBile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery
Gastric bypass surgery is one of the most effective interventions to achieve durable weight loss. Here, Flynnet al. show that, in mice, bile diversion to the small intestine results in beneficial and sustained metabolic improvements similar to Roux-en-Y gastric bypass surgery.
- Charles Robb Flynn
- , Vance L. Albaugh
- & Naji N. Abumrad
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Article
| Open AccessDesialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
Immune thrombocytopenia (ITP) is caused by autoantibody-mediated platelet clearance, but refractoriness to current immunomodulatory therapies is common. Here the authors show that desialylated platelets can be cleared via hepatic Ashwell–Morell receptor, a process that can be attenuated by sialidase inhibitors, suggesting a new therapy for ITP.
- June Li
- , Dianne E. van der Wal
- & Heyu Ni
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Article
| Open AccessGlucocorticoids limit acute lung inflammation in concert with inflammatory stimuli by induction of SphK1
Endothelial damage is a major component of acute lung injury pathogenesis. Here the authors show that in a mouse model of acute lung injury, glucocorticoids induce sphingosine kinase 1 production in macrophages, promoting endothelial barrier function and ameliorating the disease.
- Sabine Vettorazzi
- , Constantin Bode
- & Jan P. Tuckermann
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Article
| Open AccessDeactivation of excitatory neurons in the prelimbic cortex via Cdk5 promotes pain sensation and anxiety
The medial prefrontal cortex (mPFC) is implicated in pain regulation, yet the underlying mechanisms are poorly understood. Here the authors establish a critical role for mPFC in regulating pain sensation and pain-related anxiety, mediated by activation of the cyclin-dependent kinase 5 signalling pathway.
- Guo-Qiang Wang
- , Cheng Cen
- & Yun Wang
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Article
| Open AccessA novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking
Cue-based therapies for treating drug addiction have proven to be only partially effective. Here the authors demonstrate a new memory retrieval based treatment protocol for drug addiction that results in long-lasting inhibition of drug seeking behavior in rodents.
- Yi-xiao Luo
- , Yan-xue Xue
- & Lin Lu
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| Open AccessGenetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study
Graves’ disease is the leading cause of hyperthyroidism but treatment options can cause life-threatening complications. Chen et al. conduct two-stage direct HLA genotyping and genome-wide association studies to identify HLA-B*38:02 and HLA-DRB1*08:03 as major pharmacogenetic determinants.
- Pei-Lung Chen
- , Shyang-Rong Shih
- & Tien-Chun Chang
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Article
| Open AccessSpontaneous restoration of transplantation tolerance after acute rejection
An infection can break the immune tolerance of a transplanted organ, resulting in its rejection. Here the authors show that the immunological memory of transplantation tolerance dominates over the memory of allograft rejection, so that another organ transplanted later can be spontaneously accepted.
- Michelle L. Miller
- , Melvin D. Daniels
- & Anita S. Chong
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Article
| Open AccessNELL-1 in the treatment of osteoporotic bone loss
The growth factor NELL-1 induces bone formation during development, but its role in osteoporosis is unknown. This study shows that NELL-1 binding to integrin ß1 induces Wnt/ß-catenin signalling in the bone and restores bone mineral density in osteoporotic mice and sheep, suggesting the therapeutic potential of NELL-1 for the treatment of bone loss.
- Aaron W. James
- , Jia Shen
- & Chia Soo
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Article
| Open AccessSmall-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
SUMOylation of the cardiac calcium pump SERCA2a affects its activity and promotes cardiomyocyte contractility. Here the authors identify a small molecule N106 that increases SERCA2 SUMOylation and improves heart function in mice, and propose a promising therapeutic strategy for treatment of heart failure.
- Changwon Kho
- , Ahyoung Lee
- & Roger J. Hajjar
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Article
| Open AccessBruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury
Activation of inflammasome contributes to several pathologies. Here, the authors show that Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation, and that blocking it with the FDA-approved inhibitor ibrutinib limits tissue damage in a mouse model of ischaemic stroke.
- Minako Ito
- , Takashi Shichita
- & Rimpei Morita
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Article
| Open AccessPharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis
Adverse drug reactions are an important clinical problem. Here the authors combine information about drug-induced gene expression changes and genetic variability of patients with a genome-scale metabolic model to identify drug-induced changes in cellular metabolism that may be linked to drug side effects.
- Daniel C. Zielinski
- , Fabian V. Filipp
- & Bernhard O. Palsson
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Manipulation of B-cell responses with histone deacetylase inhibitors
Histone deaceytelase inhibitors are used in the treatment of haematological malignancies but can also act as modulators of the immune system. Here, the authors show that histone deaceytelase inhibitors are capable of modulating B-cell functions leading to improved outcome in autoimmune conditions.
