3,117 results match your criteria Friedreich Ataxia

Neuroinflammation in Friedreich's Ataxia.

Int J Mol Sci 2022 Jun 4;23(11). Epub 2022 Jun 4.

Department of Biology, Tor Vergata University of Rome, 00133 Roma, Italy.

Friedreich's ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron-sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms. Read More

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Clinical Evidence for Variegated Silencing in Patients With Friedreich Ataxia.

Neurol Genet 2022 Jun 17;8(3):e683. Epub 2022 May 17.

Departments of Pediatrics and Neurology (L.N.R., Y.N.D., D.R.L.), Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania; and Clinical Data Science GmbH (C.R.), Basel, Switzerland.

Background And Objectives: Friedreich ataxia (FRDA) is a neurodegenerative disease caused by a GAA triplet repeat (GAA-TR) expansion in intron 1 of the gene. Patients have 100-1,300 GAA triplets compared with less than 30 in healthy controls. The GAA-TR expansion leads to silencing, and consequent frataxin protein deficiency results in progressive ataxia, scoliosis, cardiomyopathy, and diabetes. Read More

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A Comprehensive Triple-Repeat Primed PCR and a Long-Range PCR Agarose-Based Assay for Improved Genotyping of Guanine-Adenine-Adenine Repeats in Friedreich Ataxia.

J Mol Diagn 2022 May 17. Epub 2022 May 17.

ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, Utah; Department of Pathology, University of Utah, Salt Lake City, Utah.

Friedreich ataxia is a rare autosomal recessive, neuromuscular degenerative disease caused by an expansion of a trinucleotide [guanine-adenine-adenine (GAA)] repeat in intron 1 of the FXN gene. It is common in the White population, characterized by progressive gait and limb ataxia, lack of tendon reflexes in the legs, loss of position sense, and hypertrophic cardiomyopathy. Detection and genotyping of the trinucleotide repeat length is important for the diagnosis and prognosis of the disease. Read More

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Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases.

Front Aging Neurosci 2022 3;14:750629. Epub 2022 May 3.

Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA, United States.

Repeat diseases, such as fragile X syndrome, myotonic dystrophy, Friedreich ataxia, Huntington disease, spinocerebellar ataxias, and some forms of amyotrophic lateral sclerosis, are caused by repetitive DNA sequences that are expanded in affected individuals. The age at which an individual begins to experience symptoms, and the severity of disease, are partially determined by the size of the repeat. However, the epigenetic state of the area in and around the repeat also plays an important role in determining the age of disease onset and the rate of disease progression. Read More

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Neurological Recovery with Interferon-gamma Treatment in Friedreich's Ataxia.

J Coll Physicians Surg Pak 2022 May;32(5):671-673

Department of Pediatric Cardiology, Ege University, Ege Universitesi Hastanesi Bornova, Izmir, Turkey.

Friedreich's ataxia (FA) is a rare, progressive, and degenerative hereditary disorder caused by a deficiency of frataxin protein. This disease is characterised by severe neurological dysfunction and life-threatening cardiomyopathy. Various drugs are used to slow down / stop the neurodegenerative progress. Read More

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Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle.

JCI Insight 2022 May 9;7(9). Epub 2022 May 9.

Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and.

Friedreich's ataxia (FRDA) is an inherited disorder caused by reduced levels of frataxin (FXN), which is required for iron-sulfur cluster biogenesis. Neurological and cardiac comorbidities are prominent and have been a major focus of study. Skeletal muscle has received less attention despite indications that FXN loss affects it. Read More

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2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders.

Heart Rhythm 2022 Apr 26. Epub 2022 Apr 26.

Mayo Clinic College of Medicine, Phoenix, Arizona.

This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. Read More

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Increased brain tissue sodium concentration in Friedreich ataxia: A multimodal MR imaging study.

Neuroimage Clin 2022 26;34:103025. Epub 2022 Apr 26.

Department of Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Research Centre Juelich GmbH and RWTH Aachen University, 52074 Aachen, Germany. Electronic address:

In patients with Friedreich ataxia, structural MRI is typically used to detect abnormalities primarily in the brainstem, cerebellum, and spinal cord. The aim of the present study was to additionally investigate possible metabolic changes in Friedreich ataxia using in vivo sodium MRI that may precede macroanatomical alterations, and to explore potential associations with clinical parameters of disease progression. Tissue sodium concentration across the whole brain was estimated from sodium MRI maps acquired at 3 T and compared between 24 patients with Friedreich ataxia (21-57 years old, 13 females) and 23 controls (21-60 years old, 12 females). Read More

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Inherited Ataxias in Children.

