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| Open AccessLysosomal cystine export regulates mTORC1 signaling to guide kidney epithelial cell fate specialization
Cystinosis is a lysosomal storage disease that affects the kidney. Here, the authors use preclinical models and advanced profiling techniques to discover the mechanism by which defective cystine mobilization from lysosomes disrupts kidney cell function, offering insights into potential therapies.
- Marine Berquez
- , Zhiyong Chen
- & Alessandro Luciani
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Article
| Open AccessImbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity
The accumulation of cytotoxic deoxysphingolipids causes retinopathies through unknown mechanisms. Here the authors use retinal organoids to show that photoreceptor toxicity is mediated by unfolded protein response signaling.
- Jessica D. Rosarda
- , Sarah Giles
- & Kevin T. Eade
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Article
| Open AccessIL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation
Interleukin 9 (IL-9) is a cytokine that plays causative role in airway inflammation of both infectious and allergic origin. Here authors show in a mouse model of SARS-CoV-2 infection that IL-9, predominantly produced by helper T cells, plays a critical pathogenic role in COVID-19 via an inflammatory pathway involving the transcription factor Foxo1.
- Srikanth Sadhu
- , Rajdeep Dalal
- & Amit Awasthi
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Article
| Open AccessMOBILE pipeline enables identification of context-specific networks and regulatory mechanisms
A problem in network biology is identification of context-specific networks. Here the authors report Multi-Omics Binary Integration via Lasso Ensembles (MOBILE) to nominate molecular features associated with cellular phenotypes and pathways, and use this to assess interferon-γ regulated PD-L1 expression.
- Cemal Erdem
- , Sean M. Gross
- & Marc R. Birtwistle
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Article
| Open AccessLinker histone variant H1.2 is a brake on white adipose tissue browning
Thermogenic adipocytes are ideal targets to counteract obesity and associated metabolic disorders. Here, the authors show a regulatory role of linker histone variant H1.2 on iWAT browning and thermogenesis through an H1.2-IL10rα axis.
- Yangmian Yuan
- , Yu Fan
- & Ling Zheng
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| Open AccessLoss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation
CLN3 mutations cause Batten disease, a devastating neurodegenerative lysosomal storage disease. Here, the authors discovered that CLN3 plays a crucial role in both trafficking of lysosomal proteins and autophagic lysosomal reformation.
- Alessia Calcagni’
- , Leopoldo Staiano
- & Andrea Ballabio
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Article
| Open AccessThe role of mechano-regulated YAP/TAZ in erectile dysfunction
Phosphodiesterase type 5 inhibitors (PDE5is) are used to treat erectile dysfunction, however, not all patients respond to PDE5i treatment. Here the authors report that YAP/TAZ activity contributes to erectile dysfunction and targeting YAP/TAZ improves erectile function in a PDE5i non-respondent rat model.
- Mintao Ji
- , Dongsheng Chen
- & Lei Chang
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Article
| Open AccessThe NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice
Deficiency in NAD+ has been implicated in skeletal deformities during development in both humans and mice. Here, the authors use mice that lack the critical enzyme of the NAD+ salvage pathway Nampt in mesenchymal lineage cells to show that the NAD salvage pathway is indispensable for endochondral but not intramembranous bone development.
- Aaron Warren
- , Ryan M. Porter
- & Maria Almeida
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Article
| Open AccessCharacterization of p38α autophosphorylation inhibitors that target the non-canonical activation pathway
The p38α protein kinase is an attractive druggable target for many human diseases. Here, the authors show how the structural plasticity of p38α can be leveraged to selectively inhibit a subset of the functions regulated by this kinase and aid in the development of therapeutic compounds.
- Lorena González
- , Lucía Díaz
- & Angel R. Nebreda
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Article
| Open AccessTisp40 prevents cardiac ischemia/reperfusion injury through the hexosamine biosynthetic pathway in male mice
Cardiac I/R injury is a deleterious issue in the clinic. Here, the authors show that Tisp40 facilitates HBP flux and protein O-GlcNAcylation through binding to the promoter of GFPT1, thereby preventing cardiac I/R injury.
