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The advancement of electrolyte systems has enabled the development of high-performance Li metal batteries (LMBs), which have tackled intractable dendritic Li growth and irreversible Li plating/stripping. In particular, the robust electrode–electrolyte interfaces created by electrolyte additives inhibit the deterioration of the cathode and the Li metal anode during repeated cycles. This paper reports the application of electrode–electrolyte interface modifiers, namely lithium nitrate (LiNO3) and lithium difluoro(bisoxalato) phosphate (LiDFBP) as a N donor and F donor, respectively. LiDFBP and LiNO3 with different electron-accepting abilities construct a mechanically robust, LiF-rich inner solid electrolyte interphase (SEI) and ion-permeable, Li3N-containing outer SEI layers on the Li metal anode, respectively. A well-structured dual-layer SEI capable of transporting Li+ ions is formed on the Li metal anode, while the cathode–electrolyte interface (CEI) on the LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode is strengthened. Ether-based electrolytes containing LiDFBP and LiNO3 lead to a long cycle life (600 cycles) of Li|NCM811 full cells at C/2 with 80.9% capacity retention and a high Coulombic efficiency (CE) of 99.94%. Structural optimization of the SEI and CEI provides an opportunity for advancing the practical uses of LMBs.

Background Hereditary cerebellar ataxias exhibit heterogeneous phenotypes and genotypes. To date, advancement of next-generation sequencing technologies have identified many causative genes for ataxia in various population. In this study, whole-exome sequencing (WES) was utilized to explore the genetic cause of ataxia among Korean patients who remained undiagnosed following routine investigation. Methods Patients with ataxia were enrolled in this study. We excluded patients with acquired, degenerative, and trinucleotide repeat ataxias, such as spinocerebellar ataxia 1 (SCA1), SCA2, SCA3, SCA6, SCA7, SCA8, SCA17, Dentatorubral-pallidoluysian atrophy, and Friedreich ataxia. WES was performed. After basic filtering based on population databases, we then performed primary filtering to screen for known ataxia-associated genes, followed by expanded filtering customized for individual patients. Results We enrolled 77 ataxia patients from 68 families. Eighteen families had pathogenic or likely pathogenic variants in 14 different genes, including NEU1, APTX, SPG7, HTRA1, POLG2, SYNE1, CACNA1G, CACNA1A, ITPR1, AHI1, SPG11, ANO10, ATM, and C5orf42, resulting in a diagnostic yield of 26.5%. Hereditary spastic paraplegia was the most common diagnosis. Adult-onset ataxias and those without family history were frequently encountered. Variants of unknown significance were found in 14 (20.6%) families, some of which were highly probable from the clinical perspective. Conclusion Using WES, we explored the molecular etiology of ataxia in patients whom were not diagnosed through routine clinical investigation. This study revealed unexpected rare disorders as well as the known ataxia-associated genes in a Korean population.

Spastin is a microtubule-severing enzyme encoded by SPAST, which is broadly expressed in various cell types originated from multiple organs. Even though SPAST is well known as a regulator of the axon growth and arborization in neurons and a genetic factor of hereditary spastic paraplegia, it also takes part in a wide range of other cellular functions including the regulation of cell division and proliferation. In this study, we investigated a novel biological role of spastin in developing brain using Spast deficient mouse embryonic neural stem cells (NSCs) and perinatal mouse brain. We found that the expression of spastin begins at early embryonic stages in mouse brain. Using Spast shRNA treated NSCs and mouse brain, we showed that Spast deficiency leads to decrease of NSC proliferation and neuronal lineage differentiation. Finally, we found that spastin controls NSC proliferation by regulating microtubule dynamics in primary cilia. Collectively, these data demonstrate that spastin controls brain development by the regulation of NSC functions at early developmental stages.

