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| Open AccessCdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice
The role of Cdo1 in exercise-mediated metabolic health and NAFLD is not clear. Here, the authors show that hepatic Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling to blunt hepatosteatosis and to promote exercise-mediated alleviation of NAFLD in mice.
- Min Chen
- , Jie-Ying Zhu
- & Liang Guo
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Article
| Open AccessOn the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging
Tryptophan metabolism through the kynurenine pathway changes with age and represents a potential intervention target for age associated disease. Here, the authors show that elevating physiological levels of the kynurenine pathway metabolite 3- hydroxyanthranilic acid can promote healthy aging.
- Hope Dang
- , Raul Castro-Portuguez
- & George L. Sutphin
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Article
| Open AccessInterleukin 31 receptor α promotes smooth muscle cell contraction and airway hyperresponsiveness in asthma
Although IL-31 has been implicated in asthma, the exact contribution of the IL-31 receptor (IL-31RA) signalling to airway hyperresponsiveness remains unexplored. Here, the authors demonstrate that IL31RA promotes muscarinic acetylcholine receptor 3 expression and calcium signalling, as well as smooth muscle cell contraction.
- Santhoshi V. Akkenepally
- , Dan J. K. Yombo
- & Satish K. Madala
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| Open AccessThe long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis
Although patients with rheumatoid arthritis (RA) usually exhibit symmetrical joint involvement, some can develop alternative patterns of arthritis, often translating into differences in responsiveness to treatment. In this study, the authors propose that the long-noncoding RNA, HOTAIR, might contribute to these differences.
- Muriel Elhai
- , Raphael Micheroli
- & Caroline Ospelt
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| Open AccessThe NERP-4–SNAT2 axis regulates pancreatic β-cell maintenance and function
Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. Here, the authors show a VGF-derived peptide NERP-4 acts as a positive allosteric modulator on the amino acid transporter SNAT2/SLC38A2, thereby contributing to β-cell maintenance and function.
- Weidong Zhang
- , Ayako Miura
- & Masamitsu Nakazato
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Article
| Open AccessSelenoprotein deficiency disorder predisposes to aortic aneurysm formation
Aortic aneurysms have a heritable basis. Here, the authors report that a selenoprotein deficiency disorder due to mutations in SECISBP2, causes oxidative stress-mediated aortic cell death, predisposing to thoracic aortic aneurysm formation.
- Erik Schoenmakers
- , Federica Marelli
- & Krishna Chatterjee
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Article
| Open AccessEndosomal Arl4A attenuates EGFR degradation by binding to the ESCRT-II component VPS36
Endosomal EGFR signaling and lysosomal degradation play important roles in controlling numerous biological processes. Here, the authors show that Arl4A negatively regulates EGFR degradation by binding to VPS36 and attenuating ESCRT-mediated late endosomal EGFR sorting.
- Shin-Jin Lin
- , Ming-Chieh Lin
- & Fang-Jen S. Lee
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Article
| Open AccessModulation of insulin secretion by RBFOX2-mediated alternative splicing
Insulin secretion from the pancreatic beta cell is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Here, the authors show that the RNA binding protein RBFOX2 is a regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis.
- Nicole D. Moss
- , Kristen L. Wells
- & Lori Sussel
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Article
| Open Access3D bioprinted multilayered cerebrovascular conduits to study cancer extravasation mechanism related with vascular geometry
Geometrical complexities of blood vessels alter biophysical behaviors of circulating tumor cells, influencing cancer metastasis. Here, the authors develop a 3D bioprinted in vitro brain blood vessel-on-a-chip to investigate continuities between vascular geometry and metastatic cancer development.
- Wonbin Park
- , Jae-Seong Lee
- & Dong-Woo Cho
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Article
| Open AccessA reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease
Mitochondrial dysfunction is a contributing factor in Parkinson’s disease. Here the authors carry out a multilayered omics analysis of Parkinson’s disease patient-derived neuronal cells, which reveals a reversible hypometabolism mediated by α-ketoglutarate dehydrogenase deficiency, which is correlated with disease progression in the donating patients.
- Sebastian Schmidt
- , Constantin Stautner
- & Wolfgang Wurst
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Article
| Open Access3D reconstructions of parasite development and the intracellular niche of the microsporidian pathogen Encephalitozoon intestinalis
Microsporidia are obligate intracellular parasitic fungi that can cause opportunistic infections in humans. Here, Antao et al. investigate the intracellular life cycle of human-infecting Encephalitozoon intestinalis using serial block-face scanning electron microscopy to characterize parasite organelle development and host-cell mitochondrial remodeling.
