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| Open AccessGWAS of 89,283 individuals identifies genetic variants associated with self-reporting of being a morning person
Circadian rhythms and related behaviours vary across individuals. Here, a large genome-wide association study reveals common single nucleotide variants influencing whether an individual reports as being a ‘morning person’ by identifying 15 significant loci, including 7 near known circadian genes.
- Youna Hu
- , Alena Shmygelska
- & David A. Hinds
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Article
| Open AccessIntestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children
The impact of antibiotics on the microbiome and health of children is poorly understood. Here, Korpela et al. study the gut microbiome of 142 children and show that the use of macrolides, but not penicillins, is associated with long-lasting shifts in microbiota composition and increased risk of asthma and overweight.
- Katri Korpela
- , Anne Salonen
- & Willem M. de Vos
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| Open AccessImaging tumour cell heterogeneity following cell transplantation into optically clear immune-deficient zebrafish
Direct visualisation of heterogeneous cell populations in live animals has been challenging. Here, the authors optimize cell transplantation into optically clear immune-deficient zebrafish, and use intravital imaging to track and to assess functional diversity of individual cancer cells in vivo.
- Qin Tang
- , John C. Moore
- & David M. Langenau
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Article
| Open AccessPrevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation
The TCOF1 gene is mutated in Treacher Collin's syndrome, a congenital craniofacial syndrome. Here, the authors show that Tcof1loss-of-function results in oxidative stress induced DNA damage and neuroepithelial cell death, and addition of antioxidants to pregnant mutant mice protected against these defects.
- Daisuke Sakai
- , Jill Dixon
- & Paul A. Trainor
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Article
| 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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| Open AccessA shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function
The current hemostasis assays are unable to predict thrombotic or bleeding risk in clinics. Here, Jain et al. present a novel microfluidic device mimicking stenosed arterioles that determines clotting times in vitroand in extracorporeal circuits, offering a simple and reliable monitoring of blood homeostasis and platelet function.
- Abhishek Jain
- , Amanda Graveline
- & Donald E. Ingber
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Article
| Open AccessIntegrative analysis of breast cancer reveals prognostic haematopoietic activity and patient-specific immune response profiles
Tumour samples are heterogeneous and are comprised of multiple cell types in addition to cancer cells. Here, the authors devised a method to estimate the relative levels of haematopoietic cells in breast cancer samples and demonstrate that this correlates with prognosis.
- Frederick S. Varn
- , Erik H. Andrews
- & Chao Cheng
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Article
| Open AccessExome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese
An important risk factor for coronary artery disease is the level of blood lipids. Here the authors conduct an exome-wide association study in Chinese cohorts and identify three novel loci associated with lipid levels as well as three Asian-specific variants in known loci.
- Clara S. Tang
- , He Zhang
- & Wei Gao
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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 AccessDual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis
Rap1, a member of the Ras family of small guanine triphosphatases, mediates lymphocyte adhesion to high endothelial venules. Here the authors show that depending on its activation status Rap1 plays a dual role in T cell adhesion and by regulating T cell homeostasis is involved in the protection from colitis.
- Sayaka Ishihara
- , Akihiko Nishikimi
- & Koko Katagiri
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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 AccessSoluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans
Brown adipose tissue (BAT) thermogenesis is an important determinant of organismal energy expenditure in mammals. Here, Whittle et al. report that the protein sLR11 is a negative regulator of BAT activity in mice, repressing thermogenesis by inhibiting BMP/Smad signalling in brown adipocytes.
- Andrew J. Whittle
- , Meizi Jiang
- & Hideaki Bujo
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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 AccessA CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma
Using molecular markers is a useful way to predict the prognosis of cancer patients. Here, Wei et al.describe a five gene methylation signature that can predict the prognosis of renal clear cell cancer and validate its use in multiple patient cohorts.
- Jin-Huan Wei
- , Ahmed Haddad
- & Jun-Hang Luo
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| Open AccessNeural dynamics of prediction and surprise in infants
Prior expectations shape neural processing in the brain and violations of these expectations can have a profound influence on learning. Here the authors demonstrate that such predictive coding mechanisms are already functional in the brains of 12-month-old infants.
- Sid Kouider
- , Bria Long
- & Sofie V. Gelskov
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| Open AccessGenetic sharing and heritability of paediatric age of onset autoimmune diseases
Autoimmune diseases are genetically complex disorders that affect up to 10% of the Western population. Here Li et al. quantify the heritability of a range of autoimmune diseases in the largest paediatric cohort examined to date, illustrating that genetic and non-genetic components variably contribute to the susceptibility of each disease.
- Yun R. Li
- , Sihai D. Zhao
- & Hakon Hakonarson
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| 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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| Open AccessMaternal bile acid transporter deficiency promotes neonatal demise
The mechanisms underlying perinatal mortality due to intrahepatic cholestasis of pregnancy are not fully understood. Here, the authors show that absence of the nuclear receptor and bile acid regulator Nrli2 and the biliary transporter Abcb11 strongly reduces maternal serum bile acid levels, improving neonatal survival.
