Characterization of the m6A regulators' landscape highlights the clinical significance of acute myocardial infarction.

Objective: Acute myocardial infarction (AMI) is a severe cardiovascular disease that threatens human life and health globally. N6-methyladenosine (m6A) governs the fate of RNAs via m6A regulators. Nevertheless, how m6A regulators affect AMI remains to be deciphered. To solve this issue, an integrative analysis of m6A regulators in AMI was conducted. Methods: We acquired transcriptome profiles (GSE59867, GSE48060) of peripheral blood samples from AMI patients and healthy controls. Key m6A regulators were used for LASSO, and consensus clustering was conducted. Next, the m6A score was also computed. Immune cell infiltration, ferroptosis, and oxidative stress were evaluated. In-vitro and in-vivo experiments were conducted to verify the role of the m6A regulator ALKBH5 in AMI. Results: Most m6A regulators presented notable expression alterations in circulating cells of AMI patients versus those of controls. Based on key m6A regulators, we established a gene signature and a nomogram for AMI diagnosis and risk prediction. AMI patients were classified into three m6A clusters or gene clusters, respectively, and each cluster possessed the unique properties of m6A modification, immune cell infiltration, ferroptosis, and oxidative stress. Finally, the m6A score was utilized to quantify m6A modification patterns. Therapeutic targeting of ALKBH5 greatly alleviated apoptosis and intracellular ROS in H/R-induced H9C2 cells and NRCMs. Conclusion: Altogether, our findings highlight the clinical significance of m6A regulators in the diagnosis and risk prediction of AMI and indicate the critical roles of m6A modification in the regulation of immune cell infiltration, ferroptosis, and oxidative stress.

Proteomics-based vaccine targets annotation and design of multi-epitope vaccine against antibiotic-resistant Streptococcus gallolyticus.

Streptococcus gallolyticus is a non-motile, gram-positive bacterium that causes infective endocarditis. S. gallolyticus has developed resistance to existing antibiotics, and no vaccine is currently available. Therefore, it is essential to develop an effective S. gallolyticus vaccine. Core proteomics was used in this study together with subtractive proteomics and reverse vaccinology approach to find antigenic proteins that could be utilized for the design of the S. gallolyticus multi-epitope vaccine. The pipeline identified two antigenic proteins as potential vaccine targets: penicillin-binding protein and the ATP synthase subunit. T and B cell epitopes from the specific proteins were forecasted employing several immunoinformatics and bioinformatics resources. A vaccine (360 amino acids) was created using a combination of seven cytotoxic T cell lymphocyte (CTL), three helper T cell lymphocyte (HTL), and five linear B cell lymphocyte (LBL) epitopes. To increase immune responses, the vaccine was paired with a cholera enterotoxin subunit B (CTB) adjuvant. The developed vaccine was highly antigenic, non-allergenic, and stable for human use. The vaccine's binding affinity and molecular interactions with the human immunological receptor TLR4 were studied using molecular mechanics/generalized Born surface area (MMGBSA), molecular docking, and molecular dynamic (MD) simulation analyses. Escherichia coli (strain K12) plasmid vector pET-28a ( +) was used to examine the ability of the vaccine to be expressed. According to the outcomes of these computer experiments, the vaccine is quite promising in terms of developing a protective immunity against diseases. However, in vitro and animal research are required to validate our findings.

Integrating network pharmacology, molecular docking and simulation approaches with machine learning reveals the multi-target pharmacological mechanism of Berberis integerrima against diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most feared complications of diabetes and key cause of end-stage renal disease (ESRD). Berberis integerrima has been widely used to treat diabetic complications, but exact molecular mechanism is yet to be discovered. Data on active ingredients of B. integerrima and target genes of both diabetic nephropathy and B.integerrima were obtained from public databases. Common results between B. integerrima and DN targets were used to create protein-protein interaction (PPI) network using STRING database and exported to Cytoscape software for the selection of hub genes based on degree of connectivity. Future, PPI network between constituents and overlapping targets was created using Cytoscape to investigate the network pharmacological effects of B. integerrima on DN. KEGG pathway analysis of core genes exposed their involvement in excess glucose-activated signaling pathway. Then, expression of core genes was validated through machine learning classifiers. Finally, PyRx and AMBER18 software was used for molecular docking and simulation. We found that Armepavine, Berberine, Glaucine, Magnoflorine, Reticuline, Quercetin inhibits the growth of diabetic nephropathy by affecting ICAM1, PRKCB, IKBKB, KDR, ALOX5, VCAM1, SYK, TBXA2R, LCK, and F3 genes. Machine learning revealed SYK and PRKCB as potential genes that could use as diagnostic biomarkers against DN. Furthermore, docking and simulation analysis showed the binding affinity and stability of the active compound with target genes. Our study revealed that B. integerrima has preventive effect on DN by acting on glucose-activated signaling pathways. However, experimental studies are needed to reveal biosafety profiles of B. integerrima in DN.Communicated by Ramaswamy H. Sarma.

