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| Open AccessPredicting nutrient content of ray-finned fishes using phylogenetic information
Humans increasingly depend on seafood for nutrition, but nutrient content is unknown for the vast majority of fish species. Here, the authors use phylogenetic analyses and data imputation to predict the nutrient content of fish that are under-studied but that could be of future dietary importance.
- Bapu Vaitla
- , David Collar
- & Christopher D. Golden
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Article
| Open AccessLineage dynamics of murine pancreatic development at single-cell resolution
Coordinated proliferation and differentiation of diverse cell populations drive pancreatic epithelial and mesenchymal development. Here, the authors profile cell type dynamics in the developing mouse pancreas using single-cell RNA sequencing, identifying mesenchymal subtypes and undescribed endocrine progenitors.
- Lauren E. Byrnes
- , Daniel M. Wong
- & Julie B. Sneddon
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Article
| Open AccessEstimating sources and sinks of malaria parasites in Madagascar
Understanding the source of malaria outbreaks in low-transmission areas is important for controlling the disease. Here, the authors use mobile phone data to map malaria transmission in Madagascar, and are able to show that primary sources of infection in the capital city are found along populated coastal areas.
- Felana Angella Ihantamalala
- , Vincent Herbreteau
- & Amy Wesolowski
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Article
| Open AccessGriffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo
Safety and efficacy remain important challenges for non-antiretroviral-based microbicides. Here, Derby et al. show that a Griffithsin-Carrageenan fast dissolving vaginal insert provides on-demand protection against SHIV infections in macaques, paving the way for the development of pre-exposure prophylaxis on-demand products.
- Nina Derby
- , Manjari Lal
- & Thomas M. Zydowsky
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Article
| Open AccessAcquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA
Acquired resistance is a major problem in cancer immunotherapy. Here the authors report a study of two patients with Merkel cell carcinoma under immunotherapy treatment who develop resistance after deep responses for >1 year and identified a novel mechanism of acquired, gene-specific transcriptional suppression of HLAs.
- K. G. Paulson
- , V. Voillet
- & A. G. Chapuis
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Article
| Open AccessCerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization
Brain function alterations in schizophrenia and other psychotic disorders remain poorly understood. Here, the authors discover that increased neural connectivity in the cerebello-thalamo-cortical circuitry predicts psychosis in those at high risk, and is present in people with schizophrenia.
- Hengyi Cao
- , Oliver Y. Chén
- & Tyrone D. Cannon
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Article
| Open AccessDiscovering human diabetes-risk gene function with genetics and physiological assays
The function of genes linked to type 2 diabetes is poorly characterized. Here the authors combine Drosophila genetics and physiology with human islet biology to identify new regulators of insulin secretion including BCL11A.
- Heshan Peiris
- , Sangbin Park
- & Seung K. Kim
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Article
| Open AccessAlpha-enolase regulates the malignant phenotype of pulmonary artery smooth muscle cells via the AMPK-Akt pathway
Metabolic reprogramming of smooth muscle cells (SMCs) plays an important role in the pathogenesis of pulmonary arterial hypertension (PAH). Here, Dai et al. show that the glycolytic enzyme alpha-enolase contributes to this reprogramming, and that its inhibition limits SMC proliferation and disease progression in animal models of PAH.
- Jingbo Dai
- , Qiyuan Zhou
- & Guofei Zhou
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Article
| Open AccessAncient and modern anticonvulsants act synergistically in a KCNQ potassium channel binding pocket
In some countries, leaves of the shrub Mallotus oppositifolius have been used to treat epilepsy. Here, authors look at the structural and molecular basis for how chemical components of M. oppositifolius have their anticonvulsant effects, via modulation of potassium channel activity.
- Rían W. Manville
- & Geoffrey W. Abbott
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Article
| Open AccessLNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment
Mechanism of lymph node (LN) metastasis induced by tumor associated macrophages (TAMs) remains unclear. Here they demonstrate that a long noncoding RNA LNMAT1 promotes LN metastasis of bladder cancer via recruitment of TAMs through epigenetic regulation of CCL2 expression.