Introduction Recent advances in next generation sequencing technologies have uncovered the genetic background of various diseases. The mutations in the SYNE1 gene was previously identified as a potential cause of pure cerebellar ataxia. Although autosomal recessive ataxias are slightly more frequent than autosomal dominant forms worldwide, autosomal recessive forms are extremely rare in Korea. In this study, we aimed to identify SYNE1-associated ataxia by whole exome sequencing in a Korean sample, and to review the prevalence of SYNE1 in non-French-Canadians. Methods Patients with suspected cerebellar ataxia who visited movement disorders clinic from March 2014 to December 2017 were clinically screened. After excluding cases with acquired causes and common genetic causes in Korea, including spinocerebellar ataxia and dentatorubral-pallidoluysian atrophy, 63 undiagnosed subjects were screened for SYNE1 mutations by next generation sequencing methods. Results We identified four novel mutations (one splicing, one truncating, and two missense mutations) distributed throughout the SYNE1 gene in two patients. The phenotype was mainly pure cerebellar ataxia in both cases. However, axonal neuropathy, mild frontal dysfunction, and autonomic dysfunction were also revealed. The age of disease onset was relatively late and the disease course was only mildly progressive. Conclusion Our results indicate that SYNE1 mutations are not an uncommon cause of recessive ataxia with additional clinical features in the Korean population. The results of this study should alert neurologists to request SYNE1 testing to aid the diagnosis of undetermined adult-onset ataxia in Korean patients.

Background: Ginsenosides, which are bioactive components in ginseng, can be converted to smaller compounds for improvement of their pharmacological activities. The conversion methods include heating; acid, alkali, and enzymatic treatment; and microbial conversion. The aim of this study was to determine the bioconversion of ginsenosides in fermented red ginseng extract (FRGE). Methods: Red ginseng extract (RGE) was fermented using Lactobacillus plantarum KCCM 11613P. This study investigated the ginsenosides and their antioxidant capacity in FRGE using diverse methods. Results: Properties of RGE were changed upon fermentation. Fermentation reduced the pH value, but increased the titratable acidity and viable cell counts of lactic acid bacteria. L. plantarum KCCM 11613P converted ginsenosides Rb2 and Rb3 to ginsenoside Rd in RGE. Fermentation also enhanced the antioxidant effects of RGE. FRGE reduced 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and reducing power; however, it improved the inhibition of β-carotene and linoleic acid oxidation and the lipid peroxidation. This suggested that the fermentation of RGE is effective for producing ginsenoside Rd as precursor of ginsenoside compound K and inhibition of lipid oxidation. Conclusion: This study showed that RGE fermented by L. plantarum KCCM 11613P may contribute to the development of functional food materials. Keywords: antioxidant effect, bioconversion, ginsenoside, Lactobacillus plantarum KCCM 11613P, red ginseng extract

The spastin protein (SPAST) contains an ATPase with diverse cellular activities (AAA) domain and regulates microtubule dynamics. Missense mutations of the SPAST gene are frequently detected in patients with hereditary spastic paraplegias (HSPs) and represent the main reason of loss of SPAST function; however, the pathogenicity of mutant SPAST is heterogeneous. Here, SPAST variant with an I344K mutation (I344K-SPAST) was identified in a Korean family with autosomal dominant-type HSP. We investigated the role of the I344K-SPAST in HSP to provide a therapeutic mechanism. The I344K-SPAST mutation prolonged the half-life of the protein compared to wild-type SPAST (WT-SPAST) in cells by modulating post-translational modifications for proteasomal degradation. I344K-SPAST was localized in microtubule but defective in microtubule severing and ATPase activity compared to WT-SPAST in vitro and in cells. Mutant M87 isoform harboring the same mutation with I344K-M1 SPAST also increased protein stability and loss of MT severing activity, but the pathogenicity was not stronger than I344K-M1 SPAST in neurite outgrowth. Overexpression of I344K-SPAST resulted in microtubule accumulation following inhibited neurite growth in neuroblastoma, neural progenitor cells and mouse primary cortical neurons. Conversely, these pathogenic effects of I344K-SPAST were reduced by overexpression of WT-M1 SPAST in a dose dependent manner since WT-SPAST could interact with I344K-SPAST. Our data therefore provide proof-of-concept that gene transfer of WT-M1 SPAST may serve as a valid therapeutic option for HSPs.

