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| Open AccessSuper-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma
Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.
- Huan-Chang Liang
- , Mariantonia Costanza
- & Olaf Merkel
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Article
| Open AccessA human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery
Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.
- Emilie Crouchet
- , Simonetta Bandiera
- & Thomas F. Baumert
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Article
| Open AccessThe ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors
Epigenetic changes are implicated in Acute myeloid leukemia (AML) tumorigenesis. Here, the authors show that the ubiquitin ligase RNF5 and its substrate RBBP4 contribute to AML development by regulating epigenetic-controlled transcription which determines AML sensitivity to HDAC inhibitors.
- Ali Khateb
- , Anagha Deshpande
- & Ze’ev A. Ronai
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Article
| Open AccessDisrupting biological sensors of force promotes tissue regeneration in large organisms
Humans and other large mammals heal wounds by forming fibrotic scar tissue with diminished function. Here, the authors show that disrupting mechanotransduction through the focal adhesion kinase pathway in large animals accelerates healing, prevents fibrosis, and enhances skin regeneration.
- Kellen Chen
- , Sun Hyung Kwon
- & Geoffrey C. Gurtner
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Article
| Open AccessAging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia
Molecular mechanisms associated with human germ cell aplasia in infertile men remain undefined. Here the authors perform single-cell transcriptome profiling to highlight differentially expressed genes and pathways in each somatic cell type in testes of men with idiopathic germ cell aplasia.
- Massimo Alfano
- , Anna Sofia Tascini
- & Andrea Salonia
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Article
| Open AccessDysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer
High cholesterol has been associated with increased risk of cancer but the underlying mechanism is not completely understood. Here, the authors show that a cholesterol metabolite induces metabolic reprogramming that generates ferroptosis-resistant cancer cells leading to increased tumour growth and metastasis.
- Wen Liu
- , Binita Chakraborty
- & Donald P. McDonnell
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Article
| Open AccessELMO1 signaling is a promoter of osteoclast function and bone loss
Osteoporosis and bone fractures affect millions of patients worldwide and are often due to increased bone resorption. Here the authors identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ promoting the bone resorption function of osteoclasts.
- Sanja Arandjelovic
- , Justin S. A. Perry
- & Kodi S. Ravichandran
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Article
| Open AccessThe pathogenesis of mesothelioma is driven by a dysregulated translatome
Treating malignant pleural mesothelioma (MpM) is challenging due to a lack of druggable genes, but other molecular features could be clinically useful. Here the authors profile mRNA translation dysregulation in MpM cell lines using polysome profiling, and identify mTORC1 and 2 as potential pharmacological targets.
- Stefano Grosso
- , Alberto Marini
- & Anne E. Willis
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Article
| Open AccessThe missing linker between SUN5 and PMFBP1 in sperm head-tail coupling apparatus
The sperm head-to-tail coupling apparatus ensures sperm head-tail integrity, but mechanistic insights remain limited. Here the authors demonstrate that CENTLEIN links and controls the interaction between SUN5 and PMFBP1, indicating that its impairments might be associated with acephalic spermatozoa syndrome.
- Ying Zhang
- , Chao Liu
- & Li Yuan
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Article
| Open AccessTargeting of eIF6-driven translation induces a metabolic rewiring that reduces NAFLD and the consequent evolution to hepatocellular carcinoma
Lipid accumulation in the liver leads to nonalcoholic fatty liver disease (NAFLD) that is a risk factor for developing hepatocellular carcinoma (HCC). Here, the authors show that activation of the translation initiation factor eIF6 promotes lipid accumulation in the liver and targeting eIF6 in murine models reduces NAFLD and associated HCC.
- Alessandra Scagliola
- , Annarita Miluzio
- & Stefano Biffo
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Article
| Open AccessAn N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer
The identification of response biomarkers for surgery, chemotherapy and immune checkpoint therapy in bladder cancer is crucial. Here, single nuclei RNA sequencing and spatial profiling identify a cancer cell population expressing Neural Type Cadherin 2 that associates with distinct treatment outcomes.
