Potato miR394 targets StA/N-INVE and StLCR to negatively regulate late blight resistance.

MicroRNAs (miRNAs) are small noncoding RNAs in eukaryotes. Plant endogenous miRNAs play pivotal roles in regulating plant development and defense responses. MicroRNA394 (miR394) has been reported to regulate plant development, abiotic stresses and defense responses. Previous reports showed that miR394 responded to P. infestans inoculation in potato, indicating that miR394 may be involved in defense responses. In this study, we further investigated its role in potato defense against P. infestans. Stable expression of miR394 in tobacco and potato enhances the susceptibility to P. infestans, which is accompanied with the reduced accumulation of ROS and down-regulation of the PTI (pattern-triggered immunity) marker genes. Besides well-known target StLCR, miR394 also targets StA/N-INVE, which encodes a chloroplast Alkaline/Neutral Invertases (A/N-INVE). Both StLCR and StA/N-INVE positively regulate late blight resistance, while miR394 degrades them. Interestingly, StA/N-INVE is located in the chloroplast, indicating that miR394 may manipulate chloroplast immunity. Degradation of StA/N-INVE may affect the chloroplast function and hence lead to the compromised ROS (reactive oxygen species) burst and reduced retrograde signaling from the chloroplast to the nucleus and cytoplasm. In summary, this study provides new information that miR394 targets and degrades StA/N-INVE and StLCR, which are positive regulators, to enhance potato susceptibility to P. infestans.

Mechanism of Porphyra Yezoensis Polysaccharides in Inhibiting Hyperoxalate-Induced Renal Injury and Crystal Deposition.

Oxidative damage to the kidneys is a primary factor in the occurrence of kidney stones. This study explores the inhibitory effect of Porphyra yezoensis polysaccharides (PYP) on oxalate-induced renal injury by detecting levels of oxidative damage, expression of adhesion molecules, and damage to intracellular organelles and revealed the molecular mechanism by molecular biology methods. Additionally, we validated the role of PYP in vivo using a crystallization model of hyperoxalate-induced rats. PYP effectively scavenged the overproduction of reactive oxygen species (ROS) in HK-2 cells, inhibited the adhesion of calcium oxalate (CaOx) crystals on the cell surface, unblocked the cell cycle, restored the depolarization of the mitochondrial membrane potential, and inhibited cell death. PYP upregulated the expression of antioxidant proteins, including Nrf2, HO-1, SOD, and CAT, while decreasing the expression of Keap-1, thereby activating the Keap1/Nrf2 signaling pathway. PYP inhibited CaOx deposition in renal tubules in the rat crystallization model, significantly reduced high oxalate-induced renal injury, decreased the levels of the cell surface adhesion proteins, improved renal function in rats, and ultimately inhibited the formation of kidney stones. Therefore, PYP, which has crystallization inhibition and antioxidant properties, may be a therapeutic option for the treatment of kidney stones.

Histone deacetylase 6 suppression of renal tubular epithelial cell promotes interstitial mineral deposition via alpha-tubulin acetylation.

Randall's plaque (RP) is derived from interstitial mineral deposition and is highly prevalent in renal calcium oxalate (CaOx) stone disease, which is predictive of recurrence. This study shows that histone deacetylase 6 (HDAC6) levels are suppressed in renal tubular epithelial cells in RP samples, in kidney tissues of hyperoxaluria rats, and in hyper-oxalate-treated or mineralized cultured renal tubular epithelial (MDCK) cells in vitro. Mineral deposition in MDCK cells was exacerbated by HDAC6 inhibition but alleviated by HDAC6 overexpression. Surprisingly, the expression of some osteogenic-associated proteins, were not increased along with the increasing of mineral deposition, and result of single-cell RNA sequencing of renal papillae samples revealed that epithelial cells possess lower calcific activity, suggesting that osteogenic-transdifferentiation may not have actually occurred in tubular epithelial cells despite mineral deposition. The initial mineral depositions facilitated by HDAC6 inhibitor were localized in extracellular dome rather than inside the cells, moreover, suppression of HDAC6 significantly increased the calcium content of co-cultured renal interstitial fibroblasts (NRK49F) and enhanced mineral deposition of indirectly co-cultured NRK49F cells, suggesting that HDAC6 may influence trans-MDCK monolayer secretion of mineral. Further experiments revealed that this regulatory role was partially alpha-tubulinLys40 acetylation dependent. Collectively, these results suggest that hyper-oxalate exposure led to HDAC6 suppression in renal tubular epithelial cells, which may contribute to interstitial mineral deposition by promoting alpha-tubulinLys40 acetylation. Therapeutic agents that influence HDAC6 activity may be beneficial in preventing RP and CaOx stone formation.