Pediatr Neurol 2022 Jun 14;131:54-62. Epub 2022 Apr 14.

Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida.

The purpose of this review is to describe the current diagnostic approach to inherited ataxias during childhood. With the expanding use and availability of gene testing technologies including large sequencing panels, the ability to arrive at a precise genetic diagnosis in this group of disorders has been improving. We have reviewed all the gene sequencing studies of ataxias available by a comprehensive literature search and summarize their results. Read More

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Cognitive Dysfunction in Repeat Expansion Diseases: A Review.

Front Aging Neurosci 2022 11;14:841711. Epub 2022 Apr 11.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.

With the development of the sequencing technique, more than 40 repeat expansion diseases (REDs) have been identified during the past two decades. Moreover, the clinical features of these diseases show some commonality, and the nervous system, especially the cognitive function was affected in part by these diseases. However, the specific cognitive domains impaired in different diseases were inconsistent. Read More

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Towards a metabolomic approach to investigate iron-sulfur cluster biogenesis.

IUBMB Life 2022 Apr 27. Epub 2022 Apr 27.

Department of Basic and Clinical Neuroscience, The Maurice Wohl Institute, King's College London, Denmark Hill Campus, London, UK.

Iron-sulfur clusters are prosthetic groups that are assembled on their acceptor proteins through a complex machine centered on a desulfurase enzyme and a transient scaffold protein. Studies to establish the mechanism of cluster formation have so far used either in vitro or in vivo methods, which have often resulted in contrasting or non-comparable results. We suggest, here, an alternative approach to study the enzymatic reaction, that is based on the combination of genetically engineered bacterial strains depleted of specific components, and the detection of the enzymatic kinetics in cellular extracts through metabolomics. Read More

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The smoothened agonist SAG reduces mitochondrial dysfunction and neurotoxicity of frataxin-deficient astrocytes.

J Neuroinflammation 2022 Apr 12;19(1):93. Epub 2022 Apr 12.

Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, 28049, Madrid, Spain.

Background: Friedreich's ataxia is a rare hereditary neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Similar to other neurodegenerative pathologies, previous studies suggested that astrocytes might contribute to the progression of the disease. To fully understand the mechanisms underlying neurodegeneration in Friedreich's ataxia, we investigated the reactivity status and functioning of cultured human astrocytes after frataxin depletion using an RNA interference-based approach and tested the effect of pharmacologically modulating the SHH pathway as a novel neuroprotective strategy. Read More

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Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia.

Front Neurosci 2022 24;16:819569. Epub 2022 Mar 24.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by deficiency of the mitochondrial protein frataxin. Lack of frataxin causes neuronal loss in various areas of the CNS and PNS. In particular, cerebellar neuropathology in FRDA patients includes loss of large principal neurons and synaptic terminals in the dentate nucleus (DN), and previous studies have demonstrated early synaptic deficits in the Knockin-Knockout mouse model of FRDA. Read More

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Bone Mineral Density and Current Bone Health Screening Practices in Friedreich's Ataxia.

Front Neurosci 2022 14;16:818750. Epub 2022 Mar 14.

Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, United States.

Introduction: Friedreich's Ataxia (FRDA) is a progressive neurological disorder caused by mutations in both alleles of the gene. Impaired bone health is a complication of other disorders affecting mobility, but there is little information regarding bone health in FRDA.

Methods: Dual energy X-ray absorptiometry (DXA) scan-based assessments of areal bone mineral density (aBMD) in individuals with FRDA were abstracted from four studies at the Children's Hospital of Philadelphia (CHOP). Read More

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Functional MRI Studies in Friedreich's Ataxia: A Systematic Review.

Front Neurol 2021 10;12:802496. Epub 2022 Mar 10.

Department of Neurorehabilitation, Pieve di Soligo, Scientific Institute, IRCCS E. Medea, Pieve di Soligo, Italy.

