Sr-centered monocyclic carbon ring Sr@C: A new stable cluster.

The study of stable neutral metal endohedral cyclo[n]carbon is helpful for discovering single-molecule devices. Extensive structural search and density functional theory calculations performed here indicate that the perfect planar alkaline metal-doped complexes Sr@C possess the well-defined global minima of the system with the metal atom located exactly at the center of the carbon ring. The configuration and bonding properties of C are different from those of pristine cyclo [14]carbon.

Break Down of the Complexity and Inconsistency Between Levels of Matriglycan and Disease Phenotype in FKRP-Related Dystroglycanopathies: A Review and Model of Interpretation.

Dystroglycanopathies are a group of muscle degenerative diseases characterized with significant reduction in matriglycan expression critical in disease pathogenesis. Missense point mutations in the Fukutin-related protein (FKRP) gene cause variable reduction in the synthesis of matriglycan on alpha-dystroglycan (α-DG) and a wide range of disease severity. Data analyses of muscle biopsies from patients fail to show consistent correlation between the levels of matriglycan and clinical phenotypes.

Misfolding of fukutin-related protein (FKRP) variants in congenital and limb girdle muscular dystrophies.

Fukutin-related protein (FKRP, MIM ID 606596) variants cause a range of muscular dystrophies associated with hypo-glycosylation of the matrix receptor, α-dystroglycan. These disorders are almost exclusively caused by homozygous or compound heterozygous missense variants in the gene that encodes a ribitol phosphotransferase. To understand how seemingly diverse missense mutations may contribute to disease, we examined the synthesis, intracellular dynamics, and structural consequences of a panel of missense mutations that encompass the disease spectrum.

Improved efficacy of FKRP AAV gene therapy by combination with ribitol treatment for LGMD2I.

Mutations in the fukutin-related protein (FKRP) gene cause dystroglycanopathy, with disease severity ranging from mild LGMD2I to severe congenital muscular dystrophy. Recently, considerable progress has been made in developing experimental therapies, with adeno-associated virus (AAV) gene therapy and ribitol treatment demonstrating significant therapeutic effect. However, each treatment has its strengths and weaknesses.

Metabolic Reprogramming by Ribitol Expands the Therapeutic Window of BETi JQ1 against Breast Cancer.

Many cancer patients still lack effective treatments, and pre-existing or acquired resistance limits the clinical benefit of even the most advanced medicines. Recently, much attention has been given to the role of metabolism in cancer, expanding from the Warburg effect to highlight unique patterns that, in turn, may improve diagnostic and therapeutic approaches. Our recent metabolomics study revealed that ribitol can alter glycolysis in breast cancer cells.

Quasi-planar Co atom-doped boron cluster: CoB.

Purpose And Methods: A global search for the lowest energy structure of CoB clusters was conducted.  RESULTS: Its ground state is a quasi-planar structure with the Co atom surrounded by a B ring. The central Co atom has an oxidation state of +1 with d electron configuration.

Ribitol alters multiple metabolic pathways of central carbon metabolism with enhanced glycolysis: A metabolomics and transcriptomics profiling of breast cancer.

Breast cancer is heterogenous in development and cell population with prognoses being highly dependent on numerous factors from driving mutations, biomarker expression and variation in extracellular environment, all affecting response to therapies. Recently, much attention has been given to the role of metabolic alteration in cancers, expanding from the Warburg effect to highlight unique patterns in different cancer cell populations for improving diagnostic and therapeutic approaches. We recently reported on modulation of mannosylation of α-dystroglycan with the metabolite ribitol in breast cancer lines.

Ribitol dose-dependently enhances matriglycan expression and improves muscle function with prolonged life span in limb girdle muscular dystrophy 2I mouse model.

Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-dystroglycan (matriglycan) resulting from mutations of Fukutin-related protein (FKRP). There is no effective therapy currently available. We recently demonstrated that ribitol supplement increases levels of matriglycan in cells in vitro and in FKRP-P448L (P448L) mutant mouse model through drinking water administration.

Effects of Chronic, Maximal Phosphorodiamidate Morpholino Oligomer (PMO) Dosing on Muscle Function and Dystrophin Restoration in a Mouse Model of Duchenne Muscular Dystrophy.

Background: Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is currently used in clinical development to treat Duchenne muscular dystrophy (DMD), with four exon-skipping drugs achieving regulatory approval. Exon skipping elicits a truncated, but semi-functional dystrophin protein, similar to the truncated dystrophin expressed in patients with Becker Muscular dystrophy (BMD) where the disease phenotype is less severe than DMD. Despite promising results in both dystrophic animal models and DMD boys, restoration of dystrophin by exon skipping is highly variable, leading to contradictory functional outcomes in clinical trials.