- Kenneth H. Gouin III
- , Nathan Ing
- & Dan Theodorescu
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Article
| Open AccessThe extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model
Variants of the extracellular chaperone Clusterin are associated with Alzheimer’s disease (AD) and Clusterin levels are elevated in AD patient brains. Here, the authors show that Clusterin binds to oligomeric Tau, which enhances the seeding capacity of Tau aggregates upon cellular uptake. They also demonstrate that Tau/Clusterin complexes enter cells via the endosomal pathway, resulting in damage to endolysosomes and entry into the cytosol, where they induce the aggregation of endogenous, soluble Tau.
- Patricia Yuste-Checa
- , Victoria A. Trinkaus
- & F. Ulrich Hartl
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Article
| Open AccessTemporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19
The immune response is key in determining disease severity of COVID19. Here Nouailles et al., apply bulk proteomics and scRNA-Seq of lung and blood samples of SARS-CoV-2 infected Syrian hamsters and provide a temporal atlas of the systemic and pulmonary cellular responses.
- Geraldine Nouailles
- , Emanuel Wyler
- & Martin Witzenrath
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Article
| Open AccessAdipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis
Hyaluronan is a naturally occurring linear polysaccharide that together with collagens, enzymes, and glycoproteins forms the extracellular matrix. Here the authors show that adipose tissue overproduction of Hyaluronan reduces fat accumulation in mice fed high-fat diet and improves systemic glucose homeostasis.
- Yi Zhu
- , Na Li
- & Philipp E. Scherer
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Article
| Open AccessNEK1-mediated retromer trafficking promotes blood–brain barrier integrity by regulating glucose metabolism and RIPK1 activation
NEK1 mutations promote lethality early in life and ALS late in life via unknown mechanisms. Here, the authors show that NEK1 mutation disrupts retromer-mediated trafficking and promotes RIPK1 activation, connecting retromer trafficking and metabolism to neuroinflammation by dietary intervention.
- Huibing Wang
- , Weiwei Qi
- & Junying Yuan
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Article
| Open AccessPRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma
Arginine methylation by PRMTs is dysregulated in cancer. Here, the authors use functional genomics screens and identify PRMT1 as a vulnerability in pancreatic ductal adenocarcinoma, and further show that PRMT1 regulates RNA metabolism and coordinates expression of genes in cell cycle progression, maintaining genomic stability and tumour growth.
- Virginia Giuliani
- , Meredith A. Miller
- & Timothy P. Heffernan
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Article
| Open AccessEndo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.
- Marie P. Schützmann
- , Filip Hasecke
- & Wolfgang Hoyer
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| Open AccessDisruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome
Patients with Cornelia de Lange Syndrome (CdLS) often have mutations in cohesin and its regulators; however, the molecular mechanism driving CdLS phenotypes is not well established. Here the authors reveal system skeletal organization genes are downregulated and show that cohesin and its loader Nipbl have altered and decreased genome-wide localization.
- Patricia Garcia
- , Rita Fernandez-Hernandez
- & Ethel Queralt
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Article
| Open AccessTSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism
Tuberous sclerosis complex (TSC) is a multiorgan disease that can lead to hyperactive mTORC1 due to deficient TSC1 or TSC2 protein function. Here, the authors find that despite high mTORC1 activity, TFEB localizes to the nucleus and drives lysosomal gene expression via a non-canonical Rag-dependent mechanism.
- Nicola Alesi
- , Elie W. Akl
- & Elizabeth P. Henske
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Article
| Open AccessThe antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells
TMPRSS2 is regulated by androgen receptor signalling in the prostate, however it is unclear if blocking this signalling is beneficial in the context of SARS-CoV-2 lung infection. Here the authors show that antiandrogen treatment downregulates TMPRSS2 in the lung and reduces viral entry and infection.
