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| Open AccessHexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice
Exon-skipping therapies such as systemic i.v. administration of morpholino are being explored as a means of treating Duchenne muscular dystrophy. Here the authors show that adding a glucose-fructose mix can enhance uptake of phosphorodiamidate morpholino oligomer and its therapeutic effect in mdxmice.
- Gang Han
- , Ben Gu
- & HaiFang Yin
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Article
| Open AccessGenomic insights into the Ixodes scapularis tick vector of Lyme disease
Ticks transmit a large number of pathogens that cause human diseases. Here, the authors sequence the genome of the tick Ixodes scapularisand uncover expansion of genes associated with parasitic processes unique to ticks and tick-host interactions.
- Monika Gulia-Nuss
- , Andrew B. Nuss
- & Catherine A. Hill
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| Open AccessGenome-wide association study identifies multiple susceptibility loci for craniofacial microsomia
Craniofacial microsomia is a congenital anomaly that affects the development of the skull. Here, the authors perform a genome-wide association study on patients in China and identify particular loci that provide insights into genetic mechanisms.
- Yong-Biao Zhang
- , Jintian Hu
- & Qingguo Zhang
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| 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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| Open AccessCell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects
A challenge in regenerative medicine is the development of cell-free, non-immunogenic miRNA-delivering scaffolds. Here the authors design a cell-free scaffold capable of efficient and prolonged delivery of miRNA-26a to endogenous cells and show that it can regenerate a full-thickness calvarial bone defect in mice.
- Xiaojin Zhang
- , Yan Li
- & Peter X. Ma
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| Open AccessNumb is required to prevent p53-dependent senescence following skeletal muscle injury
Regeneration of skeletal muscle relies on the function of muscle satellite cells. Here, Le Roux et al. show that the endocytic adaptor protein Numb promotes skeletal muscle regeneration after injury by preventing a p53-dependent senescence of satellite cells and consequent inflammation and fibrosis.
- Isabelle Le Roux
- , Julie Konge
- & Shahragim Tajbakhsh
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| Open AccessDetyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle
Microtubules are transducers of mechanical energy in muscle cells. Here, the authors show that mechanotransduction is regulated by post-translational detyrosination of microtubules in mouse heart and skeletal muscle, and that reducing detyrosination ameliorates symptoms in a model of Duchenne muscular dystrophy.
- Jaclyn P. Kerr
- , Patrick Robison
- & Christopher W. Ward
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Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss
HIV infection causes significant bone loss, which is worsened by antiretroviral therapy (ART). Here, the authors use a mouse model to show that T cell repopulation and/or immune reactivation after ART leads to complex inflammatory effects driving bone turnover and bone loss.
- Ighovwerha Ofotokun
- , Kehmia Titanji
- & M. Neale Weitzmann
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Article
| Open AccessKindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis
The Kidlins are proteins found in cell focal adhesion sites where they regulate integrins, and in the nucleus where their role is unknown. Here the authors show that Kindlin-2 controls chondrogenesis by regulating integrin b1 activation and Sox9 and TGF-β nuclear signalling.
- Chuanyue Wu
- , Hongli Jiao
- & Guozhi Xiao
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MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice
Skeletal muscle stem cells (satellite cells) express different levels of a critical transcriptional regulator Pax7. Here, the authors show that miR-431 regulates Pax7 levels in satellite cells of the developing and regenerating muscle, and that increased miR-431expression in these cells alleviates symptoms of muscular dystrophy in mice.
- Rimao Wu
- , Hu Li
- & Dahai Zhu
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Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome
Mutations in genes affecting intraflagellar transport account for some but not all cases of short rib polydactyly syndromes. Here Taylor et al. use whole exome sequencing and in vivo cell line assays to identify novel disease associated mutations in DYNC2LI1.
- S. Paige Taylor
- , Tiago J. Dantas
- & Deborah Krakow
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| Open AccessTCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Severe congenital development defects such as Jeune syndrome can result from the malfunction of primary cilia and dynein. Here Schmidts et al. report unique biallelic null mutations in a gene encoding a dynein light chain, helping to explain the nature of ciliopathies in human patients.
