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Endocrine Influence on Cardiac Metabolism in Development and Regeneration.

Endocrinology 2021 Apr 21. Epub 2021 Apr 21.

Cardiovascular Research Institute & Department of Physiology, University of California San Francisco, San Francisco, CA, USA.

Mammalian cardiomyocytes mostly utilize oxidation of fatty acids to generate ATP. The fetal heart, in stark contrast, mostly uses anaerobic glycolysis. During perinatal development, thyroid hormone drives extensive metabolic remodeling in the heart for adaptation to extrauterine life. Read More

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Dynein Harnesses Active Fluctuations of Microtubules for Faster Movement.

Nat Phys 2020 20;16:312-316. Epub 2020 Jan 20.

Physics Department, University of California, Berkeley CA 94720 USA.

The cytoskeleton forms a dynamic network that generates fluctuations larger than thermal agitation of the cytoplasm. Here, we tested whether dynein, a minus-end-directed microtubule (MT) motor, can harness energy from these fluctuations using optical trapping . We show that dynein forms an asymmetric slip bond with MTs, where its detachment rate increases more slowly under hindering forces than assisting forces. Read More

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January 2020

Cardiomyopathy Mutations Impact the Actin-Activated Power Stroke of Human Cardiac Myosin.

Biophys J 2021 Apr 14. Epub 2021 Apr 14.

Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033. Electronic address:

Cardiac muscle contraction is driven by the molecular motor myosin that uses the energy from ATP hydrolysis to generate a power stroke when interacting with actin filaments, while it is unclear how this mechanism is impaired by mutations in myosin that can lead to heart failure. We have applied a FRET strategy to investigate structural changes in the lever arm domain of human β-cardiac myosin subfragment 1 (M2β-S1). We exchanged the human ventricular regulatory light chain labeled at a single cysteine (V105C) with Alexa 488 onto M2β-S1, which served as a donor for Cy3ATP bound to the active site. Read More

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Hypoxia and brain aging: Neurodegeneration or neuroprotection?

Ageing Res Rev 2021 Apr 15;68:101343. Epub 2021 Apr 15.

Institute of Sport Sciences, University of Lausanne, CH-1015, Lausanne, Switzerland.

The absolute reliance of the mammalian brain on oxygen to generate ATP renders it acutely vulnerable to hypoxia, whether at high altitude or in clinical settings of anemia or pulmonary disease. Hypoxia is pivotal to the pathogeneses of myriad neurological disorders, including Alzheimer's, Parkinson's and other age-related neurodegenerative diseases. Conversely, reduced environmental oxygen, e. Read More

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Mitochondrial dysfunction and potential mitochondrial protectant treatments in tendinopathy.

Ann N Y Acad Sci 2021 Apr 11;1490(1):29-41. Epub 2021 Apr 11.

Orthopedic Soft Tissue Research Program, Hospital for Special Surgery, New York, New York.

Tendinopathy is a common musculoskeletal condition that affects a wide range of patients, including athletes, laborers, and older patients. Tendinopathy is often characterized by pain, swelling, and impaired performance and function. The etiology of tendinopathy is multifactorial, including both intrinsic and extrinsic mechanisms. Read More

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Evaluating the mitochondrial activity and inflammatory state of dimethyl sulfoxide differentiated PLB-985 cells.

Mol Immunol 2021 Apr 7;135:1-11. Epub 2021 Apr 7.

Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB, Canada; New Brunswick Center for Precision Medicine, Moncton, NB, Canada. Electronic address:

Neutrophils play a key role in the innate immunity with their ability to generate and release inflammatory mediators that promote the inflammatory response and consequently restore the hemostasis. As active participants in several steps of the normal inflammatory response, neutrophils are also involved in chronic inflammatory diseases such as asthma, atherosclerosis, and arthritis. Given their dual role in the modulation of inflammation, regulating the inflammatory response of neutrophils has been suggested as an important therapeutic approach by numerous researchers. Read More

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Detection of Escherichia coli using luminometer with pyruvate kinase.

J Mol Recognit 2021 Apr 6:e2896. Epub 2021 Apr 6.

National Ocean Technology Center, Tianjin, China.

Portable and quantitative detection of Escherichia coli (E. coli) has the potential to reform clinical diagnostics, food safety, and environmental monitoring. At present, most commercial devices used for pathogen detection have disadvantages such as expensive, highly complex operations, or limited detection specificity. Read More

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Mitochondrial Dysfunction: Cause or Consequence of Vascular Calcification?

Front Cell Dev Biol 2021 16;9:611922. Epub 2021 Mar 16.

Functional Genetics and Development Division, The Roslin Institute and The Royal (Dick) School of Veterinary Studies (R(D)SVS), University of Edinburgh, Midlothian, United Kingdom.

