Case Report: Compound Heterozygous Variants of the MAN1B1 Gene in a Russian Patient with Rafiq Syndrome

Rafiq syndrome (RAFQS) is a congenital disorder of glycosylation (CDG) that is caused by mutations in the MAN1B1 gene and characterized by impaired protein and lipid glycosylation. RAFQS is characterized by a delay in intellectual and motor development, facial and other dysmorphism, truncal obesity, behavior problems, and hypotonia. We describe a Russian patient with delayed intellectual and motor development, a lack of speech, disorientation in space and time, impaired attention and memory, and episodes of aggression. Screening for lysosomal, amino acid, organic acid, and mitochondrial disorders was normal. The patient was referred for the targeted sequencing of the “Hereditary Metabolic Disorders” panel. The genetic testing revealed two heterozygous pathogenic variants in the MAN1B1 gene: the previously reported c.1000C > T (p.Arg334Cys) and the novel c.1065 + 1 G > C. Thus, the patient’s clinical picture and genetic analysis confirmed RAFQS in the patient.     

Lorentzian-Corrected Apparent Exchange-Dependent Relaxation (LAREX) Ω-Plot Analysis—An Adaptation for qCEST in a Multi-Pool System: Comprehensive In Silico,In Situ,and In Vivo Studies

Based on in silico, in situ, and in vivo studies, this study aims to develop a new method for the quantitative chemical exchange saturation transfer (qCEST) technique considering multi-pool systems. To this end, we extended the state-of-the-art apparent exchange-dependent relaxation (AREX) method with a Lorentzian correction (LAREX). We then validated this new method with in situ and in vivo experiments on human intervertebral discs (IVDs) using the Kendall-Tau correlation coefficient. In the in silico experiments, we observed significant deviations of the AREX method as a function of the underlying exchange rate (k_ba) and fractional concentration (f_b) compared to the ground truth due to the influence of other exchange pools. In comparison to AREX, the LAREX-based Ω-plot approach yielded a substantial improvement. In the subsequent in situ and in vivo experiments on human IVDs, no correlation to the histological reference standard or Pfirrmann classification could be found for the f_b (in situ: τ = −0.17 p = 0.51; in vivo: τ = 0.13 p = 0.30) and k_ba (in situ: τ = 0.042 p = 0.87; in vivo: τ = −0.26 p = 0.04) of Glycosaminoglycan (GAG) with AREX. In contrast, the influence of interfering pools could be corrected by LAREX, and a moderate to strong correlation was observed for the fractional concentration of GAG for both in situ (τ = −0.71 p = 0.005) and in vivo (τ = −0.49 p < 0.001) experiments. The study presented here is the first to introduce a new qCEST method that enables qCEST imaging in systems with multiple proton pools.     

Identification and In Silico Characterization of a Novel COLGALT2 Gene Variant in a Child with Mucosal Rectal Prolapse

Rectal prolapse is influenced by many factors including connective tissue dysfunction. Currently, there is no data about genetic contribution in the etiology of this disorder. In this study, we performed trio whole-exome sequencing in an 11-year-old girl with mucosal rectal prolapse and her parents and sibling. Genetic testing revealed a novel heterozygous missense variant c.1406G>T; p.G469V in exon 11 of the COLGALT2 gene encoding the GLT25 D2 enzyme. Sanger sequencing confirmed this variant only in the patient while the mother, father and sister showed a wild-type sequence. The pathogenicity of the novel variant was predicted using 10 different in silico tools that classified it as pathogenic. Further, in silico prediction, according to Phyre2, Project HOPE, I-Mutant3.0 and MutPred2 showed that the missense variant can decrease protein stability and cause alterations in the physical properties of amino acids resulting in structural and functional changes of the GLT25D2 protein. In conclusion, the present study identifies a previously unknown missense mutation in the COLGALT2 gene that encodes the enzyme involved in collagen glycosylation. The clinical features observed in the patient and the results of in silico analysis suggest that the new genetic variant can be pathogenic.     

Strongly entangled polymer chains in a melt. Description of n.m.r. properties associated with a submolecule model

A model is proposed to illustrate properties of the transverse magnetic relaxation function, G(t), of proton pairs linked to strongly entangled polymer chains in a melt. According to this model, any polymer molecule is described as a freely jointed chain and it is divided into submolecules of equal contour length L^v_e. Every link is supposed to carry a proton pair; dipolar spin couplings between different proton pairs are neglected. The disentanglement relaxation time is supposed to be much longer than any characteristic time of the spin system; consequently, any submolecule observed on an n.m.r. time scale is supposed to have fixed ends. It is considered that the residual spin-coupling energy resulting from such a constraint governs the magnetic relaxation process. The free induction decay is expressed as a contour length function; its time evolution is shown to exhibit two ranges, which might be characterized by two relaxation times. The model is easily extended to rotating methyl groups. Theoretical results are compared with magnetic relaxation properties observed on entangled real chains: polydimethylsiloxane (PDMS) and cis-1,4-polybutadiene (PB). An attempt to adjust the contour length value to experimental results leads to the determination of average submolecule molecular weights M^v_e equal to 8200 and 2000 for PDMS and PB, respectively; the values usually obtained from viscoelastic plateau modulus measurements are 8100 and 1900, respectively.     

