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DNA damage and repair in differentiation of stem cells and cells of connective cell lineages: A trigger or a complication?

Eur J Histochem 2021 May 3;65(2). Epub 2021 May 3.


The review summarizes literature data on the role of DNA breaks and DNA repair in differentiation of pluripotent stem cells (PSC) and connective cell lineages. PSC, including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC), are rapidly dividing cells with highly active DNA damage response (DDR) mechanisms to ensure the stability and integrity of the DNA. In PSCs, the most common DDR mechanism is error-free homologous recombination (HR) that is primarily active during S phase of the cell cycle, whereas in quiescent, slow-dividing or non-dividing tissue progenitors and terminally differentiated cells, error-prone non-homologous end joining (NHEJ) mechanism of the double-strand break (DSB) repair is dominating. Read More

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Heterochromatin and Polycomb as regulators of haematopoiesis.

Biochem Soc Trans 2021 Apr 30. Epub 2021 Apr 30.

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria3052, Australia.

Haematopoiesis is the process by which multipotent haematopoietic stem cells are transformed into each and every type of terminally differentiated blood cell. Epigenetic silencing is critical for this process by regulating the transcription of cell-cycle genes critical for self-renewal and differentiation, as well as restricting alternative fate genes to allow lineage commitment and appropriate differentiation. There are two distinct forms of transcriptionally repressed chromatin: H3K9me3-marked heterochromatin and H3K27me3/H2AK119ub1-marked Polycomb (often referred to as facultative heterochromatin). Read More

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Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation.

Front Physiol 2021 1;12:624950. Epub 2021 Apr 1.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.

Tissue-resident stem cells may enter a dormant state, also known as quiescence, which allows them to withstand metabolic stress and unfavorable conditions. Similarly, hibernating mammals can also enter a state of dormancy used to evade hostile circumstances, such as food shortage and low ambient temperatures. In hibernation, the dormant state of the individual and its cells is commonly known as torpor, and is characterized by metabolic suppression in individual cells. Read More

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Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe.

J Cell Biol 2021 Jun;220(6)

Department of Medicine, Washington University in St. Louis, St. Louis, MO.

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. Read More

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Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway.

Nat Commun 2021 03 23;12(1):1826. Epub 2021 Mar 23.

Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.

Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). Read More

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Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.

Nat Commun 2021 03 12;12(1):1626. Epub 2021 Mar 12.

Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, 55455, USA.

Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. Read More

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Dual inhibition of TGFβR and ROCK reverses the epithelial to mesenchymal transition in collectively migrating zebrafish keratocytes.

Cell Biol Int 2021 Mar 12. Epub 2021 Mar 12.

Biomedical Sciences Program, College of Graduate Studies, Midwestern University, Glendale, Arizona, USA.

There is a growing controversy about the role of the epithelial to mesenchymal transition (EMT) in the fibrosis associated with chronic disease. Recent studies suggest that it is not the EMT transcriptional program but differentiation of progenitor cells, response to chronic inflammation, or some combination of both which cause the appearance of fibroblasts and the production of the extracellular matrix. To address this issue, we study the EMT process in the zebrafish keratocytes which migrate from primary explants of epithelial tissue as these cells are both terminally differentiated and able to divide. Read More

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Mitochondria's Role in the Maintenance of Cancer Stem Cells in Glioblastoma.

Front Oncol 2021 22;11:582694. Epub 2021 Feb 22.

Department of Neurosurgery, The 2nd Affiliated Hospital of Zhejiang University Medical School, Hangzhou, China.

Glioblastoma (GBM), one of the deadliest primary brain malignancies, is characterized by a high recurrence rate due to its limited response to existing therapeutic strategies such as chemotherapy, radiation therapy, and surgery. Several mechanisms and pathways have been identified to be responsible for GBM therapeutic resistance. Glioblastoma stem cells (GSCs) are known culprits of GBM resistance to therapy. Read More

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February 2021

Pre-mitotic genome re-organisation bookends the B cell differentiation process.

Nat Commun 2021 02 26;12(1):1344. Epub 2021 Feb 26.

The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, although it has been proposed to occur during DNA synthesis or after mitosis. Here, we elucidate the chromosome conformational changes in B lymphocytes as they differentiate and expand from a naive, quiescent state into antibody secreting plasma cells. Read More

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February 2021

The Role of Sialylation in Respiratory Viral Infection and Treatment.

Curr Med Chem 2021 Feb 1. Epub 2021 Feb 1.

School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong. Australia.