A universal gene correction approach for FKRP-associated dystroglycanopathies to enable autologous cell therapy.

Mutations in the fukutin-related protein (FKRP) gene result in a broad spectrum of muscular dystrophy (MD) phenotypes, including the severe Walker-Warburg syndrome (WWS). Here, we develop a gene-editing approach that replaces the entire mutant open reading frame with the wild-type sequence to universally correct all FKRP mutations. We apply this approach to correct FKRP mutations in induced pluripotent stem (iPS) cells derived from patients displaying broad clinical severity.

Revertant Phenomenon in DMD and LGMD2I and Its Therapeutic Implications: A Review of Study Under Mentorship of Terrence Partridge.

This review recollects my initial research focus on revertant fibers (expressing dystrophin in the background of frame-shifting mutation) in Duchenne muscular dystrophy (DMD) muscles in Professor Terrence Partridge's Muscle Cell Biology Laboratory in MRC Clinical Research Science Center, Harmmersmith Hospital, London, UK. Our data indicated that revertant fibers are most likely resulted from epigenetic random events which skip exon(s) flanking the mutated exon, leading to the restoration of the reading frame. Some of these events establish themselves as relatively permanent skipping patterns, a mechanism similar to multiple transcript species established in various cell types.

Structures and Properties of CoB Clusters.

A global search for the lowest energy structure of Co atom-doped boron clusters (CoB , CoB, and CoB clusters) was conducted. The lowest energy structures of them are remarkably different from those of B and CoB clusters. CoB clusters have a bowl-shaped geometry, where the Co atom is at the bottom of the bowl and is coordinated with eight B atoms.

Efficient engraftment of pluripotent stem cell-derived myogenic progenitors in a novel immunodeficient mouse model of limb girdle muscular dystrophy 2I.

Background: Defects in α-dystroglycan (DG) glycosylation characterize a group of muscular dystrophies known as dystroglycanopathies. One of the key effectors in the α-DG glycosylation pathway is the glycosyltransferase fukutin-related protein (FKRP). Mutations in FKRP lead to a large spectrum of muscular dystrophies, including limb girdle muscular dystrophy 2I (LGMD2I).

Ribitol enhances matriglycan of α-dystroglycan in breast cancer cells without affecting cell growth.

The laminin-binding glycan (matriglycan) on α-dystroglycan (α-DG) enables diverse roles, from neuronal development to muscle integrity. Reduction or loss of matriglycan has also been implicated in cancer development and metastasis, and specifically associated with high-grade tumors and poor prognoses in breast cancers. Hyperglycosylation of α-DG with LARGE overexpression is shown to inhibit cancer cell growth and tumorigenicity.

ISPD Overexpression Enhances Ribitol-Induced Glycosylation of α-Dystroglycan in Dystrophic FKRP Mutant Mice.

Dystroglycanopathy, a subgroup of muscular dystrophies, is characterized by hypoglycosylation of α-dystroglycan (α-DG), which reduces its laminin-binding activity to extracellular matrix proteins, causing progressive loss of muscle integrity and function. Mutations in the fukutin-related protein (FKRP) gene are the most common causes of dystroglycanopathy. FKRP transfers ribitol-5-phosphate to the -mannosyl glycan on α-DG from substrate cytidine diphosphate (CDP)-ribitol, which is synthesized by isoprenoid synthase domain-containing protein (ISPD).

Metabolomics Analysis of Skeletal Muscles from FKRP-Deficient Mice Indicates Improvement After Gene Replacement Therapy.

Muscular dystrophy-dystroglycanopathies comprise a heterogeneous and complex group of disorders caused by loss-of-function mutations in a multitude of genes that disrupt the glycobiology of α-dystroglycan, thereby affecting its ability to function as a receptor for extracellular matrix proteins. Of the various genes involved, FKRP codes for a protein that plays a critical role in the maturation of a novel glycan found only on α-dystroglycan. Yet despite knowing the genetic cause of FKRP-related dystroglycanopathies, the molecular pathogenesis of disease and metabolic response to therapeutic intervention has not been fully elucidated.

Morpholino-induced exon skipping stimulates cell-mediated and humoral responses to dystrophin in mdx mice.

Exon skipping is a promising genetic therapeutic strategy for restoring dystrophin expression in the treatment of Duchenne muscular dystrophy (DMD). The potential for newly synthesized dystrophin to trigger an immune response in DMD patients, however, is not well established. We have evaluated the effect of chronic phosphorodiamidate morpholino oligomer (PMO) treatment on skeletal muscle pathology and asked whether sustained dystrophin expression elicits a dystrophin-specific autoimmune response.

Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice.