Recent Progress of Remediating Heavy Metal Contaminated Soil Using Layered Double Hydroxides as Super-Stable Mineralizer.

Heavy metal contamination in soil, which is harmful to both ecosystem and mankind, has attracted worldwide attention from the academic and industrial communities. However, the most-widely used remediation technologies such as electrochemistry, elution, and phytoremediation. suffer from either secondary pollution, long cycle time or high cost. In contrast, in situ mineralization technology shows great potential due to its universality, durability and economical efficiency. As such, the development of mineralizers with both high efficiency and low-cost is the core of in situmineralization. In 2021, the concept of 'Super-Stable Mineralization' was proposed for the first time by Kong et al.[1] The layered double hydroxides (denoted as LDHs), with the unique host-guest intercalated structure and multiple interactions between the host laminate and the guest anions, are considered as an ideal class of materials for super-stable mineralization. In this review, we systematically summarize the application of LDHs in the treatment of heavy metal contaminated soil from the view of: 1) the structure-activity relationship of LDHs in in situ mineralization, 2) the advantages of LDHs in mineralizing heavy metals, 3) the scale-up preparation of LDHs-based mineralizers and 4) the practical application of LDHs in treating contaminated soil. At last, we highlight the challenges and opportunities for the rational design of LDH-based mineralizer in the future.

Band Gap and Defect Engineering Enhanced Scintillation from Ce3+-Doped Nanoglass Containing Mixed-Type Fluoride Nanocrystals.

Much can be learned from the research and development of scintillator crystals for improving the scintillation performance of glasses. Relying on the concept of "embedding crystalline order in glass", we have demonstrated that the scintillation properties of Ce3+-doped nanoglass composites (nano-GCs) can be optimized via the synergistic effects of Gd3+-sublattice sensitization and band-gap engineering. The nano-GCs host a large volume fraction of KYxGd1-xF4 mixed-type fluoride nanocrystals (NCs) and still retain reasonably good transparency at Ce3+-emitting wavelengths. The light yield of 3455 ± 20 ph/MeV is found, which is the largest value ever reported in fluoride NC-embedded nano-GCs. A comprehensive study is given on the highly selective doping of Ce3+ in the NCs and its positive effect on the scintillation properties. The favorable influence of the Y3+/Gd3+ mixing on the suppression of defects is accounted for by density functional theory and borne out experimentally. As a proof-of-concept, X-ray imaging with a good spatial resolution (7.9 lp/mm) is demonstrated by employing Ce3+-doped nano-GCs. The superior radiation hardness, repeatability, and thermal stability of the designed scintillators bode well for their long-term practical applications.

Effect of deoxynivalenol on inflammatory injury on the glandular stomach in chick embryos.

Deoxynivalenol (DON) has a strong toxic effect on the gastrointestinal mucosa of poultry. In this study, we evaluated chicken embryo development and glandular stomach damage to clarify the immunotoxic effects of DON injected through the allantoic cavity of chicken embryos. The glandular stomach index, routine blood indices, plasma inflammatory factors, pathological changes in the glandular stomach, and transcriptome results were analyzed in the hatching chicks. The results showed that DON was supertoxic to chicken embryos, causing edema, shedding, and bleeding of the mucosa of the glandular stomach, which triggered inflammatory reactions. As the toxin concentration increased, the immune system was successively activated and inhibited, and regulation was carried out by the differential regulation of the mitogen-activated protein kinase (MAPK) signal pathway. These results suggested that the immunotoxic effect of DON on the glandular stomach of chicken embryos was closely related to the regulation of the MAPK signaling pathway.

Corn Silk Polysaccharides with Different Carboxyl Contents Reduce the Oxidative Damage of Renal Epithelial Cells by Inhibiting Endocytosis of Nano-calcium Oxalate Crystals.