Respiratory infections caused by viruses such as influenza and coronavirus are a serious global problem due to their high infection rates and potential to spark pandemics, such as the current COVID-19 pandemic. Although preventing these infections by using vaccines has been the most successful strategy to date, effective vaccines are not always available. Therefore, developing broad-spectrum anti-viral drugs to treat such infections is essential, especially in the case of immunocompromised patients, or for outbreaks of novel virus strains. Read More

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February 2021

Flexible gastrointestinal endoscope processing challenges, current issues and future perspectives.

J Hosp Infect 2021 Apr 5;110:133-138. Epub 2021 Feb 5.

Research & Development Department, Advanced Sterilization Products, Irvine, CA, USA.

Background: At present, the most frequent method for processing flexible gastrointestinal (GI) endoscopes is cleaning followed by high-level disinfection as terminal sterilization is often not practicable. Post-processing monitoring studies consistently show high levels of positive cultures remaining on endoscopes, which can lead to patient infection and even fatality. The processing deficiency is attributed to the complex design of endoscopes, incomplete cleaning, formation of biofilms and lack of margin of safety with high-level disinfection. Read More

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Chronic advanced-glycation end products treatment induces TXNIP expression and epigenetic changes in glomerular podocytes in vivo and in vitro.

Life Sci 2021 Apr 13;270:118997. Epub 2021 Jan 13.

Laboratorio de Carboidratos e Radioimunoensaio (LIM-18) do Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil; Programa de Pos-Graduaçao em Medicina, Universidade Nove de Julho (UNINOVE), Sao Paulo, SP, Brazil. Electronic address:

Advanced glycation end products (AGEs) play an important role in oxidative stress and inflammation, processes implicated in the development and progression of kidney dysfunction. In the present study, we investigated the participation of the pro-oxidant protein thioredoxin-interacting protein (TXNIP) and of epigenetic mechanisms on kidney tissue (in vivo, in non-diabetic rats) and on terminally differentiated glomerular podocytes (in vitro) chronically exposed to AGEs. AGEs induced total kidney and glomerular TXNIP expression and decreased H3K27me3 content. Read More

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Antiapoptotic Bcl-2 family proteins BCL-xL and MCL-1 integrate neural progenitor survival and proliferation during postnatal cerebellar neurogenesis.

Cell Death Differ 2020 Dec 8. Epub 2020 Dec 8.

UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, 27599, USA.

The tendency of brain cells to undergo apoptosis in response to exogenous events varies across neural development, with apoptotic threshold dependent on proliferation state. Proliferative neural progenitors show a low threshold for apoptosis, while terminally differentiated neurons are relatively refractory. To define the mechanisms linking proliferation and apoptotic threshold, we examined the effect of conditionally deleting Bcl2l1, the gene that codes the antiapoptotic protein BCL-xL, in cerebellar granule neuron progenitors (CGNPs), and of co-deleting Bcl2l1 homologs, antiapoptotic Mcl-1, or pro-apoptotic Bax. Read More

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December 2020

What we know about cardiomyocyte dedifferentiation.

J Mol Cell Cardiol 2021 03 1;152:80-91. Epub 2020 Dec 1.

Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cardiovascular Disease Translational Research Programme, National University Health Systems, Singapore; Genome Institute of Singapore, Agency of Science Research and Technology, Singapore. Electronic address:

Cardiomyocytes (CMs) lost during cardiac injury and heart failure (HF) cannot be replaced due to their limited proliferative capacity. Regenerating the failing heart by promoting CM cell-cycle re-entry is an ambitious solution, currently vigorously pursued. Some genes have been proven to promote endogenous CM proliferation, believed to be preceded by CM dedifferentiation, wherein terminally differentiated CMs are initially reversed back to the less mature state which precedes cell division. Read More

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Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence.

Nat Commun 2020 11 27;11(1):6049. Epub 2020 Nov 27.

Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK.

Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. Read More

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November 2020

Effects of an Integrated Palliative Care Pathway: More Proactive GPs, Well Timed, and Less Acute Care: A Clustered, Partially Controlled Before-After Study.

J Am Med Dir Assoc 2021 Feb 19;22(2):297-304. Epub 2020 Nov 19.

Department of Health Services Research, CAPHRI School for Public Health (and Primary Care, Maastricht University, Maastricht, the Netherlands; Zuyderland Home Care, Geleen, the Netherlands.

Objectives: This study presents the design of an integrated, proactive palliative care pathway covering the full care cycle and evaluates its effects using 3 types of outcomes: (1) physician-reported outcomes, (2) outcomes reported by family, and (3) (utilization of) health care outcomes.

Design: A clustered, partially controlled before-after study with a multidisciplinary integrated palliative care pathway as its main intervention.

Setting And Participants: after assessment in hospital departments of oncology, and geriatrics, and in 13 primary care facilities, terminally ill patients were proactively included into the pathway. Read More

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February 2021

Comparative nuclear matrix proteome analysis of skeletal muscle cells in different cellular states.