- D. A. Leach
- , A. Mohr
- & G. N. Brooke
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Article
| Open AccessSuppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity
Most mutant p53 heterozygous tumours undergo loss of the remaining wildtype (WT) p53 allele which leads to stabilization of the mutant p53 protein. Here, the authors show in an autochthonous colorectal cancer model that the WT p53 allele retains partial activity and suppresses the heat shock factor 1 (HSF1)- chaperone axis to prevent mutant p53 stabilisation and mutant p53 gain-of-function activities, thereby creating selective pressure for p53 loss-of-heterozygosity.
- Tamara Isermann
- , Özge Çiçek Şener
- & Ramona Schulz-Heddergott
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Article
| Open AccessSingle-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment
Human Treg cells are central to immune tolerance, yet their heterogeneity and differentiation remain incompletely understood. Here the authors perform single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease revealing Treg complexity in health and disease.
- Yuechen Luo
- , Changlu Xu
- & Xiaoming Feng
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Article
| Open AccessCIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
Age-related macular degeneration (AMD) has been connected to deficits in autophagy. Here, the authors demonstrate, in mice and dry-AMD patient samples, that calcium and integrin binding protein 2 (CIB2) regulates Rheb-mTORC1 signaling axis, and subsequently autophagy.
- Saumil Sethna
- , Patrick A. Scott
- & Zubair M. Ahmed
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Article
| Open AccessThe Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
The Atr-Check1 pathway is involved in cell cycle and the DNA damage response. Here, the authors show that the Atr-Check1 pathway can inhibit axon regeneration in response to Piezo-mediated mechanosensation, affecting functional recovery.
- Feng Li
- , Tsz Y. Lo
- & Yuanquan Song
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Article
| Open AccessBRN2 is a non-canonical melanoma tumor-suppressor
The transcription factor BRN2 regulates melanoma migration and invasion, but its role during melanoma initiation is unclear. Here the authors show that BRN2 is a haplo-insufficient tumour suppressor that positively regulates PTEN expression and in the context of BRAF mutation and heterozygous PTEN, BRN2 loss promotes melanoma initiation and progression.
- Michael Hamm
- , Pierre Sohier
- & Lionel Larue
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Article
| Open AccessSingle-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases
Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. Here the authors employ scRNA-seq to explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases.
- Cheng-Cheng Deng
- , Yong-Fei Hu
- & Bin Yang
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Article
| Open AccessImpairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis
Endo180, a collagen binding receptor, is highly expressed in a subset of cancer-associated fibroblasts. The authors show, using knockout mice and 3D in vitro assays, that Endo180 depletion impairs tumour fibroblast contractility and viability resulting in reduced tumour growth and metastasis.
- Ute Jungwirth
- , Antoinette van Weverwijk
- & Clare M. Isacke
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Article
| Open AccessSam68 promotes hepatic gluconeogenesis via CRTC2
Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.
- Aijun Qiao
- , Junlan Zhou
- & Gangjian Qin
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Article
| Open AccessAn antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage
Mechanisms underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin treatment during anticancer therapy remain poorly understood. Here the authors show that treatment with an antibody against the L1 cell adhesion molecule inhibits nuclear L1CAM translocation, thereby controlling vascular DNA damage and preventing cardiotoxicity.
- Jae-Kyung Nam
- , A-Ram Kim
- & Yoon-Jin Lee
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Article
| Open AccessThe P-type ATPase transporter ATP7A promotes angiogenesis by limiting autophagic degradation of VEGFR2
The role of endothelial copper transporter ATP7A in vascular function and angiogenesis remains largely unexplored. Here the authors show that ATP7A promotes VEGFR2 signaling and angiogenesis by limiting autophagy-mediated degradation of VEGFR2, which enhances reparative neovascularization.
- Dipankar Ash
- , Varadarajan Sudhahar
- & Masuko Ushio-Fukai
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Article
| Open AccessINPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer
The PI(3,4)P2 4-phosphatase, INPP4B, functions as a tumour suppressor in triple negative breast cancer. Here, the authors show that INPP4B enhances proliferation and growth of PIK3CA-mutant ER+ breast cancers by promoting PI3Kα-dependent late endosome formation and trafficking that leads to the activation of Wnt/β-catenin signalling.