- Xin Zhang
- , Can Hu
- & Qi-Zhu Tang
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Article
| Open AccessIdentification of BRCA1/2 mutation female carriers using circulating microRNA profiles
BRCA1/2 mutations are known to increase risk of breast and ovarian cancer but carrier status in healthy individuals is unknown without genetic testing. Here, the authors created a circulating miRNA signature to predict BRCA1/2 carrier status in healthy individuals to aid the decision process on genetic testing.
- Kevin Elias
- , Urszula Smyczynska
- & Dipanjan Chowdhury
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Article
| Open AccessColitis ameliorates cholestatic liver disease via suppression of bile acid synthesis
The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) has been known for decades, but mechanisms of gut-liver crosstalk are incompletely understood. Here, the authors show a colitis-triggered protective circuit suppressing cholestatic liver disease which encourages multi-organ treatment strategies for PSC.
- Wenfang Gui
- , Mikal Jacob Hole
- & Kai Markus Schneider
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Article
| Open AccessSenescent immune cells accumulation promotes brown adipose tissue dysfunction during aging
With increasing age, brown adipose tissue (BAT) becomes characterized by increased adiposity and immune cell infiltration but reduced thermogenic capacity. Here the authors report that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells accumulate in BAT of male rats and mice during aging and contribute to BAT dysfunction.
- Xu Feng
- , Liwen Wang
- & Haiyan Zhou
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Article
| Open AccessSensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines
Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here the authors show studies of transgenic chemogenetic mouse lines that develop sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress.
- Shambhu Yadav
- , Markus Waldeck-Weiermair
- & Thomas Michel
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Article
| Open AccessmacroH2A2 antagonizes epigenetic programs of stemness in glioblastoma
Self-renewing cells play an important role in initiation, progression, and therapy resistance in glioblastoma. Here, the authors identify histone variant macroH2A2 as a regulator of chromatin organisation resulting in the suppression of transcriptional programs of self-renewal in glioblastoma.
- Ana Nikolic
- , Francesca Maule
- & Marco Gallo
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| Open AccessPhospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism
Phospholipase D3 polymorphisms are linked to late-onset Alzheimer’s disease but the mechanisms are not understood. Van Acker and colleagues show that Phospholipase D3 processes mitochondrial DNA in lysosomes to maintain lysosomal homeostasis and proper degradation of the amyloid precursor protein.
- Zoë P. Van Acker
- , Anika Perdok
- & Wim Annaert
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| Open AccessPeripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
Reversible mitochondrial stress leading to improved mitochondrial function (mitohormesis) has been reported as an anti-aging mechanism. Here the authors report that harmol (a beta-carboline compound) induces mitohormesis in peripheral organs, alleviates aging-related phenotypes in mice, and extends lifespan in invertebrate models.
- Luis Filipe Costa-Machado
- , Esther Garcia-Dominguez
- & Pablo J. Fernandez-Marcos
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| Open AccessRagD auto-activating mutations impair MiT/TFE activity in kidney tubulopathy and cardiomyopathy syndrome
Mutations in the RRAGD gene are causative of an autosomal dominant disorder characterized by kidney tubulopathy and cardiomyopathy. Here, the authors identify a new RRAGD P88L mutation, demonstrating that all the identified RRAGD mutations inhibit the nuclear translocation of MiT/TFE transcription factors, resulting in defective responses to lysosomal or mitochondrial damage.
- Irene Sambri
- , Marco Ferniani
- & Andrea Ballabio
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Article
| Open AccessUDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis
The mechanism underlying hepatocytes apoptosis, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here, the authors identify UGDH and its catalytic product UDP-glucuronate as suppressors of NASH-associated liver damage by inhibiting RIPK1- dependent hepatocyte apoptosis.
- Tao Zhang
- , Na Zhang
- & Jinyang Gu
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| Open AccessOrganoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss
An in-depth understanding of the molecular pathogenesis of fibrolamellar carcinoma (FLC) is hampered due to limited human preclinical models. Here the authors engineer human organoids to reflect different FLC genetic backgrounds and show that hepatocytes can be a cell-of-origin of FLC that transdifferentiate into ductal/progenitor like cells due to combined BAP1 and PRKAR2A loss.