Manganese-promoted reductive cross-coupling of disulfides with dialkyl carbonates.

Manganese is a cheap and environmentally friendly metal on Earth. Herein, we report a manganese-promoted reductive cross-coupling using easily available and odorless disulfides as thiolating agents in an excellent 100% sulfur atom economy. The protocol featured a broad substrate scope, including various alkyl disulfides and excellent functional group compatibility, constructing diverse thioethers under simple conditions. Ultimately, thioethers can be prepared in gram-scale reactions and further transformed into structurally complex molecules.

[Clinical characteristics and prognostic factors of distant metastatic penile cancer].

OBJECTIVE: To investigate the clinical features of distant metastatic penile cancer (DMPC) and the factors influencing its prognosis. METHODS: We searched the Surveillance, Epidemiology and End Results Database for cases of DMPC diagnosed between 2004 and 2019, analyzed their clinical characteristics and the cancer-specific survival (CSS) rates relating to different factors using the Kaplan-Meier method and the differences among the variables by log-rank test. We determined the variables independently associated with CSS by Cox regression analysis. RESULTS: According to the inclusion criteria, 108 cases of DMPC were identified. The patients were mainly married White people, with a median CSS of 9 months, and 1-, 2- and 3-year CSS rates of 36.4%, 17.8% and 13.5%, respectively. Pairwise comparison showed no statistically significant differences in the median overall CSS among the patients in the surgery, chemotherapy and surgery + chemotherapy groups (8 mo vs 9 mo vs 13 mo, P > 0.05). Race was an independent factor affecting the prognosis of CSS. CONCLUSION: Distant metastatic penile cancer is a rare malignancy with poor prognosis, for which there have been no existing ideal treatment options.

A Novel RHCE*cE (c.827C>A) Allele, Containing the Single-Nucleotide Change, Encodes Altered c/E Antigens.

The RH blood group system is the most complex with over 50 antigens. So far over hundreds of RhCE variant alleles have been described resulting in weakened and/or partial expression of RhCE antigens [1], some variant Rh phenotypes are caused by exchange of genetic material between the RHD and RHCE genes, resulting in many hybrid genes, other phenotypes result from missense mutations. Variant alleles encode altered phenotypes with either weakened antigens, lacked antigens, or unexpected antigens. Besides, the mutation of RH blood group genes may lead to the changes of Rh antigen epitopes. RHCE gene mutations or polymorphisms may bring about altered RH antigens in quality and quantity [2]. Serologic weaknesses or discrepancies are regularly faced by blood transfusion laboratories, and molecular background explaining this feature can be precisely characterized only by the molecular biological methods.

Ultrafine Pt Nanoparticles Anchored on 2D Metal-Organic Frameworks as Multifunctional Electrocatalysts for Water Electrolysis and Zinc-Air Batteries.

Multifunctional electrocatalysts are crucial to cost-effective electrochemical energy conversion and storage systems requiring mutual enhancement of disparate reactions. Embedding noble metal nanoparticles in 2D metal-organic frameworks (MOFs) are proposed as an effective strategy, however, the hybrids usually suffer from poor electrochemical performance and electrical conductivity in operating conditions. Herein, ultrafine Pt nanoparticles strongly anchored on thiophenedicarboxylate acid based 2D Fe-MOF nanobelt arrays (Pt@Fe-MOF) are fabricated, allowing sufficient exposure of active sites with superior trifunctional electrocatalytic activity for hydrogen evolution, oxygen evolution, and oxygen reduction reactions. The interfacial Fe─O─Pt bonds can induce the charge redistribution of metal centers, leading to the optimization of adsorption energy for reaction intermediates, while the dispersibility of ultrafine Pt nanoparticles contributes to the high mass activity. When Pt@Fe-MOF is used as bifunctional catalysts for water-splitting, a low voltage of 1.65 V is required at 100 mA cm-2 with long-term stability for 20 h at temperatures (65 °C) relevant for industrial applications, outperforming commercial benchmarks. Furthermore, liquid Zn-air batteries with Pt@Fe-MOF in cathodes deliver high open-circuit voltages (1.397 V) and decent cycling stability, which motivates the fabrication of flexible quasisolid-state rechargeable Zn-air batteries with remarkable performance.

