Salinity gradient power can be a very attractive renewable energy system because electricity is generated by salt concentration difference between two solutions without any pollutant emission. The ...representative example of salinity gradient power is reverse electrodialysis (RED), in which there are many variables such as ion exchange membrane (IEM), electrode, stack configuration, the structure of flow pathway, spacer, and solution concentration. This paper focuses on IEMs and electrodes that have not been covered in the previous review papers, as well as on the fundamental of the RED system and plant development for commercialization. In the part of IEM, the characteristics that need to be intensively studied are analyzed and the studies have been conducted to improve membrane property are summarized. In addition, the properties of major commercial IEMs and tailor-made membranes are compared and analyzed, and the relationship between properties affecting membrane performance is studied. In the part of the electrode, the main issues and materials of the electrode part in the RED system are presented, and the recent researches related to the electrode of a large-scale RED system for commercialization are summarized. Finally, this review suggests the future prospects and expectations for salinity gradient power using the RED system.
•Reverse electrodialysis (RED) system for eco-friendly and sustainable power is reviewed.•The ion exchange membrane and electrode compartment are key components in the RED system.•Importance of the electrode compartment is pretty high in a large scale RED system.•The expected applications of the RED system are suggested.•The challenges and outlooks for future developments are suggested.
Objective
Brain somatic mutations in mTOR pathway genes are a major genetic etiology of focal cortical dysplasia type II (FCDII). Despite a greater ability to detect low‐level somatic mutations in ...the brain by deep sequencing and analytics, about 40% of cases remain genetically unexplained.
Methods
We included 2 independent cohorts consisting of 21 patients with mutation‐negative FCDII without apparent mutations on conventional deep sequencing of bulk brain. To find ultra‐low level somatic variants or structural variants, we isolated cells exhibiting phosphorylation of the S6 ribosomal protein (p‐S6) in frozen brain tissues using fluorescence‐activated cell sorting (FACS). We then performed deep whole‐genome sequencing (WGS; >90×) in p‐S6+ cells in a cohort of 11 patients with mutation‐negative. Then, we simplified the method to whole‐genome amplification and target gene sequencing of p‐S6+ cells in independent cohort of 10 patients with mutation‐negative followed by low‐read depth WGS (10×).
Results
We found that 28.6% (6 of 21) of mutation‐negative FCDII carries ultra‐low level somatic mutations (less than 0.2% of variant allele frequency VAF) in mTOR pathway genes. Our method showed ~34 times increase of the average mutational burden in FACS mediated enrichment of p‐S6+ cells (average VAF = 5.84%) than in bulky brain tissues (average VAF = 0.17%). We found that 19% (4 of 21) carried germline structural variations in GATOR1 complex undetectable in whole exome or targeted gene sequencing.
Conclusions
Our method facilitates the detection of ultra‐low level somatic mutations, in specifically p‐S6+ cells, and germline structural variations and increases the genetic diagnostic rate up to ~80% for the entire FCDII cohort. ANN NEUROL 2023;93:1082–1093
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage‐specific ...transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4‐Taz axis as a new intrinsic regulator for adipo‐osteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor‐β signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz‐runt‐related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3‐E1 cells, whereas it suppressed expression of adipogenic genes through promoting Taz‐peroxisome proliferator‐activated receptor‐γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3‐L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue‐derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. Stem Cells 2019;37:368–381
Smad4 directly binds to Taz and induces the retention of Taz in the nucleus, resulting in enhancement of Taz interaction with runt‐related transcription factor 2 or peroxisome proliferator‐activated receptor‐γ. This increased interaction augments the expression of osteogenic genes or reduces the expression of adipogenic genes, respectively. Therefore, Smad4‐Taz axis reciprocally regulates osteogenic and adipogenic differentiation of mesenchymal stem cells.
Kohlschütter-Tönz syndrome (KTS) manifests as neurological dysfunctions, including early-onset seizures. Mutations in the citrate transporter SLC13A5 are associated with KTS, yet their underlying ...mechanisms remain elusive. Here, we report that a Drosophila SLC13A5 homolog, I'm not dead yet (Indy), constitutes a neurometabolic pathway that suppresses seizure. Loss of Indy function in glutamatergic neurons caused "bang-induced" seizure-like behaviors. In fact, glutamate biosynthesis from the citric acid cycle was limiting in Indy mutants for seizure-suppressing glutamate transmission. Oral administration of the rate-limiting alpha-ketoglutarate in the metabolic pathway rescued low glutamate levels in Indy mutants and ameliorated their seizure-like behaviors. This metabolic control of the seizure susceptibility was mapped to a pair of glutamatergic neurons, reversible by optogenetic controls of their activity, and further relayed onto fan-shaped body neurons via the ionotropic glutamate receptors. Accordingly, our findings reveal a micro-circuit that links neural metabolism to seizure, providing important clues to KTS-associated neurodevelopmental deficits.
Abstract
C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the ...mechanisms underlying their expression are not fully understood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD.
Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as C9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, ...we identify a neuroprotective pathway of like-Sm protein 12 (LSM12) and exchange protein directly activated by cyclic AMP 1 (EPAC1) that sustains the nucleocytoplasmic RAN gradient and thereby suppresses NCT dysfunction by the C9ORF72-derived poly(glycine-arginine) protein. LSM12 depletion in human neuroblastoma cells aggravated poly(GR)-induced impairment of NCT and nuclear integrity while promoting the nuclear accumulation of poly(GR) granules. In fact, LSM12 posttranscriptionally up-regulated EPAC1 expression, whereas EPAC1 overexpression rescued the RAN gradient and NCT defects in LSM12-deleted cells. C9-ALS patient-derived neurons differentiated from induced pluripotent stem cells (C9-ALS iPSNs) displayed low expression of LSM12 and EPAC1. Lentiviral overexpression of LSM12 or EPAC1 indeed restored the RAN gradient, mitigated the pathogenic mislocalization of TDP-43, and suppressed caspase-3 activation for apoptosis in C9-ALS iPSNs. EPAC1 depletion biochemically dissociated RAN-importin β1 from the cytoplasmic nuclear pore complex, thereby dissipating the nucleocytoplasmic RAN gradient essential for NCT. These findings define the LSM12-EPAC1 pathway as an important suppressor of the NCT-related pathologies in C9-ALS/FTD.
The cooperative effect of electrochemical activation of electroplated nickel oxide and surface modification of APTES immobilization enabled the electrochemical detection of trace glutamate ...effectively.
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•NiOx is stably introduced onto the electrode surface through electroplating.•Electrochemical activation improves the electrocatalytic properties of NiOx.•APTES immobilized on the NiOx surface promotes interactions with glutamate.•The electrode achieves sensitive glutamate detection with a wide linear range.
The electrochemical behavior and catalytic properties of nickel oxide (NiOx) are enhanced through cathodic electroplating and subsequent electrochemical activation in an alkaline aqueous electrolyte. The electrochemical detection of ʟ-glutamate becomes feasible by introducing an amine group through immobilizing APTES ((3-aminopropyl)triethoxysilane) on the NiOx surface, resulting in a positive charge. The synergistic effect of electrochemically activated electroplated NiOx and the APTES-modified surface facilitates the effective electrochemical detection of trace ʟ-glutamate. The APTES-activated NiOx electrode exhibits a linear detection range of 0.2 nM to 2 mM for glutamate. This relatively wide concentration range is promising for the analysis of human biological fluids.
Autophagy begins with the formation of autophagosomes, a process that depends on the activity of the serine/threonine kinase ULK1 (hATG1). Although earlier studies indicated that ULK1 activity is ...regulated by dynamic polyubiquitination, the deubiquitinase involved in the regulation of ULK1 remained unknown. In this study, we demonstrate that ubiquitin‐specific protease 20 (USP20) acts as a positive regulator of autophagy initiation through stabilizing ULK1. At basal state, USP20 binds to and stabilizes ULK1 by removing the ubiquitin moiety, thereby interfering with the lysosomal degradation of ULK1. The stabilization of basal ULK1 protein levels is required for the initiation of starvation‐induced autophagy, since the depletion of USP20 by RNA interference inhibits LC3 puncta formation, a marker of autophagic flux. At later stages of autophagy, USP20 dissociates from ULK1, resulting in enhanced ULK1 degradation and apoptosis. Taken together, our findings provide the first evidence that USP20 plays a crucial role in autophagy initiation by maintaining the basal expression level of ULK1.
Synopsis
The deubiquitinating enzyme USP20 acts as a positive regulator of autophagy initiation through the deubiquitination of ULK1. USP20 interferes with the lysosome‐dependent degradation of ULK1 and thereby maintains ULK1 stability at basal state.
USP20 deubiquitinates and stabilizes ULK1 at basal state.
USP20 depletion inhibits LC3 puncta formation after autophagy induction.
The USP20‐ULK1 complex dissociates after autophagy induction, resulting in enhanced ubiquitination of ULK1 and its degradation through a lysosome‐dependent pathway.
The deubiquitinating enzyme USP20 acts as a positive regulator of autophagy initiation through the deubiquitination of ULK1. USP20 interferes with the lysosome‐dependent degradation of ULK1 and thereby maintains ULK1 stability at basal state.
This randomized controlled clinical trial compared the clinical efficacy and outcome of a sealer-based obturation technique (SBO) with calcium silicate sealers and a continuous wave of condensation ...technique (CWC) with a resin-based sealer.
Root canals were prepared using rotary instruments and 2.5% sodium hypochlorite. At the next visit, patients were enrolled and randomly assigned into 2 groups on the basis of the obturation protocol: CWC with AH Plus sealer and SBO with Endoseal TCS. Patients were assessed for the level of postoperative pain using a numeric rating scale. The quality of root canal obturation was evaluated in terms of the sealer extrusion, root-filling voids, and level of root filling. The participants were recalled after at least 6 months. Healing of the teeth was determined as a decrease in Periapical Index score and resolution of symptoms. The results were statistically compared by using the χ2 test or Fisher exact test, followed by multivariate analysis with logistic regression.
A total of 74 teeth were included in the analysis (79% recalls), and the mean follow-up period was 17 months (6–29 months). Two groups expressed identical distribution of postoperative pain (P = .973) and similar quality of root canal obturation. The total success rates were 93.2% (CWC 92.3%, SBO 94.3%) by loose criteria and 60.8% (CWC 51.3%, SBO 71.4%) by strict criteria, with no significant differences between the 2 groups. The success rate by loose criteria in teeth with sealer extrusion was significantly lower than those in teeth without sealer extrusion (P = .049).
SBO using an Endoseal TCS could be a possible alternative to CWC using AH Plus. Sealer extrusion and postoperative pain were found to negatively impact prognosis of the endodontic treatment.
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