OBJECTIVE: Renal epithelial cell injury and cell-crystal interaction are closely related to kidney stone formation. METHODS: This study aims to explore the inhibition of endocytosis of nano-sized calcium oxalate monohydrate (nano-COM) crystals and the cell protection of corn silk polysaccharides (CCSPs) with different carboxyl contents (3.92, 7.75, 12.90, and 16.38%). The nano-COM crystals protected or unprotected by CCSPs were co-cultured with human renal proximal tubular epithelial cells (HK-2), and then the changes in the endocytosis of nano-COM and cell biochemical indicators were detected. RESULTS: CCSPs could inhibit the endocytosis of nano-COM by HK-2 cells and reduce the accumulation of nano-COM in the cells. Under the protection of CCSPs, cell morphology is restored, intracellular superoxide dismutase levels are increased, lipid peroxidation product malondialdehyde release is decreased, and mitochondrial membrane potential and lysosomal integrity are increased. The release of Ca2+ ions in the cell, the level of cell autophagy, and the rate of cell apoptosis and necrosis are also reduced. CCSPs with higher carboxyl content have better cell protection abilities. CONCLUSION: CCSPs could inhibit the endocytosis of nano-COM crystals and reduce cell oxidative damage. CCSP3, with the highest carboxyl content, shows the best biological activity.

LEM Domain Containing 1 Acts as a Novel Oncogene and Therapeutic Target for Triple-Negative Breast Cancer.

Breast cancer is the most common deadly malignancy in women worldwide. In particular, triple-negative breast cancer (TNBC) exhibits the worst prognosis among four subtypes of breast cancer due to limited treatment options. Exploring novel therapeutic targets holds promise for developing effective treatments for TNBC. Here, we demonstrated for the first time that LEMD1 (LEM domain containing 1) is highly expressed in TNBC and contributes to reduced survival in TNBC patients, through analysis of both bioinformatic databases and collected patient samples. Furthermore, LEMD1 silencing not only inhibited the proliferation and migration of TNBC cells in vitro, but also abolished tumor formation of TNBC cells in vivo. Knockdown of LEMD1 enhanced the sensitivity of TNBC cells to paclitaxel. Mechanistically, LEMD1 promoted the progress of TNBC by activating the ERK signaling pathway. In summary, our study revealed that LEMD1 may act as a novel oncogene in TNBC, and targeting LEMD1 may be exploited as a promising therapeutic approach to enhance the efficacy of chemotherapy against TNBC.

The association of sex steroid hormone concentrations with hearing loss: a cross-sectional study.

BACKGROUND: Hearing loss is the most prevalent sensory disorder worldwide. Several studies have indicated that sex steroid hormone levels may be vital to hearing. OBJECTIVE: We aimed to explore the associations between speech-frequency hearing loss and sex steroid hormones. METHODS: We conducted a secondary analysis based on 3558 adult participants' data from the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2016. We defined hearing loss as a pure-tone average (PTA) at 0.5, 1, 2, and 4 kHz ≥20 dB in the better ear. Multivariate logistic regression analysis was used to evaluate the association between sex steroid hormones and hearing loss risk. A nomogram model for the risk of hearing loss was constructed. RESULTS: There were 560 (15.7%) cases who had hearing loss among the participants enrolled in this study. Participants with hearing loss had a higher total testosterone level and a lower estradiol level. Individuals with estradiol levels in the highest tertile still had lower hearing loss risks than those in the lowest tertile. Nevertheless, the total testosterone level had no influence on the risk of hearing loss. CONCLUSION: Our research indicated that low estradiol concentrations were significantly associated with hearing loss, especially in menopausal women.

Targeting lncRNA DDIT4-AS1 Sensitizes Triple Negative Breast Cancer to Chemotherapy via Suppressing of Autophagy.

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both in vitro and in vivo. Using a self-activatable siRNA/drug core-shell nanoparticle system, which effectively deliver both DDIT4-AS1 siRNA and paclitaxel to the tumor-bearing mice, a significantly enhanced antitumor activity is achieved. Importantly, the codelivery nanoparticles exert a stronger antitumor effect on breast cancer patient-derived organoids. These findings indicate that lncRNA DDIT4-AS1-mediated activation of autophagy promotes progression and chemoresistance of TNBC, and targeting of DDIT4-AS1 may be exploited as a new therapeutic approach to enhancing the efficacy of chemotherapy against TNBC.

Cell Protection and Crystal Endocytosis Inhibition by Sulfated Laminaria Polysaccharides Against Nano-COM-Induced Oxidative Damage in Renal Epithelial Cells.