Functional analysis, virtual screening, and molecular dynamics revealed potential novel drug targets and their inhibitors against cardiovascular disease in human.

Cardiovascular disease (CVD) is a group of diseases, affecting the human heart and accounting for 30% of deaths worldwide. Major CVDs include heart failure, hypertension, stroke, etc. Various therapeutics are available against CVD, still there is a dire need to find out potential protein drug targets to reduce economic burden and mortality rate. Goal of the current study was to utilize sequential computational techniques to find the best cardiovascular drug targets and their inhibitors. Common human cardiovascular targets of both databases (GeneCards and Uniprot) were subjected to bioinformatics analyses. Purpose was to validate putative therapeutic targets employing the structure-based bioinformatics methods to determine their physiochemical properties and biological processes. Three stable proteins, that have 0 transmembrane helices, and possess biological processes were screened as potential protein-based therapeutic targets: Hemoglobin subunit beta (HBB), Gamma-enolase (ENO2), and Cholesteryl ester transfer protein (CETP). Tertiary structures of target proteins were retrieved from PDB, and molecular docking technique was utilized to evaluate a library of 5000 phytochemicals against the interacting residues of the target protein as well as their respective standard drugs through MOE and Pyrx software. Top five phytochemicals (d-Sesamin, 1,3-benzodioxole, Sativanone, Thiamine, and Cajanol) were identified based on their RMSD and docking scores as compared to their standard drugs. The docking studies were also validated by MM-GBSA binding free energy and molecular dynamics simulations. According to the study's findings, these phytochemicals may eventually be used as drugs to treat CVD. Further in vitro testing is required to confirm their efficacy and drug potency.Communicated by Ramaswamy H. Sarma.

369Fabrication of 3D gel-printed ß-tricalcium phosphate/titanium dioxide porous scaffolds for cancellous bone tissue engineering.

Human bone is composed of cortical bone and cancellous bone. The interior portion of natural bone is cancellous with a porosity of 50%-90%, but the outer layer is made of dense cortical bone, of which porosity was not higher than 10%. Porous ceramics were expected to be research hotspot in bone tissue engineering by virtue of their similarity to the mineral constituent and physiological structure of human bone. However, it is challenging to utilize conventional manufacturing methods to fabricate porous structures with precise shapes and pore sizes. Three-dimensional (3D) printing of ceramics is currently the latest research trend because it has many advantages in the fabrication of porous scaffolds, which can meet the requirements of cancellous bone strength, arbitrarily complex shapes, and individualized design. In this study, ß-tricalcium phosphate (ß-TCP)/titanium dioxide (TiO2) porous ceramics scaffolds were fabricated by 3D gel-printing sintering for the first time. The chemical constituent, microstructure, and mechanical properties of the 3D-printed scaffolds were characterized. After sintering, a uniform porous structure with appropriate porosity and pore sizes was observed. Besides, biological mineralization activity and biocompatibility were evaluated by in vitro cell assay. The results demonstrated that the incorporation of TiO2 (5 wt%) significantly improved the compressive strength of the scaffolds, with an increase of 283%. Additionally, the in vitro results showed that the ß-TCP/TiO2 scaffold had no toxicity. Meanwhile, the adhesion and proliferation of MC3T3-E1 cells on scaffolds were desirable, revealing that the ß-TCP/TiO2 scaffolds can be used as a promising candidate for repair scaffolding in orthopedics and traumatology.

Single-cell RNA and transcriptome sequencing profiles identify immune-associated key genes in the development of diabetic kidney disease.