- Noelle V. Antao
- , Cherry Lam
- & Gira Bhabha
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Article
| Open AccessVector-borne Trypanosoma brucei parasites develop in artificial human skin and persist as skin tissue forms
Here, authors show that tsetse-fly transmitted trypanosomes rapidly differentiate within human skin equivalents, eventually entering a reversible quiescent stage and conclude that these skin tissue forms may contribute to long-term parasite infections in asymptomatic individuals.
- Christian Reuter
- , Laura Hauf
- & Markus Engstler
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Article
| Open AccessReduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension
It is unknown whether unrepaired DNA damage in lung endothelial cells causes persistent pulmonary arterial hypertension. Here, the authors combine oxidative stress with impaired BMPR2 signaling to link a reduction in FOXF1 to unrepaired DNA damage and impaired regeneration of normal endothelium.
- Sarasa Isobe
- , Ramesh V. Nair
- & Marlene Rabinovitch
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Article
| Open AccessZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury
Mitochondria dysfunction contributes to acute liver injuries. Zhang et al. find that Zhx2 deletion enhances mitochondrial function by promoting electron transport chain gene expression via PGC-1α dependent and independent manner.
- Yankun Zhang
- , Yuchen Fan
- & Chunhong Ma
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Article
| Open AccessRNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis
The function of METTL3 and RNA methylation is important in various biological processes. Here the authors show that METTL3 is reduced in childhood asthma patients and that conditional knockout of Mettl3 in mouse myeloid cells enhances Th2 response and allergic asthma associated with changes in macrophage function.
- Xiao Han
- , Lijuan Liu
- & Yufeng Zhou
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Article
| Open AccessSpatial exosome analysis using cellulose nanofiber sheets reveals the location heterogeneity of extracellular vesicles
Extracellular vesicles (EVs) are known to be heterogeneous intravitally. Here, we present cellulose nanofiber sheets which capture EVs with high purity from trace volumes of biofluids and enable analysis of location-dependent heterogeneity to enhance understanding of pathological mechanisms and enable diagnostic readouts.
- Akira Yokoi
- , Kosuke Yoshida
- & Takao Yasui
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Article
| Open AccessFNIP1 abrogation promotes functional revascularization of ischemic skeletal muscle by driving macrophage recruitment
Functional revascularization is vital to the recovery of blood flow. Here, Sun et al. show that myofiber FNIP1 is a negative regulator of muscle functional angiogenesis and revascularization after ischemia by controlling macrophage recruitment.
- Zongchao Sun
- , Likun Yang
- & Zhenji Gan
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Article
| Open AccessSystemic and intrinsic functions of ATRX in glial cell fate and CNS myelination in male mice
Myelination is often compromised in ATR-X intellectual disability syndrome patients. Here, the authors show that the causative gene, ATRX, can regulate myelination in mice by modulating systemic thyroxine levels and by supporting oligodendrocyte progenitor differentiation.
- Megan E. Rowland
- , Yan Jiang
- & Nathalie G. Bérubé
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Article
| Open AccessTranscriptional repression of beige fat innervation via a YAP/TAZ-S100B axis
Sympathetic innervation is essential for the development of functional beige fat that maintains metabolic homeostasis. Qiu and colleagues discover that YAP/TAZ can act as a brake on the beige fat innervation by blocking PRDM16-C/EBPβ-mediated S100b expression.
- Xun Huang
- , Xinmeng Li
- & Yifu Qiu
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Article
| Open AccessWnt activation disturbs cell competition and causes diffuse invasion of transformed cells through NF-κB-MMP21 pathway
The relevance of cell competition in intestinal epithelial carcinogenesis remains to be explored. Here, the authors find aberrant Wnt activation in RasV12-transformed cells reverses the directionality of cell extrusion mediated by cell competition in intestinal epithelium, causing infiltration into basal lamina rather than apical elimination of transformed cells and consequent development of invasive carcinomas.
- Kazuki Nakai
- , Hancheng Lin
- & Shunsuke Kon
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Article
| Open AccessSpliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy
Non-alcoholic fatty liver disease affects 25% of people worldwide. Here the authors report that spliceosome component Usp39 deletion in mice leads to spontaneous steatosis and impaired autophagy through the regulation of alternative splicing.
- Donghai Cui
- , Zixiang Wang
- & Zhaojian Liu
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Article
| Open AccessIntegrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
The normal function of amyloid precursor protein (APP) implicated in Alzheimer’s disease is unclear. Here, authors use multi-omics to reveal the fly APP’s role in regulating proteostasis and validate using vertebrate and In-vivo tauopathy models.
- Vanitha Nithianandam
- , Hassan Bukhari
- & Mel B. Feany
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Article
| Open AccessDNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones
Here the authors characterize DNAJB6 mutants found in LGMDD1 patients. They show that these mutants retain aggregation-prevention activity, but have impaired regulation of Hsp70 binding, uncontrollably recruiting Hsp70s, depleting the chaperone levels and disrupting proteostasis.