- Laura Rüland
- , Francesco Andreatta
- & Benedetta Artegiani
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Article
| Open AccessPiezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis
Osteoarthritis is characterized by mechanically driven pain but lacks adequate treatments. Here, the authors show that inhibiting a mechanically-sensitive ion channel expressed by nociceptors reduces pain behaviors in mouse models of joint pain.
- Alia M. Obeidat
- , Matthew J. Wood
- & Rachel E. Miller
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| Open AccessHydrogel dressing integrating FAK inhibition and ROS scavenging for mechano-chemical treatment of atopic dermatitis
Mechanical scratching and oxidative stress can aggravate atopic dermatitis symptoms, while treatment targeting scratching is often overlooked. Here, the authors find that enhanced phosphorylation of focal adhesion kinase is associated with scratch-exacerbated AD, then develop a hydrogel dressing that integrates oxidative stress modulation with FAK inhibition to synergistically treat AD.
- Yuanbo Jia
- , Jiahui Hu
- & Feng Xu
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Article
| Open AccessAn interactive murine single-cell atlas of the lung responses to radiation injury
Radiation damages the healthy lung and triggers severe side effects. Here the authors provide a single cell atlas of the lung responses to radiation injury to explore the spatio-temporal dynamics of the mechanisms leading to radio-induced pulmonary fibrosis.
- Sandra Curras-Alonso
- , Juliette Soulier
- & Charles Fouillade
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| Open AccessIDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart
Protein targets that are affected by ROS and underly impaired inotropic effects in the heart are largely unknown. Here, the authors identify the γ-subunit of IDH3 as a redox switch linking oxidative stress to impaired metabolism and heart function.
- Maithily S. Nanadikar
- , Ana M. Vergel Leon
- & Dörthe M. Katschinski
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Article
| Open AccessNon-functional ubiquitin C-terminal hydrolase L1 drives podocyte injury through impairing proteasomes in autoimmune glomerulonephritis
In membranous nephropathy autoantibodies target podocytes of the kidney filter resulting in injury. Here the authors show that the ensuing proteostatic disturbances and proteinuria relate to aberrant interactions of non-functional UCH-L1 enzyme with the proteasome, curtailing its capacity.
- Julia Reichelt
- , Wiebke Sachs
- & Catherine Meyer-Schwesinger
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Article
| Open AccessDAXX drives de novo lipogenesis and contributes to tumorigenesis
Cancer cells have altered lipid metabolism. Here the authors show that DAXX promotes lipogenesis and tumorigenesis through interaction with SREBP1/2.
- Iqbal Mahmud
- , Guimei Tian
- & Daiqing Liao
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Article
| Open AccessLung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation
Mast cells are activated and proliferate during allergic reactions which can involve mast cell specific proteins. Here the authors show that mast cell-expressed membrane protein1 (MCEMP1) is an adaptor for KIT to promote SCF mediated mast cell proliferation and lack of MCEMP1 reduces inflammation in mouse asthma models.
- Youn Jung Choi
- , Ji-Seung Yoo
- & Jae U. Jung
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Article
| Open AccessGlucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism
GBA1 mutations cause Gaucher’s disease and are the strongest risk factor for Parkinson’s disease. Using stable cell lines and patient iPSCs, the authors show mitochondrial localization of GBA1, which may affect neurodegenerative disease risk.
- Pascale Baden
- , Maria Jose Perez
- & Michela Deleidi
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Article
| Open AccessMEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ
Life-threatening vascular tumors can be associated with uncontrolled activity of the guanine nucleotide-binding protein subunit alpha (Gαq). Here, the authors develop a murine model for these tumors and show that MEK inhibition prevents formation of vascular lesions and improves survival.
- Sandra Schrenk
- , Lindsay J. Bischoff
- & Elisa Boscolo
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Article
| Open AccessDefective BVES-mediated feedback control of cAMP in muscular dystrophy
cAMP is an important second messenger involved in many aspects of biological processes. Here, Li et al. shows that blood vessel epicardial substance (BVES) is a negative regulator of cAMP signaling required for maintaining muscle mass and function.