For application to electric vehicles, the fast charging of lithium-ion batteries is required. However, lithium-ion batteries are faced with undesirable Li plating causing the capacity fading with low Coulombic efficiency at high charge rates. Here, we present the effects of solid electrolyte interphase structures of the graphite anode and linear carbonate solvents on fast charging capability of LiNi0.6Co0.2Mn0.2O2/graphite full cells. To control the nature of the interfacial layer on the graphite anode affecting the Li plating behavior, we exploit three kinds of additives, ethylene carbonate, fluoroethylene carbonate and vinylene carbonate, as anode solid electrolyte interphase formers. In addition, the effect of ethyl methyl carbonate and dimethyl carbonate on the solvation and transport of high concentrations of Li ions de-intercalated from the LiNi0.6Co0.2Mn0.2O2 cathode in a full cell at high charge rates is explored in fluoroethylene carbonate-based electrolytes. Our investigation reveals that the combination of fluoroethylene carbonate and dimethyl carbonate in the electrolyte enables fast-charging LiNi0.6Co0.2Mn0.2O2/graphite full cells showing the excellent capacity retention of 79% after 1000 cycles at a high charging current density of 6 mA cm−2, corresponding to 2C, and a discharge rate of 1C without Li plating on the graphite anode.

An ethyl 4,4,4-trifluorobutyrate (ETFB) additive, with ester and partially fluorinated alkyl moieties, is employed to stabilize the interface structure of Ni-rich layered LiNi0.7Co0.15Mn0.15O2 (NCM) cathodes and graphite anodes. The analysis of the surface chemistry of the electrodes shows that ETFB serves as a bifunctional additive for constructing protective layers on both electrodes in a full cell. Cycling tests reveal that the addition of 1% ETFB leads to excellent capacity retention (84.8%) for the NCM/graphite full cell, which also delivers a superior discharge capacity of 167 mAh g−1 and a high Coulombic efficiency of over 99.8% after 300 cycles at 45 °C. The ETFB-derived protective layer effectively reduces intergranular cracking in secondary NCM cathode particles upon repeated charge-discharge cycling and limits the dissolution of transition metal ions from the cathode at high temperatures. In addition, after ETFB reduction, the graphite anode develops a thermally stable interface structure, which suppresses the self-discharge of graphite coupled with the NCM cathode at 60 °C.

Current in vitro liver models provide three-dimensional (3-D) microenvironments in combination with tissue engineering technology and can perform more accurate in vivo mimicry than two-dimensional models. However, a human cell-based, functionally mature liver model is still desired, which would provide an alternative to animal experiments and resolve low-prediction issues on species differences. Here, we prepared hybrid hydrogels of varying elasticity and compared them with a normal liver, to develop a more mature liver model that preserves liver properties in vitro . We encapsulated HepaRG cells, either alone or with supporting cells, in a biodegradable hybrid hydrogel. The elastic modulus of the 3D liver dynamically changed during culture due to the combined effects of prolonged degradation of hydrogel and extracellular matrix formation provided by the supporting cells. As a result, when the elastic modulus of the 3D liver model converges close to that of the in vivo liver (≅ 2.3 to 5.9 kPa), both phenotypic and functional maturation of the 3D liver were realized, while hepatic gene expression, albumin secretion, cytochrome p450-3A4 activity, and drug metabolism were enhanced. Finally, the 3D liver model was expanded to applications with embryonic stem cell-derived hepatocytes and primary human hepatocytes, and it supported prolonged hepatocyte survival and functionality in long-term culture. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Statement of Significance We provide a functionally improved 3D liver model that recapitulates in vivo liver stiffness. We have experimentally addressed the issues of orchestrated effects of mechanical compliance, controlled matrix formation by stromal cells in conjunction with hepatic differentiation, and functional maturation of hepatocytes in a dynamic 3D microenvironment. Our model represents critical progress in developing a biomimetic liver system to simulate liver tissue remodeling, and provides a versatile platform in drug development and disease modeling, ranging from physiology to pathology. Additionally, recent advances in the stem-cell technologies have made the development of 3D organoid possible, and thus, our study also provides further contribution to the development of physiologically relevant stem-cell-based 3D tissues that provide an elasticity-based predefined biomimetic 3D microenvironment.