- Miriam Schmidts
- , Yuqing Hou
- & Hou-Feng Zheng
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| Open AccessMajor histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1
Ankylosing spondylitis is a common, highly inheritable inflammatory arthritis with poorly understood biology. Here Brown, Cortes and colleagues use fine mapping of the major histocompatibility complex and identify novel associations, and identify other HLA alleles that like HLA-B27 interact with ERAP1 variants to influence disease risk.
- Adrian Cortes
- , Sara L. Pulit
- & Matthew A. Brown
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| Open AccessGenome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese
Raised serum urate levels are a risk factor for gout, a common form of inflammatory arthritis. Here Li et al.conduct a multistage genome-wide association study in a Han Chinese population and identify three novel loci likely associated with the progression from hyperuricemia to gout.
- Changgui Li
- , Zhiqiang Li
- & Yongyong Shi
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G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy
In response to injury, satellite cells (SCs) asymmetrically divide to self-renew and repair muscle. Here the authors show that a cytokine G-CSF is crucial for long-term expansion of activated SCs and muscle regeneration in mice, suggesting that G-CSF treatment may have beneficial effect in Duchenne muscular dystrophy.
- Nozomi Hayashiji
- , Shinsuke Yuasa
- & Keiichi Fukuda
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Article
| Open AccessMicroRNA29a regulates IL-33-mediated tissue remodelling in tendon disease
Collagen 3 is increased during tendon repair, but is then replaced by Collagen 1 that has superior biomechanical properties. Here the authors show that IL-33 is induced by tendon damage and regulates miR-29a, which controls Collagen 3 production and feeds back on IL-33, orchestrating tendon repair.
- Neal L. Millar
- , Derek S. Gilchrist
- & Iain B. McInnes
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| Open AccessRegulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy
FoxO transcription factors promote muscle atrophy in response to stresses such as low nutrient availability. By generating muscle-specific FoxO triple-knockout mice, Milan et al.identify mechanisms by which the FoxO transcriptional network coordinates autophagic and proteasomal protein degradation.
- Giulia Milan
- , Vanina Romanello
- & Marco Sandri
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| Open AccessA PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females
Girls are tenfold more likely than boys to require surgical treatment for idiopathic scoliosis, a common paediatric skeletal disorder. Here, Sharma et al. identify the first sexually dimorphic idiopathic scoliosis risk locus, and demonstrate that it may play a role in the regulation of spinal cells.
- Swarkar Sharma
- , Douglas Londono
- & Carol A. Wise
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| Open AccessDense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis with a significant genetic component. Here, the authors analyse immune-related genetic markers in 1,962 PsA patients and 8,923 controls to identify novel PsA risk loci and highlight distinct genetic differences between psoriasis and PsA.
- John Bowes
- , Ashley Budu-Aggrey
- & Anne Barton
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Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis
Systemic sclerosis (SSc) is an incurable disease of unknown cause, characterized by vasculopathy, autoimmunity and fibrosis. Here the authors show that simultaneous decrease in two transcription factors, KLF5 and Fli1, underlies SSc development in mice and represents a signature trait of SSc patients.
- Shinji Noda
- , Yoshihide Asano
- & Shinichi Sato
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| Open Accessptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease
Scoliosis is a complex genetic disorder characterized by spinal curvature. Here, the authors present experimental zebrafish models of idiopathic and congenital scoliosis and suggest a role for dysregulated Wnt activity in scoliosis aetiology.
- Madeline Hayes
- , Xiaochong Gao
- & Brian Ciruna
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Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules
Myotonic dystrophy type 1 (DM1) is caused by defects in the alternative splicing of pre-mRNA. Childs-Disney and colleagues report two small molecules that either induce or reverse DM1-associated splicing defects by modulating the binding of pre-mRNA to muscleblind-like 1 protein.
- Jessica L. Childs-Disney
- , Ewa Stepniak-Konieczna
- & Matthew D. Disney
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Stac3 is a component of the excitation–contraction coupling machinery and mutated in Native American myopathy
Skeletal muscle contractions are regulated by a process known as excitation–contraction coupling (ECC), defects in which can cause myopathies. Here Horstick et al.show that the protein STAC3 is a component of the ECC machinery and identify mutations in STAC3 as the cause of Native American Myopathy.
- Eric J. Horstick
- , Jeremy W. Linsley
- & John Y. Kuwada