- Samuel J. Rodgers
- , Lisa M. Ooms
- & Christina A. Mitchell
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Article
| Open AccessPPDPF alleviates hepatic steatosis through inhibition of mTOR signaling
Non-alcoholic fatty liver disease (NAFLD) has become a prevalent chronic liver disease, however, drugs to treat this disease are still lacking. Here, the authors show that PPDPF inhibits the development of hepatic steatosis by negatively regulating mTORC1-S6K-SREBP1 signaling, which provides a potential therapeutic candidate for NAFLD treatment.
- Ning Ma
- , Yi-Kang Wang
- & Dong Xie
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Article
| Open AccessOrphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue
The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.
- Anastasia Georgiadi
- , Valeria Lopez-Salazar
- & Stephan Herzig
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Article
| Open AccessCardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover
Decreased expression of BAG3 in the heart is associated with contractile dysfunction and heart failure. Here the authors show that this is due to decreased BAG3-dependent sarcomere protein turnover, which impairs mechanical function, and that sarcomere force-generating capacity is restored with BAG3 gene therapy.
- Thomas G. Martin
- , Valerie D. Myers
- & Jonathan A. Kirk
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Article
| Open AccessNeuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin
A feature of cohesin mutations in patients with Cornelia de Lange Syndrome (CdLS) is intellectual disability, but the underlying mechanisms have remained obscure. Here the authors show gene expression is deregulated in CdLS neurons and is recapitulated in a mouse model with cohesin depletion, which can be restored by re-expression of cohesin.
- Felix D. Weiss
- , Lesly Calderon
- & Matthias Merkenschlager
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Article
| Open AccessMastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation
Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.
- Do-Kyun Kim
- , Geethani Bandara
- & Ana Olivera
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Article
| Open AccessKidney intercalated cells are phagocytic and acidify internalized uropathogenic Escherichia coli
Kidney intercalated cells are involved in acid-base homeostasis in the kidneys. Here, the authors use single cell transcriptomics and find that interalated cells exhibit a transcriptional response conducive to defense and can engulf and acidify internalized bacteria, similarly to professional phagocytes.
- Vijay Saxena
- , Hongyu Gao
- & Andrew L. Schwaderer
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Article
| Open AccessCell barrier function of resident peritoneal macrophages in post-operative adhesions
Peritoneal adhesions are a major cause of complications after abdominal surgery. Here the authors use a post-operative abdominal adhesion model in mice to show that resident F4/80HighCD206− macrophages form a protective barrier that can be enhanced by IL-4 administration or adoptive transfer of these cells.
- Tomoya Ito
- , Yusuke Shintani
- & Ken Suzuki
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Article
| Open AccessLoss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration
Microglial SIRPα regulates synaptic pruning during development. Its role in neurodegeneration is unclear. Here, the authors show microglial SIRPα declines in the model of Alzheimer’s disease, leading to excessive microglia mediated synapse elimination as well as impaired cognitive function.
- Xin Ding
- , Jin Wang
- & Liang Li
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Article
| Open AccessTDP-43 and PINK1 mediate CHCHD10S59L mutation–induced defects in Drosophila and in vitro
Mutations in CHCHD10 can cause amyotrophic lateral sclerosis and frontotemporal dementia. The authors generate mutant Drosophila and HeLa cells to study the underlying mechanisms of CHCHD10S59L -induced degeneration and show it is mediated by TDP-43 and PINK1 pathways.
- Minwoo Baek
- , Yun-Jeong Choe
- & Nam Chul Kim
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Article
| Open AccessSARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition
The pandemic of COVID-19, caused by SARS-CoV-2 infection, warrants immediate investigation for therapy options. Here the authors show, using epithelial and air-liquid interface cultures, that SARS-CoV-2 hijacks host cell metabolism to facilitate viral replication, and that inhibition of mTORC1, a master metabolic regulator, suppresses viral replication.