Cell Biol Int 2021 Mar 5;45(3):580-598. Epub 2021 Jan 5.

Centre for Cellular and Molecular Biology, Council for Scientific and Industrial Research, Hyderabad, India.

The nuclear matrix (NuMat) serves as the structural framework for organizing and maintaining nuclear architecture, however, the mechanisms by which this non-chromatin compartment is constructed and regulated are poorly understood. This study presents a proteomic analysis of the NuMat isolated from cultured skeletal muscle cells in three distinct cellular states- proliferating myoblasts (MBs), terminally differentiated myotubes (MTs), and mitotically quiescent (G0) myoblasts. About 40% of the proteins identified were found to be common in the NuMat proteome of these morphologically and functionally distinct cell states. Read More

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CD138 multiple myeloma cells express high level of CHK1 which correlated to overall survival in MM patient.

Aging (Albany NY) 2020 11 10;12(22):23067-23081. Epub 2020 Nov 10.

Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Multiple myeloma (MM) is a disease in which abnormal plasma cells proliferate and secrete monoclonal immunoglobulin in the bone marrow. The main characteristic of plasma cells is the expression of the cell surface antigen syndecan-1 (CD138). However, the expression of CD138 is limited to terminally differentiated plasma cells during B cell development. Read More

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November 2020

Synergistic Effect of MC-LR and C-Terminal Truncated HBx on HepG2 Cells and Their Effects on PP2A Mediated Downstream Target of MAPK Signaling Pathway.

Front Genet 2020 15;11:537785. Epub 2020 Oct 15.

Guangxi Medical University Cancer Hospital, Nanning, China.

C-terminally truncated hepatitis B virus (HBV) X (ctHBx) infection and exposure to microcystins-LR (MC-LR) can lead to human hepatitis and liver cancer, but the mechanism associated with their synergistically effects not been fully elucidated. The ctHBx (HBxΔ4 and HBxΔ32) lentivirus were constructed and transfected into the HepG2 cells. Then we investigated the function of MC-LR and ctHBx using the molecular biology approaches, including enzyme-linked immunosorbent assay, clone formation assay, scratch wound testing, transwell assays, carried out flow cytometry respectively to examine cell cycle and apoptosis in each group, and detected the related proteins of HBx, MEK/ERK/JNK/p38 in mitogen-activated protein kinase (MAPK) pathway and the downstream proteins such as cdc2, cdc25C, and p53 by western blotting. Read More

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October 2020

The Musashi proteins MSI1 and MSI2 are required for photoreceptor morphogenesis and vision in mice.

J Biol Chem 2020 Nov 9. Epub 2020 Nov 9.

Biochemistry, West Virginia University, United States.

The Musashi family of RNA-binding proteins is known for its role in stem-cell renewal and are negative regulators of cell differentiation. Interestingly, in the retina, the Musashi proteins MSI1 and MSI2 are differentially expressed throughout the cycle of retinal development, with MSI2 protein displaying robust expression in the adult retinal tissue. In this study, we investigated the importance of Musashi proteins in the development and function of photoreceptor neurons in the retina. Read More

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November 2020

Significant transcriptomic changes are associated with differentiation of bone marrow-derived mesenchymal stem cells into neural progenitor-like cells in the presence of bFGF and EGF.

Cell Biosci 2020 28;10:126. Epub 2020 Oct 28.

Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Jalan Raja Perempuan Zainab II, 16150, Kubang Kerian, Kelantan Malaysia.

Introduction: Mesenchymal stem cells (MSCs) isolated from bone marrow have different developmental origins, including neural crest. MSCs can differentiate into neural progenitor-like cells (NPCs) under the influence of bFGF and EGF. NPCs can terminally differentiate into neurons that express beta-III-tubulin and elicit action potential. Read More

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October 2020

Isolation, Transfection, and Long-Term Culture of Adult Mouse and Rat Cardiomyocytes.

J Vis Exp 2020 10 10(164). Epub 2020 Oct 10.

Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati;

Ex vivo culture of the adult mammalian cardiomyocytes (CMs) presents the most relevant experimental system for the in vitro study of cardiac biology. Adult mammalian CMs are terminally differentiated cells with minimal proliferative capacity. The post-mitotic state of adult CMs not only restricts cardiomyocyte cell cycle progression but also limits the efficient culture of CMs. Read More

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October 2020

The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration.

Mol Neurobiol 2021 Mar 21;58(3):1062-1073. Epub 2020 Oct 21.

Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 14, 27100, Pavia, Italy.

