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| 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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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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Article
| 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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| 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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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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| 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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| Open AccessExposure to a youthful circulation rejuvenates bone repair through modulation of β-catenin
The reparative capacity of tissues decreases with age. Here, Baht et al. perform parabiosis experiments and provide evidence for the existence of a soluble factor produced by young, but not old, haematopoietic cells that is capable of improving fracture repair in old mice.
- Gurpreet S. Baht
- , David Silkstone
- & Benjamin A. Alman
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Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin
Adult expression of fetal haemoglobin is beneficial and thus desirable in patients with haemoglobin disorders. Here the authors introduce a naturally occurring mutation in the γ-globinpromoter and show that it causes binding of an activator TAL1, chromosome looping and revival of fetal haemoglobin expression in erythroid cells.
- Beeke Wienert
- , Alister P. W. Funnell
- & Merlin Crossley
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Fat, fibre and cancer risk in African Americans and rural Africans
African Americans have much higher colon cancer rates than rural South Africans, which is associated with dietary and metabolic differences. Here, O’Keefe et al.show that switching quantities of fat and fibre leads to reciprocal changes in gut microbiota, metabolites and cancer biomarkers.
- Stephen J. D. O’Keefe
- , Jia V. Li
- & Erwin G. Zoetendal
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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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APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma
Rearrangements of the Ig loci are essential for generating antibody diversity but abnormal translocations can be a driving event for myeloma. Here Walker et al. perform whole exome sequencing on myeloma patients to capture the diversity of mutational changes.
- Brian A. Walker
- , Christopher P. Wardell
- & Gareth J. Morgan
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Dietary sugar promotes systemic TOR activation in Drosophila through AKH-dependent selective secretion of Dilp3
Fruit flies have eight insulin-like peptides (Dilps), whose regulation and function is largely unexplored. Here the authors show that, whereas dietary amino acids promote secretion of Dilp2, sugar-dependent release of the glucagon-related hormone AKH drives Dilp3 secretion.
- Jung Kim
- & Thomas P. Neufeld
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Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations
Age-related macular degeneration is a prominent cause of irreversible blindness among the elderly. Here Huang et al.identify a novel missense variant in UBE3D that sheds new light on the pathogenesis of the disease.
- Lv-Zhen Huang
- , Ying-Jie Li
- & Xiao-Xin Li
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| Open AccessIL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age
T-cell responses are dysregulated in aged humans and mice, which leads to poor antitumour responses. Here, the authors demonstrate that this phenomenon is at least partially due to an overproduction of IL-6 caused by ageing and its inhibitory effect on Th1 differentiation of tumour-specific CD4 T cells.
- Hirotake Tsukamoto
- , Satoru Senju
- & Yasuharu Nishimura
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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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Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia
Myopia is a significant and increasing public health concern. Here Miyake et al. conduct a genome-wide association study and identify WNT7Bas a susceptibility gene across different ethnic groups, suggesting a possible role in the development of myopia.
- Masahiro Miyake
- , Kenji Yamashiro
- & Nagahisa Yoshimura
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Article |
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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Article
| Open AccessTrained immunity in newborn infants of HBV-infected mothers
The ability to fight infections matures after birth and is thus termed ‘trained immunity’. Here the authors show that cord blood cells from hepatitis B virus-infected mothers respond more strongly to bacterial infections, suggesting that viral exposure in uteropromotes trained immunity in newborns.
- Michelle Hong
- , Elena Sandalova
- & Antonio Bertoletti
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Article
| Open AccessRise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia
Genetic heterogeneity and clonal evolution contribute to cancer progression. Here Ma et al.use deep whole-exome sequencing to identify recurrently mutated pathways and clonal architecture in pediatric acute lymphoblastic leukaemia, shedding light on the evolutionary trajectory from diagnosis to relapse
- Xiaotu Ma
- , Michael Edmonson
- & Jinghui Zhang
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Impedance sensing device enables early detection of pressure ulcers in vivo
Sustained pressure on the skin reduces blood flow and causes wounds. Here the authors describe a flexible electronic ‘bandage’ that measures changes in tissue impedance spectra and detects early tissue damage in rats before it can be visualized, thus enabling possible prevention of pressure ulcers.
- Sarah L. Swisher
- , Monica C. Lin
- & Michel M. Maharbiz
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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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Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate
Cleft lip is one of the most common congenital birth defects with substantial impairments to quality of life. Here, Sun et al. identify a new locus associated with cleft lip in diverse Chinese populations.
- Yimin Sun
- , Yongqing Huang
- & Yinxue Yang
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| 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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Genomic landscape of paediatric adrenocortical tumours
Pediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here the authors analyse the genomes, exomes and transcriptomes of 37 such tumours and identify genetic alterations whose nature, timing and potential interactions are key events with prognostic significance in pediatric adrenocortical tumorigenesis.
- Emilia M. Pinto
- , Xiang Chen
- & Gerard P. Zambetti
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Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children
Food allergy is a growing clinical and public health burden. Here, the authors carry out a genome-wide association study in samples with well-defined allergies to a variety of foods, and identify the 6p21.32 region that significantly increases risk of developing peanut allergy.
- Xiumei Hong
- , Ke Hao
- & Xiaobin Wang