- Michaela Waibel
- , Ailsa J. Christiansen
- & Edwin D. Hawkins
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Article
| Open AccessFlavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis
The hepatic enzyme FMO3 has been linked to atherosclerosis. Here the authors show that FMO3 is upregulated in various models of diabetes and link FMO3 with key transcriptional regulators of hepatic glucose and cholesterol synthesis, thus proposing a mechanistic connection between diabetes and atherosclerosis.
- Ji Miao
- , Alisha V. Ling
- & Sudha B. Biddinger
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Article
| Open AccessA muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling
Skeletal muscle proteolysis can affect organismal energy homeostasis. Here, the authors provide molecular insight into this process by showing that muscle-derived alanine acts as a signal that triggers FGF21 secretion from the liver, which then regulates lipolysis and browning of white fat tissue.
- Noriaki Shimizu
- , Takako Maruyama
- & Hirotoshi Tanaka
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Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus
Treatment options for prevention and control of fatal H7N9 influenza infections remain limited. Here, the authors show that two human monoclonal antibodies protect mice against H7N9 strains when administered before or after H7N9 infection.
- Zhe Chen
- , Jianmin Wang
- & Qi Jin
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A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production
Receptor Interacting Protein Kinase 2 (RIPK2) mediates innate immune signalling in response to intracellular pathogens, but its aberrant activation contributes to autoimmune pathologies. Here Nachbur et al.describe a RIPK2 inhibitor that is effective in a mouse model of multiple sclerosis.
- Ueli Nachbur
- , Che A. Stafford
- & John Silke
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Article
| Open AccessPharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic
Current multiple sclerosis treatments focus on prevention of immune attack on oligodendrocytes and myelin. Here the authors show a different strategy to ameliorate disease in several mouse models, protecting oligodendrocytes from inflammation-induced death with an FDA-approved drug, guanabenz.
- Sharon W. Way
- , Joseph R. Podojil
- & Brian Popko
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The insulin and IGF1 receptor kinase domains are functional dimers in the activated state
In contrast to most receptor tyrosine kinases, the insulin and insulin-like growth factor-1 receptors are preformed, disulfide-linked dimers. Here the authors show that, after the two kinase domains of IR and IGF1R undergo autophosphorylation, they form a specific dimer to phosphorylate downstream substrates.
- M. Zulema Cabail
- , Shiqing Li
- & W. Todd Miller
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Dendritic cells induce Th2-mediated airway inflammatory responses to house dust mite via DNA-dependent protein kinase
House dust mites are a common cause of allergic asthma. Here, the authors show that the Th2-mediated inflammatory responses triggered by mites in mouse airways are mediated by the activation of DNA-dependent protein kinase (DNA-PK) in dendritic cells.
- Amarjit Mishra
- , Alexandra L. Brown
- & Jay H. Chung
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Article |
The polymeric mucin Muc5ac is required for allergic airway hyperreactivity
Asthma is associated with mucus overproduction; however, the immunological consequences of excess mucus remain poorly understood. Here the authors show that formation of airway plugs by mucus promotes airway hypersensitivity, while deletion of mucous component Muc5acablates it independently of inflammation.
- Christopher M. Evans
- , Dorota S. Raclawska
- & Burton F. Dickey
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Article
| Open AccessBotulinum toxin A complex exploits intestinal M cells to enter the host and exert neurotoxicity
It is unclear how ingested botulinum neurotoxin invades the host to cause illness. Here, the authors show that the toxin complex containing neurotoxin, hemagglutinin (HA), and NTNHA proteins traverses the epithelial barrier via HA-glycoprotein 2 interaction and endocytosis by Peyer’s patch microfold cells.
- Takuhiro Matsumura
- , Yo Sugawara
- & Yukako Fujinaga
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Identity of a Plasmodium lactate/H+ symporter structurally unrelated to human transporters
Malaria parasites generate metabolic energy through anaerobic glycolysis, yielding lactate and protons that are then secreted out of the parasite cell by an unknown transporter. Here, the authors identify and characterize a lactate/proton transporter that may be carrying out such function in Plasmodium.
- Binghua Wu
- , Janis Rambow
- & Eric Beitz
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Article
| Open AccessTemporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition
Adaptive resistance is an emerging cause of chemotherapy failure in cancer. Here the authors show that adaptive resistance to taxanes is mediated by the upregulation of SFK/Hck survival signalling, and that sequential administration of taxanes and SFK/Hck inhibition restores tumor cell chemosensitivity.
- Aaron Goldman
- , Biswanath Majumder
- & Shiladitya Sengupta
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Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation
Hyperinflammation in cystic fibrosis has been linked to decreased levels of caveolin-1, resulting in higher LPS responsiveness of TLR4. Here the authors show that in a mouse model of cystic fibrosis decreased Akt results in accumulation of miR-199a-5p directly targeting caveolin-1 in macrophages.