The peptidyl-prolyl isomerase Pin1 is a unique enzyme catalyzing the isomerization of the peptide bond between phosphorylated serine-proline or threonine-proline motifs in proteins, thereby regulating a wide spectrum of protein functions, including folding, intracellular signaling, transcription, cell cycle progression, and apoptosis. Pin1 has been reported to act as a key molecular switch inducing cell-type-specific effects, critically depending on the different phosphorylation patterns of its targets within different biological contexts. While its implication in proliferating cells, and, in particular, in the field of cancer, has been widely characterized, less is known about Pin1 biological functions in terminally differentiated and post-mitotic neurons. Read More

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A human cancer cell line initiates DNA replication normally in the absence of ORC5 and ORC2 proteins.

J Biol Chem 2020 12 28;295(50):16949-16959. Epub 2020 Sep 28.

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia, USA. Electronic address:

The origin recognition complex (ORC), composed of six subunits, ORC1-6, binds to origins of replication as a ring-shaped heterohexameric ATPase that is believed to be essential to recruit and load MCM2-7, the minichromosome maintenance protein complex, around DNA and initiate DNA replication. We previously reported the creation of viable cancer cell lines that lacked detectable ORC1 or ORC2 protein without a reduction in the number of origins firing. Here, using CRISPR-Cas9-mediated mutations, we report that human HCT116 colon cancer cells also survive when ORC5 protein expression is abolished via a mutation in the initiator ATG of the ORC5 gene. Read More

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December 2020

LRP6 downregulation promotes cardiomyocyte proliferation and heart regeneration.

Cell Res 2021 Apr 24;31(4):450-462. Epub 2020 Sep 24.

Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.

The adult mammalian heart is thought to be a terminally differentiated organ given the postmitotic nature of cardiomyocytes. Consequently, the potential for cardiac repair through cardiomyocyte proliferation is extremely limited. Low-density lipoprotein receptor-related protein 6 (LRP6) is a Wnt co-receptor that is required for embryonic heart development. Read More

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Significance of nuclear cathepsin V in normal thyroid epithelial and carcinoma cells.

Biochim Biophys Acta Mol Cell Res 2020 12 7;1867(12):118846. Epub 2020 Sep 7.

Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany. Electronic address:

Altered expression and/or localization of cysteine cathepsins is believed to involve in thyroid diseases including cancer. Here, we examined the localization of cathepsins B and V in human thyroid tissue sections of different pathological conditions by immunolabeling and morphometry. Cathepsin B was mostly found within endo-lysosomes as expected. Read More

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December 2020

Human NK cell deficiency as a result of biallelic mutations in MCM10.

J Clin Invest 2020 10;130(10):5272-5286

Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA.

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. Read More

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October 2020

Subcellular Localization and Mitotic Interactome Analyses Identify SIRT4 as a Centrosomally Localized and Microtubule Associated Protein.

Cells 2020 08 24;9(9). Epub 2020 Aug 24.

Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

The stress-inducible and senescence-associated tumor suppressor SIRT4, a member of the family of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5), regulates bioenergetics and metabolism via NAD-dependent enzymatic activities. Next to the known mitochondrial location, we found that a fraction of endogenous or ectopically expressed SIRT4, but not SIRT3, is present in the cytosol and predominantly localizes to centrosomes. Confocal spinning disk microscopy revealed that SIRT4 is found during the cell cycle dynamically at centrosomes with an intensity peak in G and early mitosis. Read More

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Adult Cardiomyocyte Proliferation: a New Insight for Myocardial Infarction Therapy.

J Cardiovasc Transl Res 2020 Aug 20. Epub 2020 Aug 20.

Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, 215123, Jiangsu, China.

Myocardial infarction leads to cardiomyocyte loss, ensuing ventricular pathological remodeling, dramatic impairment of cardiac function, and ultimately heart failure. Unfortunately, the existing therapeutical treatments cannot directly replenish the lost myocytes in the injured myocardium and the long-term prognosis of heart failure after myocardial infarction remains poor. Growing investigations have demonstrated that the adult mammalian cardiomyocytes possess very limited proliferation capacity, and that was not enough to restore the injured heart. Read More

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The UPRosome - decoding novel biological outputs of IRE1α function.

J Cell Sci 2020 08 11;133(15). Epub 2020 Aug 11.

Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago 8380453, Chile

Different perturbations alter the function of the endoplasmic reticulum (ER), resulting in the accumulation of misfolded proteins in its lumen, a condition termed ER stress. To restore ER proteostasis, a highly conserved pathway is engaged, known as the unfolded protein response (UPR), triggering adaptive programs or apoptosis of terminally damaged cells. IRE1α (also known as ERN1), the most conserved UPR sensor, mediates the activation of responses to determine cell fate under ER stress. Read More

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