- Changhao Chen
- , Wang He
- & Tianxin Lin
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Article
| Open AccessStructural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody
Pfs48/45 is a promising component for a transmission-blocking malaria vaccine. Here, the authors develop a system to produce full-length Pfs48/45 for immunisation, characterise a panel of monoclonal antibodies and determine the structure of a potent transmission-blocking epitope.
- Frank Lennartz
- , Florian Brod
- & Matthew K. Higgins
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Article
| Open AccessHuman Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments
At inflammatory sites, ectopic lymphoid-like structures (ELS) can be induced through the function of chemokine CXCL13 produced by CD4+ T cells. Here the authors show that a transcription factor, Sox4, induces the expression of CXCL13 in CD4 T cells in vitro, and is associated with ELS formation in patients with rheumatoid arthritis.
- Hiroyuki Yoshitomi
- , Shio Kobayashi
- & Junya Toguchida
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Article
| Open AccessImplementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers
Fluorescent tracers are being tested in clinical trials to improve detection of tumor margins, but procedures are not standardised. Here, the authors develop an analytical framework that is compatible with the workflow in the operating theatre, and show that it leads to an 88% increase in intraoperative detection of tumor margins in patients with breast cancer.
- Marjory Koller
- , Si-Qi Qiu
- & Gooitzen M. van Dam
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Article
| Open AccessArtemisinin kills malaria parasites by damaging proteins and inhibiting the proteasome
Artemisinin (ART) is a widely used antimalarial drug, but its mechanism of action is poorly understood. Here, Bridgford et al. show that ART kills parasites by a two-pronged mechanism, causing protein damage and compromising proteasome function, and that accumulation of proteasome substrates activates the ER stress response.
- Jessica L. Bridgford
- , Stanley C. Xie
- & Leann Tilley
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Article
| Open AccessAlpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis
The Hiccs locus has been associated with susceptibility to colitis in mice. Here the authors identify a Hiccs locus gene encoding Alpha kinase 1 as a potent regulator of intestinal inflammation via modulation of the IL-12/Th1 axis.
- Grigory Ryzhakov
- , Nathaniel R. West
- & Fiona Powrie
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Article
| Open AccessRecurrent WNT pathway alterations are frequent in relapsed small cell lung cancer
Small cell lung cancer (SCLC) patients frequently relapse and become resistant to chemotherapy. Here, the authors analyse the genomic and transcriptomic landscape of primary and relapsed SCLC patients as well as in vitro models, and discover that activation of WNT signalling can drive chemotherapy resistance.
- Alex H. Wagner
- , Siddhartha Devarakonda
- & Ramaswamy Govindan
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Article
| Open AccessGenome-scale metabolic reconstructions of multiple Salmonella strains reveal serovar-specific metabolic traits
Salmonella serovars colonize a wide range of hosts but the underlying genetic determinants remain poorly understood. Here, Seif et al. use a network-based computational analysis to link specific metabolic capabilities with host range and nutritional niche.
- Yara Seif
- , Erol Kavvas
- & Jonathan M. Monk
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| Open AccessThe gut microbiota promotes hepatic fatty acid desaturation and elongation in mice
The role of the gut microbiota in hepatic lipid metabolism is controversial and incompletely understood. Here the authors perform multi-omics analyses of altered lipid metabolic processes in germ-free and specific pathogen-free mice, revealing how the gut microbiota affects hepatic fatty acid desaturation and elongation.
- Alida Kindt
- , Gerhard Liebisch
- & Josef Ecker
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| Open AccessConditional and interaction gene-set analysis reveals novel functional pathways for blood pressure
Gene-set analysis (GSA) is widely used to infer functional and biological properties of a gene set. Here, the authors develop a conditional and interaction gene-set analysis approach that can considerably refine results from traditional GSA.
- Christiaan A. de Leeuw
- , Sven Stringer
- & Danielle Posthuma
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Article
| Open AccessIdentification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
Multiple myeloma is a cancer of the plasma cells, and the complete aetiology of the disease is still unclear. Here the authors perform an additional GWAS analysis followed by a meta-analysis with existing GWAS and replication genotyping and identify 6 novel risk loci and utilise gene expression, epigenetic profiling and in situ Hi-C data to further our understanding of MM susceptibility.