- Haiwen Li
- , Peipei Wang
- & Renzhi Han
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Article
| Open AccessNeuraminidase 1 promotes renal fibrosis development in male mice
The influenza virus neuraminidase has been well documented, yet the functions of mammalian neuraminidases remain less explored. Here, the authors show that neuraminidase 1 promotes renal fibrosis development by interacting with ALK5 to activate SMAD2/3.
- Qian-Qian Chen
- , Kang Liu
- & Lei Zhang
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Article
| Open AccessIGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis
Glioblastoma stem-like cells (GSCs) contribute to therapeutic resistance and recurrence of glioblastomas. Here the authors show that Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) promotes GSCs invasion.
- Weiwei Lin
- , Rui Niu
- & Jinlong Yin
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Article
| Open AccessEvolutionary conservation of the fidelity of transcription
The molecular mechanisms that ensure faithful transcription of genetic information are still unclear. Chung et al. identify various genes, alleles and processes that affect the fidelity of transcription multiple organisms, suggesting evolutionary conservation of fidelity factors, and compare the error rate of transcription among these species.
- Claire Chung
- , Bert M. Verheijen
- & Marc Vermulst
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| Open AccessPolynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis
Renal tubular atrophy is a hallmark of chronic kidney disease. The study by Zhu et al. reveals the protective role of tubular polynucleotide phosphorylase (PNPT1) against renal atrophy by blocking the leakage of mitochondrial dsRNAs into cytoplasm where they activate the PKReIF2α axis and terminate translation.
- Yujie Zhu
- , Mingchao Zhang
- & Ke Zen
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Article
| Open AccessTHADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass
THADA has been identified as a type 2 diabetes-associated gene whose function is not fully understood. Here the authors report that THADA deficiency protects mice from hyperglycemia and glucose intolerance by promoting insulin secretion and inhibiting β-cell apoptosis, suggesting THADA could be explored as a potential therapeutic target for diabetes.
- Yuqing Zhang
- , Shan Han
- & Han Zhao
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| Open AccessThe usherin mutation c.2299delG leads to its mislocalization and disrupts interactions with whirlin and VLGR1
The c.2299delG mutation in usherin causes loss of hearing and vision. Here, the authors show in a mouse model of this disease that the expression of mutant usherin leads to retinitis pigmentosa and structural defects in the photoreceptor cilium associated with mislocalization of VLGR1 and WHRN.
- Lars Tebbe
- , Maggie L. Mwoyosvi
- & Muna I. Naash
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Article
| Open AccessSpatial proteomics reveals secretory pathway disturbances caused by neuropathy-associated TECPR2
Disease-associated mutations in the protein TECPR2 have so far been mainly studied with respect to autophagy. Using complementary proteomics approaches, the authors identify trafficking and sorting defects along the secretory pathway upon TECPR2 deficiency and provide evidence that TECPR2 associates with the ER-Golgi interface.
- Karsten Nalbach
- , Martina Schifferer
- & Christian Behrends
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Article
| Open AccessSVEP1 is an endogenous ligand for the orphan receptor PEAR1
SVEP1 is linked to numerous human diseases, though its disease-promoting mechanism has remained unclear. Here, the authors identify SVEP1 as a ligand for the orphan receptor PEAR1 and provide insight into the role of this interaction in cardiovascular disease.
- Jared S. Elenbaas
- , Upasana Pudupakkam
- & Nathan O. Stitziel
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Article
| Open AccessLipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats
How the liver mitochondria seamlessly regulate lipogenesis and lipid oxidation is unknown. Here, the authors report two functionally distinct populations of mitochondria, cytoplasmic and lipid droplet-associated mitochondria, and demonstrate that the latter’s lipid oxidation function is impaired in a rat NAFLD model.