- Meital Abayev-Avraham
- , Yehuda Salzberg
- & Rina Rosenzweig
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| Open AccessFollicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets
Follicle-stimulating hormone (FSH) is involved in mammalian reproduction, but several studies have suggested a role of FSH and its receptor in extragonadal tissue. Here, the authors show that FSH orchestrates glucose-stimulated insulin secretion (GSIS) via its receptor on pancreatic β-cells, with pre-menopausal FSH levels dose-dependently promoting GSIS and postmenopausal FSH levels inhibiting this effect.
- Yi Cheng
- , Hong Zhu
- & He-Feng Huang
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Article
| Open AccessHomodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
| Open AccessAntiviral responses in a Jamaican fruit bat intestinal organoid model of SARS-CoV-2 infection
Bats are natural reservoirs for several zoonotic viruses including SARS-CoV-2 thus there is a need to better define bat antiviral responses. Here, Hashimi et al. profile antiviral responses to SARS-CoV-2 in bat intestinal organoids finding that interferon and regenerative responses where induced.
- Marziah Hashimi
- , T. Andrew Sebrell
- & Diane Bimczok
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Article
| Open AccessFolding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling
The conformational biogenesis of multi-domain ABC-transporters is poorly understood. Here the authors show the critical role of dynamic allosteric coupling networks, its perturbation and restoration in CFTR folding, misfolding, and pharmacological rescue, respectively.
- Naoto Soya
- , Haijin Xu
- & Gergely L. Lukacs
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Article
| Open AccessSmall leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment
The mechanical properties of central nervous system (CNS) scar tissue are considered to contribute to axon regeneration failure. Here, the authors identify members of the small leucine-rich proteoglycan family as modulators of the inhibitory viscoelastic response of CNS lesions.
- Julia Kolb
- , Vasiliki Tsata
- & Daniel Wehner
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Article
| Open AccessThe mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury
The role of the mitochondrial fusion protein OPA1 in liver function is unknown. Here, authors showed that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 deletion prevents liver injury and contributes to liver resiliency.
- Hakjoo Lee
- , Tae Jin Lee
- & Yisang Yoon
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Article
| Open AccessLactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis
Currently the structure and biological function of Lactate Dehydrogenase D (LDHD) are unclear. Here the authors report the structure of LDHD bound with various ligands and show that LDHD is a general dehydrogenase for D-2-hydroxyacids with small to moderate-size hydrophobic moieties and investigate loss-of-function mutations that play an important role in D-lactic acidosis.
- Shan Jin
- , Xingchen Chen
- & Jianping Ding
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Article
| Open AccessGut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis
Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here, the authors show in a mice model that insulin action in the gut may play a protective role in the development of NASH and HCC in diabetes.
- Kotaro Soeda
- , Takayoshi Sasako
- & Kohjiro Ueki
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Article
| Open AccessReprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice
Skeletal muscle’s metabolic status has an impact on health and the prognosis of chronic diseases. Here the authors unveil an atlas of open chromatin regions in skeletal muscles using single-nucleus techniques on juvenile male mice, highlight regulatory dynamics between normal and denervated states, and pinpoint ELK4 as a pivotal factor in muscle atrophy.
- Hongchun Lin
- , Hui Peng
- & Zhaoyong Hu
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Article
| Open AccessA human lung alveolus-on-a-chip model of acute radiation-induced lung injury
Acute exposure to radiation can lead to acute pneumonitis, fibrosis or death. Here the authors develop an alveolus-on chip model to study the molecular characteristics of radiation induced lung injury, better understand radiation induced lung disease and facilitate drug screening.
- Queeny Dasgupta
- , Amanda Jiang
- & Donald E. Ingber
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Article
| Open AccessSpecies-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
The innate immune cells undergo metabolic reprogramming upon inflammation. Here, the authors report that both mouse and human microglia display a metabolic reprogramming in the presence of a TLR4 activation, however species-specific enzymes are responsible for this process.
- Angélica María Sabogal-Guáqueta
- , Alejandro Marmolejo-Garza
- & Amalia Dolga
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| Open AccessPalmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma
Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.
- Do-Won Jeong
- , Jong-Wan Park
- & Yang-Sook Chun
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Article
| Open AccessHuman cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype
β-thalassemia is a prevalent genetic disorder causing severe anemia, with study of the underlying molecular defects impeded by paucity of suitable patient material. Here, the authors show that cellular model systems of βthalassemia can be used to identify new therapeutic targets and as screening platforms for new drugs and reagents.