Friedreich's ataxia (FRDA) is an inherited neurodegenerative movement disorder with early onset, widespread cerebral and cerebellar pathology, and no cure still available. Functional MRI (fMRI) studies, although currently limited in number, have provided a better understanding of brain changes in people with FRDA. This systematic review aimed to provide a critical overview of the findings and methodologies of all fMRI studies conducted in genetically confirmed FRDA so far, and to offer recommendations for future study designs. Read More

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Modelling Protein Plasticity: The Example of Frataxin and Its Variants.

Molecules 2022 Mar 17;27(6). Epub 2022 Mar 17.

Dipartimento di Fisica, Università di Roma Tor Vergata and Sezione di Roma Tor Vergata, INFN, Via della Ricerca Scientifica 1, I-00133 Roma, Italy.

Frataxin (FXN) is a protein involved in storage and delivery of iron in the mitochondria. Single-point mutations in the gene lead to reduced production of functional frataxin, with the consequent dyshomeostasis of iron. FXN variants are at the basis of neurological impairment (the Friedreich's ataxia) and several types of cancer. Read More

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Recessive cerebellar and afferent ataxias - clinical challenges and future directions.

Nat Rev Neurol 2022 05 24;18(5):257-272. Epub 2022 Mar 24.

Axe Neurosciences, CHU de Québec-Université Laval, Québec, QC, Canada.

Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement. Read More

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Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases.

Cells 2022 03 19;11(6). Epub 2022 Mar 19.

Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.

Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot-Marie-Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich's ataxia, dominant optic atrophy, and Alzheimer's, Huntington's, and Parkinson's diseases. Read More

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DNA methylation in Friedreich ataxia silences expression of frataxin isoform E.

Sci Rep 2022 03 23;12(1):5031. Epub 2022 Mar 23.

Department of Pediatrics, University of Oklahoma Health Sciences Center, OU Children's Physician Building, Suite 12100, 1200 Children's Avenue, Oklahoma City, OK, 73104, USA.

Epigenetic silencing in Friedreich ataxia (FRDA), induced by an expanded GAA triplet-repeat in intron 1 of the FXN gene, results in deficiency of the mitochondrial protein, frataxin. A lesser known extramitochondrial isoform of frataxin detected in erythrocytes, frataxin-E, is encoded via an alternate transcript (FXN-E) originating in intron 1 that lacks a mitochondrial targeting sequence. We show that FXN-E is deficient in FRDA, including in patient-derived cell lines, iPS-derived proprioceptive neurons, and tissues from a humanized mouse model. Read More

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Friedreich's Ataxia related Diabetes: Epidemiology and management practices.

Diabetes Res Clin Pract 2022 Apr 14;186:109828. Epub 2022 Mar 14.

Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Aims: Friedreich's Ataxia (FRDA) is a progressive neuromuscular disorder typically caused by GAA triplet repeat expansions in both frataxin gene alleles. FRDA can be complicated by diabetes mellitus (DM). The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related DM. Read More

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The cognitive profile of Friedreich ataxia: a systematic review and meta-analysis.

BMC Neurol 2022 Mar 17;22(1):97. Epub 2022 Mar 17.

Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Australia.

Background: Study the cognitive profile of individuals with Friedreich ataxia (FRDA) and seek evidence for correlations between clinical, genetic and imaging characteristics and neuropsychological impairments.

Methods: Based on PRISMA guidelines, a meta-analysis was realized using the Pubmed and Scopus databases to identify studies (1950-2021) reporting neuropsychological test results in genetically confirmed FRDA and control participants in at least one of the following cognitive domains: attention/executive, language, memory and visuo-spatial functions as well as emotion. Studies using identical outcomes in a minimum of two studies were pooled. Read More

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Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice.

RNA Biol 2022 31;19(1):364-372. Epub 2021 Dec 31.

Department of Pharmacology and Biochemistry, UT Southwestern Medical Center, Dallas, Texas, United States.

Friedreich's ataxia (FA) is an inherited neurodegenerative disorder caused by decreased expression of frataxin (FXN) protein. Previous studies have shown that antisense oligonucleotides (ASOs) and single-stranded silencing RNAs can be used to increase expression of frataxin in cultured patient-derived cells. In this study, we investigate the potential for oligonucleotides to increase frataxin expression in a mouse model for FA. Read More

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Control of arm movements in Friedreich's ataxia patients: role of sensory feedback.

Exp Brain Res 2022 May 14;240(5):1411-1422. Epub 2022 Mar 14.

Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.