- Molly Went
- , Amit Sud
- & Stephen N. Thibodeau
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Article
| Open AccessCharacterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes
Myelodysplastic syndrome (MDS) arises from mutations in hematopoietic stem cells (HSCs). Here, the authors demonstrate that HSCs in higher-risk MDS express the surface marker CD123 and are characterized by activation of protein synthesis machinery and increased oxidative phosphorylation.
- Brett M. Stevens
- , Nabilah Khan
- & Craig T. Jordan
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Article
| Open AccessBrain and psychological determinants of placebo pill response in chronic pain patients
People vary in the extent to which they feel better after taking an inert, placebo, treatment, but the basis for individual placebo response is unclear. Here, the authors show how brain structural and functional variables, as well as personality traits, predict placebo response in those with chronic back pain.
- Etienne Vachon-Presseau
- , Sara E. Berger
- & A. Vania Apkarian
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Article
| Open AccessDifferential processing of HIV envelope glycans on the virus and soluble recombinant trimer
HIV envelope (Env) is a potential vaccine antigen and its N-glycans are part of the epitope of broadly neutralizing antibodies. Here, the authors show that glycosylation of Env from infectious virus closely matches Env from recombinant membrane-bound trimers, while it differs significantly from recombinant soluble, cleaved Env trimers.
- Liwei Cao
- , Matthias Pauthner
- & James C. Paulson
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| Open AccessAugmentation of vaccine-induced humoral and cellular immunity by a physical radiofrequency adjuvant
Vaccine adjuvants ensure sufficient engagement of the immune system in vaccination, however safety issues can be associated with novel chemical adjuvants. Here, Cao et al. report a physical radiofrequency adjuvant to simultaneously augment vaccine-induced humoral and cellular immune responses without potentially harmful adverse reactions.
- Yan Cao
- , Xiaoyue Zhu
- & Xinyuan Chen
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| Open AccessGWAS for Interleukin-1β levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation
IL-1β in gingival crevicular fluid (GCF) is a marker of inflammation in periodontal disease. Here, Offenbacher et al. identify genetic variants in the IL37 locus associated with GCF-IL-1β and show that the IL-1β-increasing allele at rs3811046 leads to an enhanced inflammatory response in vitro and in vivo.
- Steven Offenbacher
- , Yizu Jiao
- & Kari E. North
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Article
| Open AccessGut fungal dysbiosis correlates with reduced efficacy of fecal microbiota transplantation in Clostridium difficile infection
Fecal microbiota transplantation (FMT) is effective in treating recurrent Clostridium difficile infection (CDI). Here, the authors show that the composition of the gut fungal microbiota of donors and recipients, and especially the abundance of Candida, correlates with FMT outcome in CDI patients.
- Tao Zuo
- , Sunny H. Wong
- & Siew C. Ng
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Article
| Open AccessDifferent patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years
Hofvander and colleagues compare the patterns of clonal evolution in different pathogenetic subgroups of sarcoma. They show that sarcomas driven by gene fusion or amplification display few additional changes over time, whereas sarcomas with complex karyotypes show a gradual increase of nucleotide- and chromosome-level mutations.
- Jakob Hofvander
- , Björn Viklund
- & Fredrik Mertens
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Article
| Open AccessER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes
HRD1 is an E3 ligase known to play a role in targeting degradation of misfolded proteins in the ER. Here the authors show that HRD1 interacts with metabolic enzymes and its liver specific deficiency results in lower body weight, blood glucose and plasma lipids during high fat diet in mice.
- Juncheng Wei
- , Yanzhi Yuan
- & Deyu Fang
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Article
| Open AccessDynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy
Fibro-adipogenic progenitors (FAPs) resident in skeletal muscle are involved in both regeneration and maladaptive processes. Here, the authors identify subpopulations of FAPs with biological activities implicated in physiological muscle repair that are altered in pathological conditions such as muscular dystrophies.
- Barbora Malecova
- , Sole Gatto
- & Pier Lorenzo Puri
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Article
| Open AccessCXCL12 and MYC control energy metabolism to support adaptive responses after kidney injury
Injuries in the embryonal kidney can be repaired by a cell migratory response but how this is regulated at a molecular level is unclear. Here, the authors show in mice that deletion of Cxcl12 and Myc delays pronephros injury repair by changing mitochondrial metabolism and glycolysis.