Lithium difluoro(oxalato)borate (LiDFOB) with one oxalate moiety bonded to a central boron core was employed as a salt-type additive to enhance the interfacial stabilities of high-voltage Li-rich cathodes and graphite anodes. Our investigation revealed that the LiDFOB additive modified the surface film on the electrodes and effectively restrained degradation of the cycling performance of the electrodes. Investigation of the surface chemistries of the electrodes confirmed that LiDFOB produces a LiF-less surface film on the Li-rich cathode and a LiF-rich surface film on the graphite anode. Moreover, the use of 1% LiDFOB drastically improved the rate capabilities of Li-rich cathodes and graphite anodes. Within 100 cycles at a rate of C/2 at 25 °C, only 45.8% of the initial discharge capacity of a high-voltage Li-rich/graphite full cell was delivered in the baseline electrolyte, while the LiDFOB-containing electrolyte retained 82.7%.

The cycling and storage performances of LiCoO 2 (LCO)-LiNi 0.5 Co 0.2 Mn 0.3 O 2 (NCM)/pitch-coated silicon alloy-graphite (Si-C) full cells with ethylene carbonate (EC)–based and fluoroethylene carbonate (FEC)–based electrolytes are investigated at elevated temperatures. Excess FEC (used as a co-solvent in LiPF 6 -based electrolytes), which is not completely consumed during the formation of the solid electrolyte interphase (SEI) layer on the electrodes, is prone to defluorination in the presence of Lewis acids such as PF 5 ; this reaction can generate unwanted HF and various acids (H 3 OPF 6 , HPO 2 F 2 , H 2 PO 3 F, H 3 PO 4 ) at elevated temperatures. Our investigation reveals that the HF and acid compounds that are formed by FEC decomposition causes significant dissolution of transition metal ions (from the LCO-NCM cathode) into the electrolyte at elevated temperatures; as a result, the reversible capacity of the full cells reduces because of the deposition of the dissolved metal ions onto the anode. Moreover, we demonstrate possible mechanisms that account for the thermal instability of FEC in LiPF 6 -based electrolytes at elevated temperatures using model experiments.

Background & Aims Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is suggested as a proto-oncogene. Paradoxically, SQLE is degraded by excess cholesterol, and low SQLE is associated with aggressive colorectal cancer (CRC). Therefore, we studied the functional consequences of SQLE reduction in CRC progression. Methods Gene and protein expression data and clinical features of CRCs were obtained from public databases and 293 human tissues, analyzed by immunohistochemistry. In vitro studies showed underlying mechanisms of CRC progression mediated by SQLE reduction. Mice were fed a 2% high-cholesterol or a control diet before and after cecum implantation of SQLE genetic knockdown/control CRC cells. Metastatic dissemination and circulating cancer stem cells were demonstrated by in vivo tracking and flow cytometry analysis, respectively. Results In vitro studies showed that SQLE reduction helped cancer cells overcome constraints by inducing the epithelial-mesenchymal transition required to generate cancer stem cells. Surprisingly, SQLE interacted with GSK3β and p53. Active GSK3β contributes to the stability of SQLE, thereby increasing cell cholesterol content, whereas SQLE depletion disrupted the GSK3β/p53 complex, resulting in a metastatic phenotype. This was confirmed in a spontaneous CRC metastasis mice model, where SQLE reduction, by a high-cholesterol regimen or genetic knockdown, strikingly promoted CRC aggressiveness through the production of migratory cancer stem cells. Conclusions We showed that SQLE reduction caused by cholesterol accumulation aggravates CRC progression via the activation of the β-catenin oncogenic pathway and deactivation of the p53 tumor suppressor pathway. Our findings provide new insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC aggressiveness and a prognostic biomarker.

Nanostructured silicon is a promising candidate material for practical use in energy storage devices. However, high temperature operation remains a significant challenge because of severe electrochemical side reactions. Here, we show the design of ultra-durable silicon made by introducing dual coating layers on the silicon surface, allowing stable operation at high temperature. The double layers, which consist of amorphous metal titanate and carbon, provide several advantages including: (i) suppression of volume expansion during Li + insertion; (ii) creation of a stable solid-electrolyte−interface layer; and (iii) preservation of original Si morphology over 600 cycles at high temperature. The resulting silicon-based anode exhibits a reversible capacity of 990 mA h g −1 after 500 cycles at 25 °C and 1300 mA h g −1 after 600 cycles at 60 °C with a rate of 1 C.