Background: The damage to renal tubular epithelial cells is closely related to the formation of kidney stones. At present, research on drugs that can protect cells from damage remains limited. Methods: This study aims to explore the protective effects of four different sulfate groups (-OSO3 -) of Laminaria polysaccharides (SLPs) on human kidney proximal tubular epithelial (HK-2) cells and determine the difference in the endocytosis of nano-sized calcium oxalate monohydrate (COM) crystals before and after protection. COM with a size of 230 ± 80 nm was used to damage HK-2 cells to establish a damage model. The protection capability of SLPs (LP0, SLP1, SLP2, and SLP3) with -OSO3 - contents of 0.73, 15, 23, and 31%, respectively, against COM crystal damage and the effect of SLPs on the endocytosis of COM crystals were studied. Results: Compared with that of the SLP-unprotected COM-injured group, the cell viability of the SLP-protected group was improved, healing capability was enhanced, cell morphology was restored, production of reactive oxygen species was reduced, mitochondrial membrane potential and lysosome integrity were increased, intracellular Ca2+ level and autophagy were decreased, cell mortality was reduced, and internalized COM crystals were lessened. The capability of SLPs to protect cells from damage and inhibit the endocytosis of crystals in cells enhanced with an increase in the -OSO3 - content of SLPs. Conclusions: SLPs with a high -OSO3 - content may become a potential green drug for preventing the formation of kidney stones.

Identification of miRNAs Involving Potato-Phytophthora infestans Interaction.

sRNAs (small RNAs) play an important role in regulation of plant immunity against a variety of pathogens. In this study, sRNA sequencing analysis was performed to identify miRNAs (microRNAs) during the interaction of potato and Phytophthora infestans. Totally, 171 potato miRNAs were identified, 43 of which were annotated in the miRNA database and 128 were assigned as novel miRNAs in this study. Those potato miRNAs may target 878 potato genes and half of them encode resistance proteins. Fifty-three potato miRNAs may target 194 P. infestans genes. Three potato miRNAs (novel 72, 133, and 140) were predicted to have targets only in the P. infestans genome. miRNAs transient expression and P. infestans inoculation assay showed that miR396, miR166, miR6149-5P, novel133, or novel140 promoted P. infestans colonization, while miR394 inhibited colonization on Nicotiana benthamiana leaves. An artificial miRNA target (amiRNA) degradation experiment demonstrated that miR394 could target both potato gene (PGSC0003DMG400034305) and P. infestans genes. miR396 targets the multicystatin gene (PGSC0003DMG400026899) and miR6149-5p could shear the galactose oxidase F-box protein gene CPR30 (PGSC0003DMG400021641). This study provides new information on the aspect of cross-kingdom immune regulation in potato-P. infestans interaction at the sRNAs regulation level.

New role of gramicidin A in RIG-I-like receptors-mediated IFN signalling.

The pattern recognition receptors (PRRs) sense exogenous molecular patterns most commonly derived from invading pathogens, to active the interferon (IFN) signalling. In the cytoplasm, the viral double-stranded RNAs (dsRNAs) are sensed by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5), depending on the length and chemical properties. Through the binding and oligomerizing onto the RNAs, they form filament to initiate the signalling cascade. Regulation of these receptors' activities are essential for manipulating the strength of IFN signalling. Here, through the virtual screening of chemical reagents using the published MDA5-dsRNA complex structure (PDB: 4GL2), we identified an antibiotic, gramicidin A as a stimulator that enhanced MDA5-mediated IFN signalling. Cytotoxic assay and IFN signalling assay suggested that disruption of lipid membrane, which is a well-defined mechanism of gramicidin A to perform its action, was dispensable in this process. Sucrose gradient ultracentrifugation assay showed that the gramicidin A treatment enhanced MDA5 oligomerization status in the presence of dsRNA. Our work implicated a new role of gramicidin A in innate immunity and presented a new tool to manipulate MDA5 activity.

Designing Intelligent Nanomaterials to Achieve Highly Sensitive Diagnoses and Multimodality Therapy of Bladder Cancer.

Bladder cancer (BC) is among the most common malignant tumors of the genitourinary system worldwide. In recent years, the rate of BC incidence has increased, and the recurrence rate is high, resulting in poor quality of life for patients. Therefore, how to develop an effective method to achieve synchronous precise diagnoses and BC therapies is a difficult problem to solve clinically. Previous reports usually focus on the role of nanomaterials as drug delivery carriers, while a summary of the functional design and application of nanomaterials is lacking. Summarizing the application of functional nanomaterials in high-sensitivity diagnosis and multimodality therapy of BC is urgently needed. This review summarizes the application of nanotechnology in BC diagnosis, including the application of nanotechnology in the sensoring of BC biomarkers and their role in monitoring BC. In addition, conventional and combination therapies strategy in potential BC therapy are analyzed. Moreover, different kinds of nanomaterials in BC multimodal therapy according to pathological features of BC are also outlined. The goal of this review is to present an overview of the application of nanomaterials in the theranostics of BC to provide guidance for the application of functional nanomaterials to precisely diagnose and treat BC.