Mitochondria are crucial bioenergetics powerhouses and biosynthetic hubs within cells, which can generate and sequester toxic reactive oxygen species (ROS) in response to oxidative stress. Oxidative stress-stimulated ROS production results in ATP depletion and the opening of mitochondrial permeability transition pores, leading to mitochondria dysfunction and cellular apoptosis. Mitochondrial loss of function is also a key driver in the acquisition of a senescence-associated secretory phenotype that drives senescent cells into a pro-inflammatory state. Read More

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Generation and Evaluation of Isogenic iPSC as a Source of Cell Replacement Therapies in Patients with Kearns Sayre Syndrome.

Cells 2021 Mar 5;10(3). Epub 2021 Mar 5.

St. Boniface Hospital Albrechtsen Research Centre, Regenerative Medicine Program, Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Institute of Cardiovascular Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada.

Kearns Sayre syndrome (KSS) is mitochondrial multisystem disorder with no proven effective treatment. The underlying cause for multisystem involvement is the energy deficit resulting from the load of mutant mitochondrial DNA (mtDNA), which manifests as loss of cells and tissue dysfunction. Therefore, functional organ or cellular replacement provides a promising avenue as a therapeutic option. Read More

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The Importance of Mitochondrial Pyruvate Carrier in Cancer Cell Metabolism and Tumorigenesis.

Cancers (Basel) 2021 Mar 24;13(7). Epub 2021 Mar 24.

Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB/CSIC), 28049 Madrid, Spain.

Pyruvate is a key molecule in the metabolic fate of mammalian cells; it is the crossroads from where metabolism proceeds either oxidatively or ends with the production of lactic acid. Pyruvate metabolism is regulated by many enzymes that together control carbon flux. Mitochondrial pyruvate carrier (MPC) is responsible for importing pyruvate from the cytosol to the mitochondrial matrix, where it is oxidatively phosphorylated to produce adenosine triphosphate (ATP) and to generate intermediates used in multiple biosynthetic pathways. Read More

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The Phosin PptA Plays a Negative Role in the Regulation of Antibiotic Production in .

Antibiotics (Basel) 2021 Mar 20;10(3). Epub 2021 Mar 20.

Institute for Integrative Biology of the Cell (I2BC), Université Paris-Saclay, CEA, CNRS, 91198 Gif-sur-Yvette, France.

In , antibiotic biosynthesis is triggered in phosphate limitation that is usually correlated with energetic stress. Polyphosphates constitute an important reservoir of phosphate and energy and a better understanding of their role in the regulation of antibiotic biosynthesis is of crucial importance. We previously characterized a gene, , encoding a polyphosphate kinase, whose disruption greatly enhanced the weak antibiotic production of . Read More

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Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology.

Life (Basel) 2021 Mar 15;11(3). Epub 2021 Mar 15.

Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy.

Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the FF-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. Read More

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Lung Metabolomics Profiling of Congenital Diaphragmatic Hernia in Fetal Rats.

Metabolites 2021 Mar 18;11(3). Epub 2021 Mar 18.

Center for Fetal and Placental Research, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH 45229, USA.

Congenital diaphragmatic hernia (CDH) is characterized by the herniation of abdominal contents into the thoracic cavity during the fetal period. This competition for fetal thoracic space results in lung hypoplasia and vascular maldevelopment that can generate severe pulmonary hypertension (PH). The detailed mechanisms of CDH pathogenesis are yet to be understood. Read More

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Hydrolysis of Extracellular ATP by Vascular Smooth Muscle Cells Transdifferentiated into Chondrocytes Generates P but Not PP.

Int J Mol Sci 2021 Mar 14;22(6). Epub 2021 Mar 14.

Institute for Molecular and Supramolecular Chemistry and Biochemistry, Université Lyon 1, French National Centre for Scientific Research, F-69622 Lyon, France.

(1) Background: Tissue non-specific alkaline phosphatase (TNAP) is suspected to induce atherosclerosis plaque calcification. TNAP, during physiological mineralization, hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PP). Since atherosclerosis plaques are characterized by the presence of necrotic cells that probably release supraphysiological concentrations of ATP, we explored whether this extracellular adenosine triphosphate (ATP) is hydrolyzed into the mineralization inhibitor PP or the mineralization stimulator inorganic phosphate (P), and whether TNAP is involved. Read More

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Properties of FDA-approved small molecule phosphatidylinositol 3-kinase inhibitors prescribed for the treatment of malignancies.

Authors:
Robert Roskoski

Pharmacol Res 2021 Mar 26;168:105579. Epub 2021 Mar 26.

Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742-8814, United States. Electronic address:

The discovery of the phosphatidylinositol 3-kinase (PI 3-kinase) pathway was a major advance in understanding eukaryotic signal transduction. The high frequency of PI 3-kinase pathway mutations in many cancers stimulated the development of drugs targeting these oncogenic mutants. The PI 3-kinases are divided into three classes and Class I PI 3-kinases, which catalyze the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), are the main subject of this review. Read More

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Photobiomodulation and Oxidative Stress: 980 nm Diode Laser Light Regulates Mitochondrial Activity and Reactive Oxygen Species Production.

Oxid Med Cell Longev 2021 3;2021:6626286. Epub 2021 Mar 3.

Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy.

Photobiomodulation with 808 nm laser light electively stimulates Complexes III and IV of the mitochondrial respiratory chain, while Complexes I and II are not affected. At the wavelength of 1064 nm, Complexes I, III, and IV are excited, while Complex II and some mitochondrial matrix enzymes seem to be not receptive to photons at that wavelength. Complex IV was also activated by 633 nm. Read More

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Analysis of patient-specific quality assurance for Elekta Unity adaptive plans using statistical process control methodology.

J Appl Clin Med Phys 2021 Apr 23;22(4):99-107. Epub 2021 Mar 23.

University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

The Elekta Unity MR-linac utilizes daily magnetic resonance imaging (MRI) for online plan adaptation. In the Unity workflow, adapt to position (ATP) and adapt to shape (ATS) treatment planning options are available which represent a virtual shift or full re-plan with contour adjustments respectively. Both techniques generate a new intensity modulated radiation therapy (IMRT) treatment plan while the patient lies on the treatment table and thus adapted plans cannot be measured prior to treatment delivery. Read More

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Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats.

BMC Complement Med Ther 2021 Mar 22;21(1):100. Epub 2021 Mar 22.

Key Laboratory of Ministry of Education for Traditional Chinese Medicine Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang, China.

Background: Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Read More

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A self-organized synthetic morphogenic liposome responds with shape changes to local light cues.

Nat Commun 2021 03 9;12(1):1548. Epub 2021 Mar 9.

Department of Systemic Cell Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany.

Reconstituting artificial proto-cells capable of transducing extracellular signals into cytoskeletal changes can reveal fundamental principles of how non-equilibrium phenomena in cellular signal transduction affect morphogenesis. Here, we generated a Synthetic Morphogenic Membrane System (SynMMS) by encapsulating a dynamic microtubule (MT) aster and a light-inducible signaling system driven by GTP/ATP chemical potential into cell-sized liposomes. Responding to light cues in analogy to morphogens, this biomimetic design embodies basic principles of localized Rho-GTPase signal transduction that generate an intracellular MT-regulator signaling gradient. Read More

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Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia.

ACS Chem Biol 2021 Apr 16;16(4):586-595. Epub 2021 Mar 16.

Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, OX3 7DQ.

Classic galactosemia is caused by loss-of-function mutations in galactose-1-phosphate uridylyltransferase (GALT) that lead to toxic accumulation of its substrate, galactose-1-phosphate. One proposed therapy is to inhibit the biosynthesis of galactose-1-phosphate, catalyzed by galactokinase 1 (GALK1). Existing inhibitors of human GALK1 (hGALK1) are primarily ATP-competitive with limited clinical utility to date. Read More

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Effects of phthalates on the functions and fertility of mouse spermatozoa.

Toxicology 2021 Apr 9;454:152746. Epub 2021 Mar 9.

Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Gyeonggi-do, 17546, Republic of Korea. Electronic address:

Phthalates are common environmental pollutants that are presumed to negatively impact male fertility including animals and humans. Particularly, these potential xenoestrogens may alter male fertility by binding to specific sperm receptors. Although several studies have characterized the toxic effects of single phthalates, epidemiological studies indicate that humans are typically exposed to phthalate mixtures. Read More

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Rotary Ion-Translocating ATPases/ATP Synthases: Diversity, Similarities, and Differences.

Biochemistry (Mosc) 2020 Dec;85(12):1613-1630

Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119991, Russia.

Ion-translocating ATPases and ATP synthases (F-, V-, A-type ATPases, and several P-type ATPases and ABC-transporters) catalyze ATP hydrolysis or ATP synthesis coupled with the ion transport across the membrane. F-, V-, and A-ATPases are protein nanomachines that combine transmembrane transport of protons or sodium ions with ATP synthesis/hydrolysis by means of a rotary mechanism. These enzymes are composed of two multisubunit subcomplexes that rotate relative to each other during catalysis. Read More

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December 2020

CHK1 kinase inhibition: identification of allosteric hits using MD simulations, pharmacophore modeling, docking and MM-PBSA calculations.