Employing linear carbonates such as dimethyl carbonate (DMC), ethyl methyl carbonate (EMC), and diethyl carbonate (DEC) as electrolyte solvents provides an opportunity to design appropriate electrolyte systems for high-performance sodium-ion batteries (SIBs). However, in practice, the use of linear carbonate-containing electrolytes is quite challenging because linear carbonates readily decompose at Na metal electrodes or sodiated anodes. One of the promising approaches is using an electrolyte additive to resolve the critical problems related to linear carbonates. Our investigation reveals that remarkable enhancement in electrochemical performance of Na 4 Fe 3 (PO 4 ) 2 (P 2 O 7 ) cathodes with linear carbonate-containing electrolytes is achieved by using a fluoroethylene carbonate (FEC) additive. Importantly, the initial Coulombic efficiency of the Na deposition/stripping on a stainless steel (SS) electrode is drastically improved from 16% to 90% by introducing the FEC additive into ethylene carbonate (EC)/propylene carbonate (PC)/DEC (5/3/2, v/v/v)/0.5 M NaClO 4 . The underlying mechanism of FEC at the electrode-electrolyte interface is clearly demonstrated by 13 C nuclear magnetic resonance (NMR). In addition, the Na 4 Fe 3 (PO 4 ) 2 (P 2 O 7 ) cathode in EC/PC/DEC (5/3/2, v/v/v)/0.5 M sodium perchlorate (NaClO 4 ) with FEC delivers a discharge capacity of 90.5 mAh g −1 at a current rate of C/2 and exhibits excellent capacity retention of 97.5% with high Coulombic efficiency of 99.6% after 300 cycles at 30 °C.

A family of organophosphorus compounds including triphenyl phosphite (TPP), trimethyl phosphite (TMP), tris(2,2,2-trifluoroethyl) phosphite (TFEP), and tris(trimethylsilyl) phosphite (TMSP) is investigated as additives for the stabilization of high-voltage LiNi 0.5 Mn 1.5 O 4 (LNMO) cathode-electrolyte interface. Our investigation reveals that the cycling performance of Li/LNMO half cells with the TMP, TFEP or TMSP additive is drastically improved at 60 °C compared to the baseline electrolyte. Among the various phosphite-based additives tested, TMSP additive enables facile Li ion transport at high C rates and significantly enhances the storage performance of the Li/LNMO cells at 60 °C. To understand the effects of the phosphite-based additives on electrolyte oxidative decomposition at high voltages, the surface chemistry of the cathode after precycling is investigated via ex-situ X-ray photoelectron spectroscopy (XPS). Additionally, the roles of phosphite-based additives to suppress LiPF 6 hydrolysis and to remove HF are examined via 19 F and 31 P NMR spectroscopies.

Fast-charging lithium-ion batteries (LIBs) can be achieved using structurally optimized electrodes and electrolytes. Electrolytes largely affect the interfacial structures of electrodes that are critical to reducing charging time of LIBs without sacrificing battery durability. However, most widely used LiPF6-based electrolytes suffer from reactive species, such as HF and PF5, that seriously damage interfacial structures of electrodes on repeated cycling and form resistive species at the electrode surface that hamper the fast charging of LIBs. To resolve these detrimental effects of LiPF6-based electrolytes, we report an electrolyte additive, (trimethylsilyl)isothiocyanate (TMSNCS) based on aminosilane, with a high electron donating ability that can scavenge HF and PF5. TMSNCS effectively deactivates reactive species and attains long-term stability of interfacial layers formed on anodes and cathodes in LiPF6-based electrolytes. After 300 cycles at a 2C charge rate and a 1C discharge rate, the NCM622/graphite full cell with 0.1% TMSNCS delivers a superior discharge capacity of 144 mAh/g and exhibits an excellent capacity retention of 91.8%. Furthermore, the stabilization of PF5 by the TMSNCS additive drastically alleviates undesired decomposition reactions of fluoroethylene carbonate (FEC) and enhances high-temperature performances of the FEC-containing full cells.