- Deborah E. Daniels
- , Ivan Ferrer-Vicens
- & Jan Frayne
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Article
| Open AccessInterferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Here the authors show that the basal activation of the interferon/ISG15 pathway is required for the stability of nascent DNA during replication and its upregulation promotes viability, proliferation and acquisition of drug resistance in BRCA1/2 deficient cells.
- Ramona N. Moro
- , Uddipta Biswas
- & Lorenza Penengo
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Article
| Open AccessFEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins
When and how microglia engulf synapses and myelin is still unclear. Here, the authors provide a suite of flow cytometry-based approaches to quantify engulfment, paving the way for high-throughput assessment of microglial function in health and disease.
- Lasse Dissing-Olesen
- , Alec J. Walker
- & Beth Stevens
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Article
| Open AccessAltered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell culture model
Using a 3-D neural platform, the authors show that a ubiquitin variant is sufficient to induce Alzheimer’s disease-like pathology in human neurons. Suppressing expression of this variant improved pathology in neurons carrying familial mutations.
- Inbal Maniv
- , Mahasen Sarji
- & Michael H. Glickman
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Article
| Open AccessSingle-cell transcriptome analysis indicates fatty acid metabolism-mediated metastasis and immunosuppression in male breast cancer
Male breast cancer may involve different populations of immune cells. Here the authors use single cell transcriptomics to show that infiltration of T cells is lower in male breast cancer relative to female breast cancer, and find that this is accompanied by distinct metabolic changes.
- Handong Sun
- , Lishen Zhang
- & Qiang Ding
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Article
| Open AccessFAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination
The mechanisms underlying vascular smooth muscle cell reprogramming in abdominal aortic aneurism (AAA) remain unclear. Here they show that FAM3A, a metabolic cytokine, serves as a cell fate-shaping regulator of smooth muscle cells to protect against AAA formation.
- Chuxiang Lei
- , Haoxuan Kan
- & Yuehong Zheng
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Article
| Open AccessImpaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence
Plakophilin-2 is a key component of desmosomes required to maintain cardiac tissue cohesion. Here the authors uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired Plakophilin-2 in subjects with obesity.
- Aina Lluch
- , Jessica Latorre
- & Francisco J. Ortega
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Article
| Open AccessCD36 mediates SARS-CoV-2-envelope-protein-induced platelet activation and thrombosis
Aberrant coagulation and thrombosis are associated with severe SARS-CoV-2 infection. Here, the authors show that the E protein are associated with coagulation disorders in COVID-19 patients and could directly enhance platelet activation and thrombosis through a CD36/p38 MAPK/NF-kB signaling axis.
- Zihan Tang
- , Yanyan Xu
- & Tingting Liu
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Article
| Open AccessAn ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress
How cancer cells develop and emerge has long been a matter of debate. Here, the authors reveal a crucial role of ATR-PrimPol in enabling precancerous cells to survive KRASinduced replication stress and expand clonally with genomic instability.
- Taichi Igarashi
- , Marianne Mazevet
- & Bunsyo Shiotani
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Article
| Open AccessIRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice
Cardiac fibrosis is a common feature of chronic heart failure, and the mechanisms of cardiac fibrosis are unclear. Here, the authors show that iroquois homeobox 2 (IRX2) regulates the early growth response factor 1 (EGR1) pathway upon fibrotic stimulation and drives cardiac fibrosis.
- Zhen-Guo Ma
- , Yu-Pei Yuan
- & Qi-Zhu Tang
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Article
| Open AccessIntegrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis
Zhang et al. show that the adhesion receptor integrin β3 directly inhibits G protein mediated RhoA activation and granule secretion. A peptide mimicking this effect selectively inhibits platelet secretion but not integrin-mediated platelet adhesion.
- Yaping Zhang
- , Xiaojuan Zhao
- & Xiaoping Du
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Article
| Open AccessExtravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape
Invasive extravillous trophoblast cells are a key feature of placentation and successful pregnancy. Here, the authors identify transcription factors and regulatory mechanisms critical for extravillous trophoblast cell lineage development.
- Kaela M. Varberg
- , Esteban M. Dominguez
- & Elin Grundberg
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Article
| Open AccessSingle-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction
This study identified a subset of osteoclastogenic fibroblasts expressing INHBA/activin A in human cholesteatoma. It further elucidated the mechanism behind the induction of inflammatory bone destruction, suggesting a potential therapeutic target.
- Kotaro Shimizu
- , Junichi Kikuta
- & Masaru Ishii
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Article
| Open AccessGain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis
TP53 alteration and TMPRSS2-ERG fusion are often found together in prostate cancer. Here, the authors show that gain-of-function mutant p53 collaborates with ERG proto-oncogene to drive prostate cancer tumourigenesis by activating beta-catenin expression and afterwards pyrimidine synthesis.
- Donglin Ding
- , Alexandra M. Blee
- & Haojie Huang