- Toma A. Yakulov
- , Abhijeet P. Todkar
- & Gerd Walz
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| Open AccessHepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology
The RNA-induced silencing complex (RISC) represses gene expression via micro-RNA guided mRNA silencing. Here, the authors show that RISC component Argonaute 2 in the liver regulates energy metabolism by inducing microRNAs that cause metabolic disruption and by suppressing protein translation linked to AMPK activation.
- Cai Zhang
- , Joonbae Seo
- & Takahisa Nakamura
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Article
| Open AccessVariants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits
Uterine leiomyomas are common benign tumors. Here, a meta-analysis of two European leiomyoma GWAS uncovers 21 leiomyoma risk variants at 16 loci, providing evidence of genetic overlap between leiomyoma and various benign and malignant tumors and highlighting the role of estrogen in tumor growth.
- Thorunn Rafnar
- , Bjarni Gunnarsson
- & Kari Stefansson
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| Open AccessRefined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning
Clinical trials for the CYD-TDV dengue vaccine showed that vaccine efficacy varies with prior dengue exposure, but baseline serostatus is only known for 12% of subjects. Here, Dorigatti et al. use machine learning to impute baseline serostatus and determine vaccine efficacy by baseline serostatus, age and dengue serotype.
- I. Dorigatti
- , C. A. Donnelly
- & N. M. Ferguson
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Article
| Open AccessNecroptosis mediates myofibre death in dystrophin-deficient mice
Muscular dystrophies are characterised by extensive myofibre cell death. Here Morgan et al. show that RIPK3-mediated necroptosis contributes to myofibre cell death in Duchenne muscular dystrophy, and that RIPK3 deletion protects dystrophic mice against myofibre degeneration.
- Jennifer E. Morgan
- , Alexandre Prola
- & Maximilien Bencze
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| Open AccessLY6E mediates an evolutionarily conserved enhancement of virus infection by targeting a late entry step
The interferon-induced gene LY6E increases virus infection, but the underlying mechanism is poorly understood. Here, Mar et al. show that LY6E enhances uncoating of influenza A virus after endosomal escape and that viral enhancement by LY6E is conserved across evolution.
- Katrina B. Mar
- , Nicholas R. Rinkenberger
- & John W. Schoggins
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Article
| Open AccessUnravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq
Triple-negative breast cancer is highly heterogeneous and aggressive. Here, the authors utilise single-cell RNA sequencing to investigate this heterogeneity, and discover a subpopulation of cells associated with metastasis and treatment resistance signatures, and linked to long term survival outcomes.
- Mihriban Karaayvaz
- , Simona Cristea
- & Leif W. Ellisen
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Article
| Open AccessAp4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells
The c-MYC oncoprotein has many targets whose actions are not fully understood including TFAP4/AP4. Here, the authors show in a mouse model of inherited colorectal cancer that deletion of AP4 decreased the frequency of c-MYC-driven intestinal adenomas, and reveal Ap4 as a mediator of adenoma initiation and regulator of colonic and intestinal stem cell and Paneth cell homeostasis.
- Stephanie Jaeckel
- , Markus Kaller
- & Heiko Hermeking
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Article
| Open AccessMicrobiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis
T cells play a critical role in intestinal homeostasis, with increasing evidence suggesting a role for the microbiome metabolome in modulating this response. Here the authors show short-chain fatty acids promote IL-10 production in Th1 cells.
- Mingming Sun
- , Wei Wu
- & Yingzi Cong
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Article
| Open AccessSCFFBW7-mediated degradation of Brg1 suppresses gastric cancer metastasis
Upstream pathways regulating Brg1 stability and their role in carcinogenesis are unknown. Here they show Brg1 to be phosphorylated by CK1δ to promote its ubiquitination by SCFFBW7 (FBW7), Brg1 stabilization to promote gastric cancer metastasis, and suggest targeting Brg1 in FBW7 compromised gastric cancer.
- Li-Yu Huang
- , Junjie Zhao
- & Wenyi Wei
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Article
| Open AccessA study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers
Biomarker identification requires prohibitively large cohorts with gene expression and phenotype data. The approach introduced here learns polygenic predictors of expression from genetic and expression data, used to infer biomarker levels in patients with genetic and disease information.
