Deciphering the regulatory mechanisms and biological implications of ARID1A missense mutations in cancer.

ARID1A is a key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex and functions as a critical tumor suppressor in various cancers. In this study, we find that tumor cells with hotspot missense mutations in ARID1A (AT-rich interactive domain-containing protein 1A) exhibit a malignant phenotype. Mechanistically, these mutations facilitate the translocation of ARID1A mutant proteins to the cytoplasm by the nucleocytoplasmic shuttler XPO1 (exportin 1).

Liver cancer initiation requires translational activation by an oncofetal regulon involving LIN28 proteins.

It is unknown which posttranscriptional regulatory mechanisms are required for oncogenic competence. Here, we show that the LIN28 family of RNA-binding proteins (RBPs), which facilitate posttranscriptional RNA metabolism within ribonucleoprotein networks, is essential for the initiation of diverse oncotypes of hepatocellular carcinoma (HCC). In HCC models driven by NRASG12V/Tp53, CTNNB1/YAP/Tp53, or AKT/Tp53, mice without Lin28a and Lin28b were markedly impaired in cancer initiation.

Single-Cell RNA Sequencing Identifies WARS1+ Mesenchymal Stem Cells with Enhanced Immunomodulatory Capacity and Improved Therapeutic Efficacy.

Psoriasis is a common inflammatory skin disorder with no cure. Mesenchymal stem cells (MSCs) have immunomodulatory properties for psoriasis, but the therapeutic efficacies varied, and the molecular mechanisms were unknown. In this study, we improved the efficacy by enhancing the immunomodulatory effects of umbilical cord-derived MSCs (UC-MSCs).

Improved performance of a fiber-optic hydrogen sensor based on a controllable optical heating technology.

A novel, to the best of our knowledge, and compact fiber-optic hydrogen sensor based on light intensity demodulation and controllable optical heating technology is proposed and experimentally investigated. This system employs three photodetectors for optic signal transformation. The first PD is used to receive a little fraction of the amplified spontaneous emission (ASE) for calibration, and the second PD is utilized to detect optic signal reflected by a single mode fiber deposited with WO-PdPt-Pt composite film.

ZFYVE19 deficiency: a ciliopathy involving failure of cell division, with cell death.

Background And Aims: Variants in underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.

Methods: knockout ( ) mice were generated and exposed to different liver toxins.

The chromatin remodeling factor Arid1a cooperates with Jun/Fos to promote osteoclastogenesis by epigenetically upregulating Siglec15 expression.

Osteoporosis is characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-related bone formation, particularly increased osteoclastogenesis. However, the mechanisms by which epigenetic factors regulate osteoclast precursor differentiation during osteoclastogenesis remain poorly understood. Here, we show that the specific knockout of the chromatin remodeling factor Arid1a in bone marrow-derived macrophages (BMDMs) results in increased bone mass.

Discovery of Podofilox as a Potent cGAMP-STING Signaling Enhancer with Antitumor Activity.

Cyclic GMP-AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I IFNs and other cytokines. Pharmacologic activation of STING is considered a potent therapeutic strategy in cancer. In this study, we used a cell-based phenotypic screen and identified podophyllotoxin (podofilox), a microtubule destabilizer, as a robust enhancer of the cGAMP-STING signaling pathway.

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling.

The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration.

MoS nanosheets on plasma-nitrogen-doped carbon cloth for high-performance flexible supercapacitors.

With the surging demand for flexible and portable electronic devices featuring high energy and power density, the development of next-generation lightweight, flexible energy storage devices is crucial. However, achieving the expected energy and power density of supercapacitors remains a great challenge. This work reports a facile plasma-enabled method for preparing supercapacitor electrodes made of MoS nanosheets grown on flexible and lightweight N-doped carbon cloth (NCC).

LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity.

Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons to drive immune responses against tumors and pathogens. Exogenous cGAMP produced by infected and malignant cells and synthetic cGAMP used in immunotherapy must traverse the cell membrane to activate STING in target cells. However, as an anionic hydrophilic molecule, cGAMP is not inherently membrane permeable.

Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes.

SWI/SNF chromatin remodelers play critical roles in development and cancer. The causal links between SWI/SNF complex disassembly and carcinogenesis are obscured by redundancy between paralogous components. Canonical cBAF-specific paralogs ARID1A and ARID1B are synthetic lethal in some contexts, but simultaneous mutations in both ARID1s are prevalent in cancer.