- Yuanyuan Zhang
- , Fei Li
- & John D. Schuetz
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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 AccessGenome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls
The authors perform a genome-wide association study of adolescent idiopathic scoliosis patients of Han Chinese descent, and identify 3 new loci for disease susceptibility.
- Zezhang Zhu
- , Nelson Leung-Sang Tang
- & Jack Chun-Yiu Cheng
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| Open AccessInternational genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways
Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.
- Heather J. Cordell
- , Younghun Han
- & Katherine A. Siminovitch
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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 |
In vivo capture and label-free detection of early metastatic cells
Tumour metastasis is a significant source of mortality, often because it is detected at an advanced stage. In this study, in an effort to identify metastasis at an early stage, Azarin et. al. capture and image metastasizing cells in mice in vivousing a biomaterial scaffold.
- Samira M. Azarin
- , Ji Yi
- & Lonnie D Shea
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| Open AccessPostnatal β-cell maturation is associated with islet-specific microRNA changes induced by nutrient shifts at weaning
Pancreatic β-cells are less responsive to changes in glucose concentration in newborn than in adult rats. Here, the authors show that functional β-cell maturation is associated with changes in miRNA expression induced by nutritional shifts at the suckling-to-weaning transition.
- Cécile Jacovetti
- , Scot J. Matkovich
- & Romano Regazzi
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| Open AccessGenome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations
Polycystic Ovary Sydrome is a highly heritable, complex reproductive disorder with unknown underlying genetic factors. Here Hayes and Urbanek et al. identify three loci in European women strongly associated with neuroendocrine changes and disease susceptibility.
- M. Geoffrey Hayes
- , Margrit Urbanek
- & Andrea Dunaif
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Article
| Open AccessWhole-central nervous system functional imaging in larval Drosophila
To understand how neuronal networks function, it is important to measure neuronal network activity at the systems level. Here Lemon et al. develop a framework that combines a high-speed multi-view light-sheet microscope, a whole-CNS imaging assay and computational tools to demonstrate simultaneous functional imaging across the entire isolated Drosophilalarval CNS.
- William C. Lemon
- , Stefan R. Pulver
- & Philipp J. Keller
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Article
| Open AccessLonger-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study
Long-chain omega-3 polyunsaturated fatty acids are essential for neural development and lack of these fatty acids has been implicated in a number of mental health conditions. Here the authors report the longer-term efficacy of a randomized, double-blind, placebo-controlled clinical trial assessing the effects of fish oil capsules in individuals at ultrahigh risk for psychosis.
- G. Paul Amminger
- , Miriam R. Schäfer
- & Patrick D. McGorry
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| 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 AccessLarge-scale genomics unveil polygenic architecture of human cortical surface area
How genetic variation contributes to brain morphology is still poorly understood. Here Chenet al. combine brain imaging with single-nucleotide polymorphism data to discover that a substantial degree of cortical variation is derived from underlying genetic differences.
- Chi-Hua Chen
- , Qian Peng
- & Anders M. Dale
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Mesoscale infraslow spontaneous membrane potential fluctuations recapitulate high-frequency activity cortical motifs
The brain exists in a state of constant activity but little is known about very low frequency forms of activity. Here, the authors use high-speed, wide-field, voltage-sensitive dye imaging to investigate the presence and functional structure of infraslow spontaneous activity in anaesthetized and awake mouse cortex.
- Allen W. Chan
- , Majid H. Mohajerani
- & Timothy H. Murphy
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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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Article
| Open AccessStereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes
The gut epithelium is damaged in inflammatory bowel disease, but capturing such lesions by histology can be difficult. Here, the authors use stereomicroscopy to visualize different 3D inflammatory structures and associated microbes in humans and in 16 genetic mouse models relevant to intestinal inflammation.
- Alex Rodriguez-Palacios
- , Tomohiro Kodani
- & Fabio Cominelli
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Article
| 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 AccessIdentifying active vascular microcalcification by 18F-sodium fluoride positron emission tomography
Atherosclerotic plaques with macrocalcification are stable, whereas microcalcification is a key feature of rupture-prone plaques. Here the authors show that18F-NaF PET/CT imaging can distinguish between macro- and microcalcification providing a potential, non-invasive imaging technique to identify patients with high-risk atheroma.
- Agnese Irkle
- , Alex T. Vesey
- & Anthony P. Davenport
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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 AccessIntegrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma
Rhabdomyosarcoma is a common childhood soft-tissue cancer. Here Seki and Nishimura analyse the exome, transcriptome, copy number and DNA methylome of 60 sarcomas and identify distinct methylation subgroups associated with genetic and clinical features.
- Masafumi Seki
- , Riki Nishimura
- & Junko Takita
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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 AccessDirect wavefront sensing for high-resolution in vivo imaging in scattering tissue
Direct wavefront sensing with laser ‘guide stars’ is used in astronomy and microscopy to correct for optical aberrations. Wang et al.use near-infrared guide stars to extend this approach to the highly scattering mouse brain, allowing high-resolution fluorescence imaging at 700μm depth.
- Kai Wang
- , Wenzhi Sun
- & Na Ji
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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