- Jonathan D. Mosley
- , QiPing Feng
- & Dan M. Roden
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Article
| Open AccessArgininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer
Patients with mutations in the ASL gene present with argininosuccinic aciduria characterised by hyperammonaemia and cognitive impairment. Here, the authors show that cerebral disease involves neuronal nitrosative/oxidative stress that is not induced by hyperammonaemia, and that it can be reversed using AAV-ASL directed to liver and brain in mice.
- Julien Baruteau
- , Dany P. Perocheau
- & Simon N. Waddington
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Article
| Open AccessHigh-fidelity CRISPR/Cas9- based gene-specific hydroxymethylation rescues gene expression and attenuates renal fibrosis
Suppression of gene expression due to aberrant promoter methylation contributes to organ fibrosis. Here, the authors couple a deactivated Cas9 to the TET3 catalytic domain to induce expression of four antifibrotic genes, and show that lentiviral-mediated delivery is effective in reducing kidney fibrosis in mouse models.
- Xingbo Xu
- , Xiaoying Tan
- & Michael Zeisberg
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Article
| Open AccessA feed forward loop enforces YAP/TAZ signaling during tumorigenesis
The Hippo pathway is frequently dysregulated in cancer. Here, the authors identify NUAK2 as negative regulator of the Hippo pathway from a siRNA kinome screen and show that NUAK2 promotes YAP/TAZ nuclear localisation while NUAK2 is a transcriptional target of YAP/TAZ, thus providing a feed forward loop to promote tumorigenesis.
- Mandeep K. Gill
- , Tania Christova
- & Liliana Attisano
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Perspective
| Open AccessEvaluating intrinsic and non-intrinsic cancer risk factors
Understanding the contributions of extrinsic and intrinsic factors on cancer risk is fundamental in determining the intervention and prevention strategies to tackle cancer. Here the authors provide a review of the different factors impacting cancer risk and discuss the limitations of different approaches in evaluating the relative contributions of these factors.
- Song Wu
- , Wei Zhu
- & Yusuf A Hannun
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Article
| Open AccessSelf-decoupled radiofrequency coils for magnetic resonance imaging
Conventional coil arrays require complex decoupling technologies to reduce electromagnetic coupling between coil elements. Here, the authors report a self-decoupled RF coil design that achieves high inter-coil isolation between adjacent and non-adjacent elements and mixed arrays of loops and dipoles
- Xinqiang Yan
- , John C. Gore
- & William A. Grissom
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Article
| Open AccessGroup I Paks are essential for epithelial- mesenchymal transition in an Apc-driven model of colorectal cancer
Group I Paks, like Pak1, are required for the activation of several key oncogenic signaling pathways. Here the authors study an inducible peptide mimicking the auto-inhibitory domain of Pak1 and show promising anti-tumor effects in a mouse model of colorectal cancer.
- H. Y. Chow
- , B. Dong
- & J. Chernoff
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Article
| Open AccessNCK-dependent pericyte migration promotes pathological neovascularization in ischemic retinopathy
Pericytes are perivascular cells that regulate blood vessel formation and function. Here Dubrac et al. show that pericyte recruitment contributes to pathological neovascularisation in a mouse model of ischemic retinopathy, and that this depends on the regulation of PDGF-B signaling by NCK adaptor proteins.
- Alexandre Dubrac
- , Steffen E. Künzel
- & Anne Eichmann
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Article
| Open AccessRibitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice
Mutations in FKRP impair glycosylation of alpha-dystroglycan, leading to muscular dystrophy. Here, the authors show that oral administration of ribitol increases dystropglycan glycosylation and ameliorates symptoms of muscular dystrophy in FKRP-deficient mouse models.
- Marcela P. Cataldi
- , Peijuan Lu
- & Qi Long Lu
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Article
| Open AccessDysregulation of the NUDT7-PGAM1 axis is responsible for chondrocyte death during osteoarthritis pathogenesis
Osteoarthritis is a common joint disease that is a major public health problem. Here, the authors identify a role for the NUDT7 protein in pathogenesis of the disease, and report the potential for NUDT7 to be a target for future therapies.
- Jinsoo Song
- , In-Jeoung Baek
- & Eun-Jung Jin