- Peter J. Mullen
- , Gustavo Garcia Jr
- & Heather R. Christofk
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Article
| Open AccessAdipocyte PHLPP2 inhibition prevents obesity-induced fatty liver
Obesity can be associated with an increased risk of metabolic complications. Here, the authors show that adipocyte-specific ablation of the phosphatase PHLPP2 improves glucose homeostasis in high-fat diet fed obese mice, and that this may be due at least in part to PHLPP2 dephosphorylation of HSL.
- KyeongJin Kim
- , Jin Ku Kang
- & Utpal B. Pajvani
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Article
| Open AccessCanonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice
Mutations of Neuroligin 3 (NLGN3) have been associated with autism spectrum disorder (ASD). Here, the authors identify a previously undescribed interaction between NLGN3 and a splice variant of protein tyrosine phosphatase δ (PTP δ) and its role in development of social behaviour in mice.
- Tomoyuki Yoshida
- , Atsushi Yamagata
- & Shuya Fukai
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Article
| Open AccessThe release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells
The self-assembly of α-synuclein (αS) is a pathological feature of Parkinson’s disease. The αS species responsible for neuronal damage are not well characterized. Here, the authors show that αS fibrils release soluble prefibrillar oligomeric species responsible for neurotoxicity in vitro.
- Roberta Cascella
- , Serene W. Chen
- & Cristina Cecchi
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Article
| Open AccessSchwann cell plasticity regulates neuroblastic tumor cell differentiation via epidermal growth factor-like protein 8
Schwann cells (SCs) can acquire a repair phenotype following nerve injury. Here, the authors show that stromal SCs in ganglioneuromas express nerve-repair genes. Importantly, neuroblastoma cells respond to repair-related SCs increasing neuronal differentiation and reducing proliferation via EGFL8.
- Tamara Weiss
- , Sabine Taschner-Mandl
- & Inge M. Ambros
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Article
| Open AccessAsc-1 regulates white versus beige adipocyte fate in a subcutaneous stromal cell population
Adipose tissue is composed of a variety of cell types, including adipocyte precursor populations, that contribute to adipose tissue function upon differentiation. Here, using scRNA-sequencing of adolescent and adult mouse subcutaneous adipose tissue, the authors identify an Asc-1 positive preadipocyte population that is enriched in adolescent subcutaneous fat and demonstrate that loss of Asc-1 triggers spontaneous beige adipocyte differentiation.
- Lisa Suwandhi
- , Irem Altun
- & Siegfried Ussar
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Article
| Open AccessSingle cell transcriptomic analysis of murine lung development on hyperoxia-induced damage
It is unclear how changes in gene expression are induced by changes in oxygen levels during late lung development. Here, the authors provide data from MULTI-seq scRNAseq in mice showing exposure to higher oxygen levels affects cell fates, especially for alveolarisation, and define gene/cell signatures of impaired lung development under hyperoxia.
- Maria Hurskainen
- , Ivana Mižíková
- & Bernard Thébaud
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Article
| Open AccessMissense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice
The R138Q mutation in the Fragile X Mental Retardation 1 (FMR1) gene has been associated with Fragile X syndrome (FXS). Here, the authors present a Fmr1R138Q Knock-In mouse model and show that R138Q mutation results in impaired long-term potentiation and socio-cognitive performance in these mice.
- Marta Prieto
- , Alessandra Folci
- & Stéphane Martin
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Article
| Open AccessNeuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension
TRPV4 dominant mutations cause neuropathy. Here, the authors show that TRPV4 binds and interacts with RhoA, modulating the actin cytoskeleton. Neuropathy-causing mutations of TRPV4 disrupt this complex, leading to RhoA activation and impairment of neurite extension in cultured cells and flies.
- Brett A. McCray
- , Erika Diehl
- & Charlotte J. Sumner