Muscular dystrophy-dystroglycanopathies (MDDGs) resulting from fukutin-related protein () gene mutations are rare disorders that result in a wide spectrum of clinical severity based on the age of onset, the degree of myogenic atrophy, and/or neurologic involvement. There is no cure for any of the -related disorders, and few options are available for symptom management. Herein, we examine the longitudinal effects of a dose-escalation study to evaluate the safety and therapeutic potential of FKRP gene-replacement therapy in a p.

In Vivo Evaluation of Dystrophin Exon Skipping in mdx Mice.

Dystrophin exon skipping in mdx mice has been the key model for the development of antisense therapy in vivo. Evaluation of exon skipping in this model involves the following two aspects: (1) efficiency and accuracy of exon skipping and levels of dystrophin expression determined by RT-PCR, immunochemistry, and western blotting; (2) therapeutic effects on muscle pathology and functions assessed by histology and functional assays including grip strength measurement, treadmill test, echocardiogram, and hemodynamics for cardiac functions. Here we describe some key considerations and the essential methodologies in detail for exon skipping in mdx mice.

Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice.

O-mannosylated α-dystroglycan (α-DG) serves as receptors for cell-cell and cell-extracellular matrix adhesion and signaling. Hypoglycosylation of α-DG is involved in cancer progression and underlies dystroglycanopathy with aberrant neuronal development. Here we report that ribitol, a pentose alcohol with previously unknown function in mammalian cells, partially restores functional O-mannosylation of α-DG (F-α-DG) in the dystroglycanopathy model containing a P448L mutation in fukutin-related protein (FKRP) gene, which is clinically associated with severe congenital muscular dystrophy.

Overexpression of Mutant FKRP Restores Functional Glycosylation and Improves Dystrophic Phenotype in FKRP Mutant Mice.

Autosomal recessive homozygous or compound heterozygous mutations in FKRP result in forms of muscular dystrophy-dystroglycanopathy varying in age of onset, clinical presentation, and disease progression, ranging from the severe Walker-Warburg, type A,5 (MDDGA5), muscle-eye-brain (MDDGB5) with or without cognitive deficit, to limb-girdle type 2I (MDDGC5). Phenotypic variation indicates degrees of functionality of individual FKRP mutation, which has been supported by the presence of residual expression of functionally glycosylated α-dystroglycan (DG) in muscles of both animal models and patients. However, direct evidence showing enhancement in glycosylation of α-DG by mutant FKRP is lacking.

Long-Term Treatment of Tamoxifen and Raloxifene Alleviates Dystrophic Phenotype and Enhances Muscle Functions of FKRP Dystroglycanopathy.

The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available. Selective estrogen receptor modulators, tamoxifen and raloxifene, have been widely used for human conditions for their anti-inflammatory, antifibrosis, prevention of bone loss, and muscle building effects (essential features for muscular dystrophy therapies). We evaluated therapeutic values of tamoxifen and raloxifene in FKRPP448L mutant mouse with severe dystrophic phenotype.

Planarization of B clusters by Si and C atom substitution.

An optimization strategy combining a global semi-empirical quantum mechanical search and all-electron density functional theory was adopted to determine the lowest energy structures of BSi and BC clusters. The planarization of a B cluster by Si and C atom substitution was observed. The structural transition was from the double-ring tubular B to an almost perfect planar BSi and a quasi-planar bowl BC.

Efficacy of Gene Therapy Is Dependent on Disease Progression in Dystrophic Mice with Mutations in the FKRP Gene.

Loss-of-function mutations in the Fukutin-related protein () gene cause limb-girdle muscular dystrophy type 2I (LGMD2I) and other forms of congenital muscular dystrophy-dystroglycanopathy that are associated with glycosylation defects in the α-dystroglycan (α-DG) protein. Systemic administration of a single dose of recombinant adeno-associated virus serotype 9 (AAV9) vector expressing human to a mouse model of LGMD2I at various stages of disease progression was evaluated. The results demonstrate rescue of functional glycosylation of α-DG and muscle function, along with improvements in muscle structure at all disease stages versus age-matched untreated cohorts.

Adeno-Associated Virus-Mediated Mini-Agrin Delivery Is Unable to Rescue Disease Phenotype in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2I.

Agrin is a basement membrane-specific proteoglycan that can regulate orientation of cytoskeleton proteins and improve function of dystrophic skeletal muscle. In skeletal muscle, agrin binds with high affinity to laminin(s) and α-dystroglycan (α-DG), an integral part of the dystrophin-glycoprotein complex. Miniaturized forms of agrin (mAgrin) have been shown to ameliorate disease pathology in a laminin-α2 knockout mouse model of muscular dystrophy, acting as a link between α-DG and laminin(s).