- Ping-xia Zhang
- , Jijun Cheng
- & Emanuela M. Bruscia
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Article
| Open AccessStructural characterization of a protective epitope spanning A(H1N1)pdm09 influenza virus neuraminidase monomers
Neuraminidase inhibitors offer a line of defence against flu infections, but resistance can occur even in the absence of prior exposure. Here Wan et al. describe the mode of action of CD6, a monoclonal antibody that protects against a common influenza strain, as a new therapeutic intervention model.
- Hongquan Wan
- , Hua Yang
- & Maryna C. Eichelberger
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Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases
TLR7 triggers immune responses upon sensing microbial RNA, and its endosomal localization is thought to prevent TLR7 activation by host RNA. Here, Kanno et al. show that TLR7 is also present on the surface of immune cells, and that anti-TLR7 antibody can prevent TLR7-mediated autoimmunity.
- Atsuo Kanno
- , Natsuko Tanimura
- & Kensuke Miyake
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Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation
Small-molecule C21 inhibits Rac GTPase activation by Dock5, which decreases osteoclast activity in vitro. Using three mouse models where bone loss is caused by hyperactive osteoclasts, Vives et al. show that C21 treatment safely and efficiently prevents osteoporosis while preserving bone formation.
- Virginie Vives
- , Gaëlle Cres
- & Anne Blangy
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Article
| Open AccessTargeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias
Chondroitin sulfate proteoglycans (CSP) in the myocardial scar inhibit the tissue’s reinnervation, rendering it prone to arrhythmia. Here the authors show that blocking the activity of the CSP receptor, protein tyrosine phosphatase receptor σ, promotes scar reinnervation and prevents arrhythmia in mice.
- R. T. Gardner
- , L. Wang
- & B. A. Habecker
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Article |
Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling
ARID1A is frequently mutated in ovarian clear-cell carcinoma. Here the authors show that ARID1A loss in mice cooperates with PI3K activation to recapitulate the human disease, and implicate IL-6 signalling as the underlying mechanism.
- Ronald L. Chandler
- , Jeffrey S. Damrauer
- & Terry Magnuson
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Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. Here the authors link mutations in the gene PNPLA6 with childhood blindness in seven families with retinal degeneration and show that the gene plays a role in photoreceptor survival in Drosophila.
- S. Kmoch
- , J. Majewski
- & R. K. Koenekoop
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Article |
Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour
Synthetic compounds that alter circadian rhythms have been shown to modulate energy expenditure and systemic metabolism in rodents. Here, the authors study the psychological effects of such compounds, and find synthetic REV-ERB agonists increase wakefulness and reduce anxiety-like behaviour in mice.
- Subhashis Banerjee
- , Yongjun Wang
- & Thomas P. Burris
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Article
| Open AccessMitochondrial protein sorting as a therapeutic target for ATP synthase disorders
Effective treatment options for mitochondrial diseases are scarce. Here, Aiyar et al. identify the TIM23 mitochondrial protein sorting machinery as a potential intervention point for mitochondrial ATP synthase disorders.
- Raeka S. Aiyar
- , Maria Bohnert
- & Lars M. Steinmetz
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The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice
Atrial fibrillation and heart failure often coexist but are difficult to treat. Here the authors report a therapeutic strategy for atrial fibrillation and heart failure in mice, based on the activating effect of a small molecule, BGP-15, on IGF1 receptor signalling.
- Geeta Sapra
- , Yow Keat Tham
- & Julie R. McMullen
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Article
| Open AccessIntestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status
Gut microbes are known to influence whole-body metabolism. Here Everard et al.show the adaptor protein MyD88 in intestinal epithelial cells is sensitive to changes in the diet and affects composition of the gut microbiota, which influences the development of obesity and associated diseases.
- Amandine Everard
- , Lucie Geurts
- & Patrice D. Cani
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Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma
Despite the treatment efficacy of combining BRAF and MEK inhibitors, a third of BRAF-mutant metastatic melanoma patients treated with this therapy progress within 6 months. Here, the authors sequence tumours from patients with BRAFV600-mutant melanoma metastases and identify mutations that confer resistance to combination therapy.
- Georgina V. Long
- , Carina Fung
- & Helen Rizos
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Tolerance induction to human stem cell transplants with extension to their differentiated progeny
Immunosuppression has been shown to induce tolerance to transplanted stem cells, but differentiation of these cells may trigger immune rejection later on. Here, Lui et al. show that a short-term immunosuppression regimen confers long-term tolerance to stem cells and their differentiated progeny.
- Kathy O. Lui
- , Duncan Howie
- & Herman Waldmann
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