- Noble Kumar Talari
- , Ushodaya Mattam
- & Naresh Babu V. Sepuri
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Article
| Open AccessStructural insights into pathogenic mechanism of hypohidrotic ectodermal dysplasia caused by ectodysplasin A variants
EDA variants are associated with X-linked hypohidrotic dysplasia. Here, the authors report the crystal structure of the human EDA-EDAR complex, reveal the important role of this complex in ectodermal development and uncover the structural mechanism of disease-related mutations in EDA.
- Kang Yu
- , Chenhui Huang
- & Yiqun Wu
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Article
| Open AccessAdipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo
Extracellular vesicles (EVs) convey inter-organ communication in health and disease. Here, the authors report that adipocyte-derived EVs isolated from insulin-resistant obese but not lean male mice stimulate insulin secretion via the targeted transfer of insulinotropic proteins from adipose tissue to β-cells.
- Konxhe Kulaj
- , Alexandra Harger
- & Kerstin Stemmer
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Article
| Open AccessGenetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure
β-cell dedifferentiation is a key feature of type 2 diabetes. Here, the authors show evidence of re-differentiation of de-differentiated β-cells and identify ALDH1A3 as a key player in this process, proposing inhibition of ALDH1A3 as a treatment method for β-cell dysfunction in diabetes.
- Jinsook Son
- , Wen Du
- & Domenico Accili
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Article
| Open AccessPolyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV
Polyamine metabolism is a determinant of T helper cell polarization. Here, Mahalingam et al analyse the metabolic and transcriptomic profile of oral mucosa from people living with HIV to demonstrate the effect of polyamine synthesis on T cell dysfunction during HIV-1 infection.
- S. S. Mahalingam
- , S. Jayaraman
- & P. Pandiyan
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Article
| Open AccessAge-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity
Matrix stiffening is a quintessential feature of aged tissues. Authors show that an aged (stiff) matrix epigenetically represses the gene encoding the longevity factor, α-Klotho, resulting in chondrocyte dysfunction, a leading cause of osteoarthritis.
- Hirotaka Iijima
- , Gabrielle Gilmer
- & Fabrisia Ambrosio
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Article
| Open AccessSARS-CoV-2 viral entry and replication is impaired in Cystic Fibrosis airways due to ACE2 downregulation
Patients with cystic fibrosis are not reporting particularly sever outcomes upon SARS-CoV-2 infection. Here, the authors demonstrate decreased ACE2 levels is cystic fibrosis airway epithelia associated with impaired viral entry and replication.
- Valentino Bezzerri
- , Valentina Gentili
- & Marco Cipolli
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Article
| Open AccessApremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus
Pemphigus vulgaris is a life-threatening blistering skin disease caused by autoantibodies which destabilize cell adhesion of keratinocytes. The phosphodiesterase 4 inhibitor apremilast prevents skin blistering by stabilizing the keratin filament anchorage of desmosomes.
- Anna M. Sigmund
- , Markus Winkler
- & Jens Waschke
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Article
| Open AccessAn entosis-like process induces mitotic disruption in Pals1 microcephaly pathogenesis
Entosis is a process of cell cannibalism observed in cancer. Here, Sterling and colleagues report that entosis can also play a role in brain development and can contribute to the pathogenesis of microcephaly.
- Noelle A. Sterling
- , Jun Young Park
- & Seonhee Kim
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Article
| Open AccessAntagonizing cholecystokinin A receptor in the lung attenuates obesity-induced airway hyperresponsiveness
The underlying mechanisms of how obesity increases asthma prevalence and severity are not well understood. Here, the authors show that antagonizing cholecystokinin and its receptor, CCKAR, in the lung attenuates obesity-associated airway hyperresponsiveness in mice.
- Ronald Allan M. Panganiban
- , Zhiping Yang
- & Quan Lu
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Article
| Open AccessControl of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2
The role of soluble angiotensin converting enzyme 2 (sACE2) in SARS-CoV-2 infection is not well understood. Here, authors show that membrane type 1 matrix metalloproteinase (MT1-MMP) releases sACE2 to promote SARS-CoV-2 cell entry in vitro and in vivo, and the upregulation of MT1-MMP may contribute to increased susceptibility to SARS-CoV-2 infection in ageing.
- Xuanming Guo
- , Jianli Cao
- & Hoi Leong Xavier Wong