Accurate diagnosis of prostate cancer with CRISPR-based nucleic acid test strip by simultaneously identifying PCA3 and KLK3 genes.

Although serum prostate specific antigen (PSA) testing could decrease the morality of prostate cancer (PCa), its low specificity usually led to misdiagnosis due to prostatitis or benign prostatic hyperplasia (BPH). Prostate cancer antigen 3 (PCA3) as an alternative prostate tumor-specificity biomarker could be used to increase the specificity of PCa diagnosis, however, it usually required sophisticated operation and expensive equipment for routine detection. Herein, we constructed an early detection platform for prostate cancer with reverse transcriptase-recombinase aided amplification (RT-RAA) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 based nucleic acid test strip. The amplicons of PCA3 and kallikrein related peptidase 3 (KLK3) gene, which amplified simultaneously by single-amplification unit of RT-RAA were specifically recognized by Cas9-sgRNA and visual on the nucleic acid test strip by naked eyes without instruments. Simultaneously detection of PCA3 and KLK3 gene could improve specificity and accuracy of the diagnosis but avoid mutual interference. In addition, the platform presented a detection limit of 500 fg/µL and 50 fg/µL in PCA3 and KLK3 gene, respectively. Furthermore, the analysis result of signal ratio of PCA3 to KLK3 gene of urine and peripheral blood specimens from 32 men with suspected prostate cancer on test strips illustrated that the area under the curve values of urine and peripheral blood specimens were 0.998 and 1.0 respectively. In summary, our study highlighted a facile strategy to design an accurate prostate cancer gene detection platform which had the potential to conduct prostate cancer early detection in the resource-limited or other point-of-care testing (POCT) environments.

Identification of KCNK1 as a potential prognostic biomarker and therapeutic target of breast cancer.

BACKGROUND: Breast cancer is the most common malignant cancer and is the second most common cause of cancer-related deaths among females worldwide. Thus, it warrants the urgent development of new therapeutic targets and strategies. Potassium channels are aberrantly expressed in various tumors and are related to tumor progression. However, studies on potassium channels in breast cancer remain limited. METHOD: First, The Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) were used to screen the differentially expressed potassium channels in breast cancer. Several other databases were utilized for further data analysis and visualization, including Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Human Protein Atlas (HPA), GeneMANIA, Tumor Immune Estimation Resource 2 (TIMER2), Catalog of Somatic Mutations in Cancer (COSMIC), cBioPortal, and UCSC Xena tool. Besides, cell proliferation was detected by cell counting kit-8 (CCK8) and 5-Ethynyl-20-deoxyuridine (EdU), and cell migration was detected by wound healing and Transwell assays after knocking down KCNK1. Furthermore, the effect of KCNK1 knockdown on the sensitivity of breast cancer cells to paclitaxel was also evaluated. RESULT: KCNK1 was overexpressed in breast cancer. Higher KCNK1 expression predicted an unfavorable prognosis. Moreover, the abnormal expression of KCNK1 was attributed to promoter hypomethylation of KCNK1 in breast cancer. Besides, cell proliferation and migration were significantly inhibited post-KCNK1 silencing, while KCNK1 knockdown significantly increased breast cancer cell sensitivity to paclitaxel. CONCLUSION: Taken together, our findings demonstrated that KCNK1 is a potential prognostic biomarker and therapeutic target of breast cancer. Thus, targeting KCNK1 might help synergize with paclitaxel function in breast cancer treatment.

Cerium oxide-based nanozyme suppresses kidney calcium oxalate crystal depositions via reversing hyperoxaluria-induced oxidative stress damage.

