Neurogenetic diseases are neurological conditions with a genetic cause (s). There are thousands of neurogenetic diseases, and most of them are incurable. The development of bioinformatics and ...elucidation of the mechanism of pathogenesis have allowed the development of gene therapy approaches, which show great potential in treating neurogenetic diseases. Viral vectors delivery, antisense oligonucleotides, gene editing, RNA interference, and burgeoning viroid delivery technique are promising gene therapy strategies, and commendable therapeutic effects in the treatment of neurogenetic diseases have been achieved (Fig.
1
). This review highlights a sampling of advances in gene therapies for neurogenetic disorders.
Fig. 1
Examples of gene therapy strategies used in the treatment of neurogenetic diseases. The schematic diagram shows different gene therapy approaches used for treating a sampling of neurogenetic disorders, such as ASO therapy, gene editing, gene augmentation, and RNA interference
CRISPR-mediated genome editing is a revolutionary technology for genome manipulation that uses the CRISPR-Cas systems and base editors. Currently, poor efficiency and off-target problems have impeded ...the application of CRISPR systems. The on-target efficiency has been improved in several advanced versions of CRISPR systems, whereas the off-target detection still remains a key challenge. Here, we outline the different versions of CRISPR systems and off-target detection strategies, discuss the merits and limitations of off-target detection methods, and provide potential implications for further gene editing research.
Abstract
Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and ...immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the
CMPK2
gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust
Cmpk2
expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in
Cmpk2-
knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the
Cmpk2-
KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous
Cmpk2
-KO mice thalamus region as well as in the
Cmpk2-
knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of
CMPK2
as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.
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•A low-cost and environment-friendly biosorbent for scandium was prepared.•Scandium was successfully recovered from red mud leachates.•The used biochar could recover Sc3+ ion with ...high selectivity from Al3+, Fe3+, Dy3+, Y3+ ions coexistence solution.•The used biochar showed ideal reusability after five adsorption/ desorption cycles.•The adsorption mechanism of 750 °C calcined H3PO4 activated biochar was identified through characterization analysis.
In recent years, the global demand for scandium has increased due to its essential role in the high-technology industry. Red mud leachates constitute a significant source of scandium and an efficient and environmentally friendly approach that attracted considerable interest. In this study, H3PO4 activated biochar (P40s) is manufactured from pitaya peel (PP) as a novel material to be used for scandium adsorption and recovery from red mud leachates. The material was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), nitrogen adsorption isotherms, X-ray photoelectron spectroscopy (XRF), zeta potential, and element analysis (such as C, H, O, N and P) to characterize adsorbents. The results indicated that the phosphorus-containing functional groups were successfully introduced to improve the physicochemical properties of biochar. The pseudo-second-order kinetic model and Freundlich isotherm fit experimental data, verifying that the scandium adsorption by activated biochar is dominated by chemisorption and belongs to multilayer sorption. The maximal adsorption capacity of 750 °C calcinated H3PO4 activated biochar (P40-750) was 20.77 mg/g. Notably, the adsorbent was better for selective recovery of Sc3+ from Al3+, Fe3+, Dy3+, Y3+ coexistence ions. The separation coefficients (SF) of scandium for aluminum, iron, dysprosium, and yttrium are 137.03, 27.04, 77.74, and 208.25 times respectively, at pH3. Importantly, scandium is efficiently extracted from the leaching solution of red mud with an 83% recovery rate. Meanwhile, P40-750 exhibited a stable scandium adsorption capacity after 5 adsorption/desorption cycles. Overall, P40-750 could be considered a low-cost and environment-friendly biosorbent for recovering scandium from red mud leaching solution.
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