Mol Divers 2021 Mar 8. Epub 2021 Mar 8.

Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.

The CHK1 kinase plays a pivotal role in the DNA damage response pathway. Hence, inhibition of CHK1 appeared as a promising strategy to overcome the resistance problem of chemotherapeutic agents resulting from the overexpression of CHK1 that enables cancerous cells to repair their chemotherapy-induced DNA damage. In this study, different computational drug design techniques were employed to identify new CHK1 inhibitors targeting its allosteric pocket. Read More

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A multiplier peroxiporin signal transduction pathway powers piscine spermatozoa.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Institute of Agrifood Research and Technology, Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;

The primary task of a spermatozoon is to deliver its nuclear payload to the egg to form the next-generation zygote. With polyandry repeatedly evolving in the animal kingdom, however, sperm competition has become widespread, with the highest known intensities occurring in fish. Yet, the molecular controls regulating spermatozoon swimming performance in these organisms are largely unknown. Read More

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Increasing hepatic glycogen moderates the diabetic phenotype in insulin-deficient Akita mice.

J Biol Chem 2021 Mar 2:100498. Epub 2021 Mar 2.

Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.

Hepatic glycogen metabolism is impaired in diabetes. We previously demonstrated that strategies to increase liver glycogen content in a high-fat-diet mouse model of obesity and insulin resistance led to a reduction in food intake and ameliorated obesity and glucose tolerance. These effects were accompanied by a decrease in insulin levels, but whether this decrease contributed to the phenotype observed in this animal was unclear. Read More

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Recent advances in understanding the role of metabolic heterogeneities in cell migration.

Fac Rev 2021 28;10. Epub 2021 Jan 28.

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.

Migration is an energy-intensive, multi-step process involving cell adhesion, protrusion, and detachment. Each of these steps require cells to generate and consume energy, regulating their morphological changes and force generation. Given the need for energy to move, cellular metabolism has emerged as a critical regulator of both single cell and collective migration. Read More

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January 2021

NADPH and Mito-Apocynin Treatment Protects Against KA-Induced Excitotoxic Injury Through Autophagy Pathway.

Front Cell Dev Biol 2021 11;9:612554. Epub 2021 Feb 11.

Department of Pharmacology and Laboratory of Aging and Nervous Diseases and Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.

Aim: Previous research recognizes that NADPH can produce reduced glutathione (GSH) as a coenzyme and produce ROS as a substrate of NADPH oxidase (NOX). Besides, excessive activation of glutamate receptors results in mitochondrial impairment. The study aims at spelling out the effects of NADPH and Mito-apocynin, a NOX inhibitor which specifically targets the mitochondria, on the excitotoxicity induced by Kainic acid (KA) and its mechanism. Read More

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February 2021

Mitochondrial dysfunction and traffic jams in amyotrophic lateral sclerosis.

Mitochondrion 2021 Feb 25;58:102-110. Epub 2021 Feb 25.

Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania.

Neurodegenerative diseases are characterized by progressive neuronal loss anatomically or physiologically and accumulation of protein in the cells. Mitochondria provide energy to these neuronal cells consuming 20% of the body's oxygen. Mitochondria are the dynamic membrane-bound cell organelles that function to generate ATP, regulate calcium homeostasis, and produce reactive oxygen species. Read More

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February 2021

Alternative Polyadenylation and Differential Regulation of : Implications for Brown Adipose Tissue Thermogenesis Across Species.

Front Pediatr 2020 9;8:612279. Epub 2021 Feb 9.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Brown adipose tissue (BAT) is a thermogenic organ owing to its unique expression of uncoupling protein 1 (UCP1), which is a proton channel in the inner mitochondrial membrane used to dissipate the proton gradient and uncouple the electron transport chain to generate heat instead of adenosine triphosphate. The discovery of metabolically active BAT in human adults, especially in lean people after cold exposure, has provoked the "thermogenic anti-obesity" idea to battle weight gain. Because BAT can expend energy through UCP1-mediated thermogenesis, the molecular mechanisms regulating UCP1 expression have been extensively investigated at both transcriptional and posttranscriptional levels. Read More

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February 2021

Alzheimer's Risk Gene TREM2 Determines Functional Properties of New Type of Human iPSC-Derived Microglia.

Front Immunol 2020 3;11:617860. Epub 2021 Feb 3.

Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Microglia are key in the homeostatic well-being of the brain and microglial dysfunction has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). Due to the many limitations to study microglia or isolated for large scale drug discovery applications, there is a high need to develop robust and scalable human cellular models of microglia with reliable translatability to the disease. Here, we describe the generation of microglia-like cells from human induced pluripotent stem cells (iPSC) with distinct phenotypes for mechanistic studies in AD. Read More

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February 2021