Oxidative stress damage to renal epithelial cells is the main pathological factor of calcium oxalate calculi formation. The development of medicine that could alleviate oxidative damage has become the key to the prevention and treatment of urolithiasis. Herein, porous nanorods CeO2 nanoparticles (CNPs) were selected from CeO2 with different morphologies as an antioxidant reagent to suppress kidney calcium oxalate crystal depositions with excellent oxidation resistance due to its larger specific surface area. The reversible transformation from Ce3+ to Ce4+ could catalyze the decomposition of excess free radicals and act as a biological antioxidant enzyme basing on its strong ability to scavenge free radicals. The protection capability of CNPS against oxalate-induced damage and the effect of CNPS on calcium oxalate crystallization were studied. CNPS could effectively reduce reactive oxygen species production, restore mitochondrial membrane potential polarity, recover cell cycle progression, reduce cell death, and inhibit the formation of calcium oxalate crystals on the cell surface in vitro. The results of high-throughput sequencing of mRNA showed that CNPs could protect renal epithelial cells from oxidative stress damage caused by high oxalate by suppressing the expression gene of cell surface adhesion proteins. In addition, CNPS can significantly reduce the pathological damage of renal tubules and inhibit the deposition of calcium oxalate crystals in rat kidneys while having no significant side effect on other organs and physiological indicators in vivo. Our results provide a new strategy for CNPS as a potential for clinical prevention of crystalline kidney injury and crystal deposition.

Theoretical insights into interfacial stability and ionic transport of Li2OHBr solid electrolyte for all-solid-state batteries.

Li-rich antiperovskite materials are promising candidates as inorganic solid electrolytes (ISEs) for all-solid-state Li-ion batteries (ASSLIBs). However, the material faces several pressing issues for its application, concerning the phase stability and electrochemical stability of the synthesized material and the Li-ion transport mechanism in it. Herein, we performed first-principles computational studies on the phase stability, interfacial stability, defect chemistry, and electronic/ionic transport properties of Li2OHBr material. The calculation results show that the Li2OHBr is thermodynamically metastable at 0 K and can be synthesized experimentally. This material exhibits a wider intrinsic electrochemical stability window (0.80-3.15 V) compared with sulfide solid electrolytes. Moreover, the Li2OHBr displays significant chemical stability when in contact with typical cathode materials (LiCoO2, LiMn2O4, LiFePO4) and moisture. The dominant defects of Li2OHBr are predicted to be VLi- and Lii +, corresponding to lower Li-ion migration barriers of 0.38 and 0.49 eV, respectively, while the replacement of some of the OH- by F- is shown to be effective in decreasing migration barriers in Li2OHBr. These findings provide a theoretical framework for further designing high performance ISEs.

RSK2 promotes melanoma cell proliferation and vemurafenib resistance via upregulating cyclin D1.

BRAF inhibitors are commonly used in targeted therapies for melanoma patients harboring BRAFV600E mutant. Despite the benefit of vemurafenib therapy, acquired resistance during or after treatment remains a major obstacle in BRAFV600E mutant melanoma. Here we found that RSK2 is overexpressed in melanoma cells and the high expression of RSK2 indicates poor overall survival (OS) in melanoma patients. Overexpression of RSK2 leads to vemurafenib resistance, and the deletion of RSK2 inhibits cell proliferation and sensitizes melanoma cells to vemurafenib. Mechanistically, RSK2 enhances the phosphorylation of FOXO1 by interacting with FOXO1 and promoting its subsequent degradation, leading to upregulation of cyclin D1 in melanoma cells. These results not only reveal the presence of a RSK2-FOXO1-cyclin D1 signaling pathway in melanoma, but also provide a potential therapeutic strategy to enhance the efficacy of vemurafenib against cancer.

Insights into LiMXO4F (M-X = Al-P and Mg-S) as Cathode Coatings for High-Performance Lithium-Ion Batteries.

Cathode coatings have received extensive attention due to their ability to delay electrochemical performance degradation in lithium-ion batteries. However, the development of cathode coatings possessing high ionic conductivity and good interfacial stability with cathode materials has proven to be a challenge. Here, we performed first-principles computational studies on the phase stability, thermodynamic stability, and ionic transport properties of LiMXO4F (M-X = Al-P and Mg-S) used as cathode coatings. We find that the candidate coatings are thermodynamically metastable and can be synthesized experimentally. The coating materials possess high oxidative stability, with the materials predicted to decompose above 4.2 V, suggesting that they have good electrochemical stability under a high-voltage cathode. In addition, the candidate coatings exhibit significant chemical stability when in contact with oxide cathodes. Finally, we have studied the Li-ion transport paths and migration barriers of LiMXO4F (M-X = Al-P and Mg-S) and calculated the low migration barriers to be 0.19 and 0.09 eV, respectively. Our findings indicate that LiMXO4F (M-X = Al-P and Mg-S) are promising cathode coatings, among which LiAlPO4F has been experimentally confirmed. The theoretical cathode coating computational methods presented here can be extended to the solid-state battery system.