The Role of Molecular Imaging as a Marker of Remyelination and Repair in Multiple Sclerosis

The appearance of new disease-modifying therapies in multiple sclerosis (MS) has revolutionized our ability to fight inflammatory relapses and has immensely improved patients’ quality of life. Although remarkable, this achievement has not carried over into reducing long-term disability. In MS, clinical disability progression can continue relentlessly irrespective of acute inflammation. This “silent” disease progression is the main contributor to long-term clinical disability in MS and results from chronic inflammation, neurodegeneration, and repair failure. Investigating silent disease progression and its underlying mechanisms is a challenge. Standard MRI excels in depicting acute inflammation but lacks the pathophysiological lens required for a more targeted exploration of molecular-based processes. Novel modalities that utilize nuclear magnetic resonance’s ability to display in vivo information on imaging look to bridge this gap. Displaying the CNS through a molecular prism is becoming an undeniable reality. This review will focus on “molecular imaging biomarkers” of disease progression, modalities that can harmoniously depict anatomy and pathophysiology, making them attractive candidates to become the first valid biomarkers of neuroprotection and remyelination.     

Graphene oxide/zinc ferrite nanocomposite loaded with doxorubicin as a potential theranostic mediu in cancer therapy and magnetic resonance imaging

Hybrid functional biomaterials are attracting increasing interest due to their biocompatibility and therapeutic and diagnostic characteristics. The theranostic properties of functional biomaterials favor their application. When these materials are responded to stimuli, they confer target site delivery. Although various types of nanocomposites have been developed for drug delivery and diagnostics, no ideal composites have been reported yet. Here, we report the synthesis of graphene oxide–zinc ferrite hybrid nanocomposites (GO-ZnFe₂O₄) conjugated with doxorubicin (GO-ZnFe₂O₄/DOX) for cancer therapy and magnetic resonance (MR) imaging-based diagnosis. The optical properties, crystal phase, particle size, functional groups, elemental composition, surface morphology, and magnetism of GO-ZnFe₂O₄ nanocomposites were characterized using state-of-the-art available techniques, including Fourier-Transform Infrared Spectroscopy (FTIR), Ultraviolet visible spectroscopy (UV–Vis), Transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Dynamic light scattering (DLS), Vibrating sample magneto meter (VSM) Scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and X-ray photoelectron spectra (XPS). The in vitro analysis showed that GO-ZnFe₂O₄ conjugated with DOX is more cytotoxic than GO-ZnFe₂O₄. GO-ZnFe₂O₄/DOX induced the production of reactive oxygen species (ROS), which induced damage to nuclear DNA and mitochondrial DNA (mtDNA) when internalized by cells. This damage consequently drove mitochondrial malfunction and ultimately the apoptosis of cancer cells. Further studies were performed to investigate the diagnostic efficacy of these nanocomposites using MR imaging. GO-ZnFe₂O₄/DOX nanocomposites were developed and successfully employed in the MR imaging of HeLa cells. As shown in the present study, GO-ZnFe₂O₄/DOX might play a potential role in the development of chemotherapy and noninvasive MR imaging of tumor cells.     

ATRP in the design of functional materials for biomedical applications

Atom Transfer Radical Polymerization (ATRP) is an effective technique for the design and preparation of multifunctional, nanostructured materials for a variety of applications in biology and medicine. ATRP enables precise control over macromolecular structure, order, and functionality, which are important considerations for emerging biomedical designs. This article reviews recent advances in the preparation of polymer-based nanomaterials using ATRP, including polymer bioconjugates, block copolymer-based drug delivery systems, cross-linked microgels/nanogels, diagnostic and imaging platforms, tissue engineering hydrogels, and degradable polymers. It is envisioned that precise engineering at the molecular level will translate to tailored macroscopic physical properties, thus enabling control of the key elements for realized biomedical applications.     

Chitosan—A versatile semi-synthetic polymer in biomedical applications

This review outlines the new developments on chitosan-based bioapplications. Over the last decade, functional biomaterials research has developed new drug delivery systems and improved scaffolds for regenerative medicine that is currently one of the most rapidly growing fields in the life sciences. The aim is to restore or replace damaged body parts or lost organs by transplanting supportive scaffolds with appropriate cells that in combination with biomolecules generate new tissue. This is a highly interdisciplinary field that encompasses polymer synthesis and modification, cell culturing, gene therapy, stem cell research, therapeutic cloning and tissue engineering. In this regard, chitosan, as a biopolymer derived macromolecular compound, has a major involvement. Chitosan is a polyelectrolyte with reactive functional groups, gel-forming capability, high adsorption capacity and biodegradability. In addition, it is innately biocompatible and non-toxic to living tissues as well as having antibacterial, antifungal and antitumor activity. These features highlight the suitability and extensive applications that chitosan has in medicine. Micro/nanoparticles and hydrogels are widely used in the design of chitosan-based therapeuticsystems. The chemical structure and relevant biological properties of chitosan for regenerative medicine have been summarized as well as the methods for the preparation of controlled drug release devices and their applications.     

Dendrimer as nanocarrier for drug delivery

Dendrimers are novel three dimensional, hyperbranched globular nanopolymeric architectures. Attractive features like nanoscopic size, narrow polydispersity index, excellent control over molecular structure, availability of multiple functional groups at the periphery and cavities in the interior distinguish them amongst the available polymers. Applications of dendrimers in a large variety of fields have been explored. Drug delivery scientists are especially enthusiastic about possible utility of dendrimers as drug delivery tool. Terminal functionalities provide a platform for conjugation of the drug and targeting moieties. In addition, these peripheral functional groups can be employed to tailor-make the properties of dendrimers, enhancing their versatility. The present review highlights the contribution of dendrimers in the field of nanotechnology with intent to aid the researchers in exploring dendrimers in the field of drug delivery.