Friedreich's ataxia (FA) is a hereditary system degeneration, which progressively affects sensory functions such as proprioceptive feedback, which causes progressive ataxia in FA patients. While major clinical features of movement disorders in FA patients have been identified, the underlying impaired neural control is not sufficiently understood. To elucidate the underlying control mechanism, we investigated single-joint movements of the upper limb in FA patients. Read More

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Gene therapy for Friedreich ataxia: Too much, too little, or just right?

R Mark Payne

Mol Ther Methods Clin Dev 2022 Jun 4;25:1-2. Epub 2022 Mar 4.

Indiana University School of Medicine, Wells Center for Pediatric Research, 1044 West Walnut, R4302b, Indianapolis, IN 46202, USA.

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[email protected] NPs alleviate Friedreich's ataxia in a mouse model through synergistic iron chelation and antioxidation.

J Nanobiotechnology 2022 Mar 9;20(1):118. Epub 2022 Mar 9.

Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China.

Abnormal iron metabolism, mitochondrial dysfunction and the derived oxidative damage are the main pathogeneses of Friedrich's ataxia (FRDA), a single-gene inherited recessive neurodegenerative disease characterized by progressive cerebellar and sensory ataxia. This disease is caused by frataxin (FXN) mutation, which reduces FXN expression and impairs iron sulfur cluster biogenesis. To date, there is no effective therapy to treat this condition. Read More

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overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency.

Mol Ther Methods Clin Dev 2022 Mar 7;24:367-378. Epub 2022 Feb 7.

Rare Disease Research Unit, Worldwide Research, Development and Medical, Pfizer Inc., 610 Main Street, Cambridge, MA 02139, USA.

Friedreich's ataxia is a rare disorder resulting from deficiency of frataxin, a mitochondrial protein implicated in the synthesis of iron-sulfur clusters. Preclinical studies in mice have shown that gene therapy is a promising approach to treat individuals with Friedreich's ataxia. However, a recent report provided evidence that AAVrh10-mediated overexpression of frataxin could lead to cardiotoxicity associated with mitochondrial dysfunction. Read More

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Downregulation of Three Immune-Specific Core Genes and the Regulatory Pathways in Children and Adult Friedreich's Ataxia: A Comprehensive Analysis Based on Microarray.

Front Neurol 2021 14;12:816393. Epub 2022 Feb 14.

Department of Pharmacy, Fujian Children's Hospital, Fuzhou, China.

Background: Friedreich's ataxia (FRDA) is a familial hereditary disorder that lacks available therapy. Therefore, the identification of novel biomarkers and key mechanisms related to FRDA progression is urgently required.

Methods: We identified the up-regulated and down-regulated differentially expressed genes (DEGs) in children and adult FRDA from the GSE11204 dataset and intersected them to determine the co-expressed DEGs (co-DEGs). Read More

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February 2022

Drug Repositioning in Friedreich Ataxia.

Front Neurosci 2022 9;16:814445. Epub 2022 Feb 9.

Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.

Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. Read More

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February 2022

Coenzyme Q10 effects in neurological diseases.

H Rauchová

Physiol Res 2021 12;70(Suppl4):S683-S714

Institute of Physiology Czech Academy of Sciences, Prague, Czech Republic.

Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. Read More

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December 2021

A Standardized Pipeline for Examining Human Cerebellar Grey Matter Morphometry using Structural Magnetic Resonance Imaging.

J Vis Exp 2022 02 4(180). Epub 2022 Feb 4.

Department of Neuroscience, Central Clinical School, Monash University; Monash Biomedical Imaging, Monash University.

Multiple lines of research provide compelling evidence for a role of the cerebellum in a wide array of cognitive and affective functions, going far beyond its historical association with motor control. Structural and functional neuroimaging studies have further refined understanding of the functional neuroanatomy of the cerebellum beyond its anatomical divisions, highlighting the need for the examination of individual cerebellar subunits in healthy variability and neurological diseases. This paper presents a standardized pipeline for examining cerebellum grey matter morphometry that combines high-resolution, state-of-the-art approaches for optimized and automated cerebellum parcellation (Automatic Cerebellum Anatomical Parcellation using U-Net Locally Constrained Optimization; ACAPULCO) and voxel-based registration of the cerebellum (Spatially Unbiased Infra-tentorial Template; SUIT) for volumetric quantification. Read More

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February 2022