Assessment of SENP3-interacting proteins in hepatocytes treated with diethylnitrosamine by BioID assay.

SUMOylation of proteins regulates cell behaviors and is reversibly removed by small ubiquitin-like modifier (SUMO)-specific proteases (SENPs). The SENP family member SENP3 is involved in SUMO2/3 deconjugation and has been reported to sense cell stress and accumulate in several human cancer cells and macrophages. We previously reported that Senp3-knockout heterozygous mice showed smaller liver, but the pertinent mechanisms of SENP3 and SUMOylated substrates remain unclear.

A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo.

SENP3 loss promotes M2 macrophage polarization and breast cancer progression.

Tumor-associated macrophages (TAM) play a crucial role in promoting cancer progression. Upon cytokine stimulation, TAM preferentially polarize to the anti-inflammatory and pro-tumor M2 subtype. The mechanism underlying such preferential polarization remains elusive.

SENP3 Suppresses Osteoclastogenesis by De-conjugating SUMO2/3 from IRF8 in Bone Marrow-Derived Monocytes.

Bone metabolism depends on the balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases like osteoporosis are characterized by increased bone destruction due to partially enhanced osteoclastogenesis. Here, we report that the post-translational SUMO modification is critical for regulating osteoclastogenesis.

Arid1a Loss Drives Nonalcoholic Steatohepatitis in Mice Through Epigenetic Dysregulation of Hepatic Lipogenesis and Fatty Acid Oxidation.

Nonalcoholic steatohepatitis (NASH) is a rapidly growing cause of chronic liver damage, cirrhosis, and hepatocellular carcinoma. How fatty liver pathogenesis is subject to epigenetic regulation is unknown. We hypothesized that chromatin remodeling is important for the pathogenesis of fatty liver disease.

SWI/SNF component restrains pancreatic neoplasia formation.

Objective: is commonly mutated in pancreatic ductal adenocarcinoma (PDAC), but the functional effects of mutations in the pancreas are unclear. Understanding the molecular mechanisms that drive PDAC formation may lead to novel therapies.

Design: Concurrent conditional deletion and activation mutations were modelled in mice.

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer.

ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metastatic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation.

haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment.

Sequencing studies have implicated haploinsufficiency of , a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al.

A redox mechanism underlying nucleolar stress sensing by nucleophosmin.

The nucleolus has been recently described as a stress sensor. The nucleoplasmic translocation of nucleolar protein nucleophosmin (NPM1) is a hallmark of nucleolar stress; however, the causes of this translocation and its connection to p53 activation are unclear. Using single live-cell imaging and the redox biosensors, we demonstrate that nucleolar oxidation is a general response to various cellular stresses.

Suppression of the SWI/SNF Component Arid1a Promotes Mammalian Regeneration.

Mammals have partially lost the extensive regenerative capabilities of some vertebrates, possibly as a result of chromatin-remodeling mechanisms that enforce terminal differentiation. Here, we show that deleting the SWI/SNF component Arid1a substantially improves mammalian regeneration. Arid1a expression is suppressed in regenerating tissues, and genetic deletion of Arid1a increases tissue repair following an array of injuries.

Gene expression profiling on the molecular action of danshen-gegen formula in a randomized placebo-controlled trial of postmenopausal women with hypercholesterolemia.

The Danshen-Gegen formula (DG) is a traditional Chinese herbal formula which has long been used to treat cardiovascular disease. DG was found to be a cardiovascular tonic in our recent research. However, a comprehensive investigation of the molecular mechanism of DG in cardiovascular disease has not been performed.

Surgicopathological classification of hepatic space-occupying lesions: a single-center experience with literature review.

Accompanying rapid developments in hepatic surgery, the number of surgeries and identifications of histological types of primary hepatic space-occupying lesions (PHSOLs) have increased dramatically. This has led to many changes in the surgicopathological spectrum of PHSOLs, and has contributed to a theoretical basis for modern hepatic surgery and oncological pathology. Between 1982 and 2009 at the Eastern Hepatobiliary Surgery Hospital (EHBH) in Shanghai, 31 901 patients underwent surgery and were diagnosed as having a PHSOL.