Background: There is a growing public concern about diabetic kidney disease (DKD), which poses a severe threat to human health and life. It is important to discover noninvasive and sensitive immune-associated biomarkers that can be used to predict DKD development. ScRNA-seq and transcriptome sequencing were performed here to identify cell types and key genes associated with DKD. Methods: Here, this study conducted the analysis through five microarray datasets of DKD (GSE131882, GSE1009, GSE30528, GSE96804, and GSE104948) from gene expression omnibus (GEO). We performed single-cell RNA sequencing analysis (GSE131882) by using CellMarker and CellPhoneDB on public datasets to identify the specific cell types and cell-cell interaction networks related to DKD. DEGs were identified from four datasets (GSE1009, GSE30528, GSE96804, and GSE104948). The regulatory relationship between DKD-related characters and genes was evaluated by using WGCNA analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) datasets were applied to define the enrichment of each term. Subsequently, immune cell infiltration between DKD and the control group was identified by using the "pheatmap" package, and the connection Matrix between the core genes and immune cell or function was illuminated through the "corrplot" package. Furthermore, RcisTarget and GSEA were conducted on public datasets for the analysis of the regulation relationship of key genes and it revealed the correlation between 3 key genes and top the 20 genetic factors involved in DKD. Finally, the expression of key genes between patients with 35 DKD and 35 healthy controls were examined by ELISA, and the relationship between the development of DKD rate and hub gene plasma levels was assessed in a cohort of 35 DKD patients. In addition, we carried out immunohistochemistry and western blot to verify the expression of three key genes in the kidney tissue samples we obtained. Results: There were 8 cell types between DKD and the control group, and the number of connections between macrophages and other cells was higher than that of the other seven cell groups. We identified 356 different expression genes (DEGs) from the RNA-seq, which are enriched in urogenital system development, kidney development, platelet alpha granule, and glycosaminoglycan binding pathways. And WGCNA was conducted to construct 13 gene modules. The highest correlations module is related to the regulation of cell adhesion, positive regulation of locomotion, PI3K-Akt, gamma response, epithelial-mesenchymal transition, and E2F target signaling pathway. Then we overlapped the DEGs, WGCNA, and scRNA-seq, SLIT3, PDE1A and CFH were screened as the closely related genes to DKD. In addition, the findings of immunological infiltration revealed a remarkable positive link between T cells gamma delta, Macrophages M2, resting mast cells, and the three critical genes SLIT3, PDE1A, and CFH. Neutrophils were considerably negatively connected with the three key genes. Comparatively to healthy controls, DKD patients showed high levels of SLIT3, PDE1A, and CFH. Despite this, higher SLIT3, PDE1A, and CFH were associated with an end point rate based on a median follow-up of 2.6 years. And with the gradual deterioration of DKD, the expression of SLIT3, PDE1A, and CFH gradually increased. Conclusions: The 3 immune-associated genes could be used as diagnostic markers and therapeutic targets of DKD. Additionally, we found new pathogenic mechanisms associated with immune cells in DKD, which might lead to therapeutic targets against these cells.

Coupling annealed silver nanoparticles with a porous silicon Bragg mirror SERS substrate and machine learning for rapid non-invasive disease diagnosis.

Ag2O-Ag-porous silicon Bragg mirror (PSB) composite SERS substrates were successfully synthesized by using a combination of electrochemical and thermochemical methods. Test results showed that the SERS signal increased and decreased as the annealing temperature used for the substrate increased, where the most intense SERS signal was obtained using a substrate annealed at 300 °C. Stability test results showed substantial enhancement of the SERS signal intensity of the Ag2O-Ag-PSB composite one month after preparation compared with that of conventional Ag-PSB. We conclude that Ag2O nanoshells play an essential role in SERS signal enhancement. Ag2O prevents natural oxidation of Ag nanoparticles (AgNPs) and has a solid localized surface plasmon resonance (LSPR). SERS signal enhancement was tested using this substrate for serum from patients with Sjögren's syndrome (SS) and Diabetic nephropathy (DN), as well as from healthy controls (HC). SERS feature extraction was performed using principal component analysis (PCA). The extracted features were analyzed by a support vector machine (SVM) algorithm. Finally, a rapid screening model for SS and HC, as well as DN and HC, was developed and used to perform controlled experiments. The results showed that the diagnostic accuracy, sensitivity and selectivity for SERS technology combined with machine learning algorithms reached 90.7%, 93.4% and 86.7% for SS/HC and 89.3%, 95.6% and 80% for DN/HC, respectively. The results of this study show that the composite substrate has excellent potential to be developed into a commercially available SERS chip for medical testing.

Causal effects for genetic variants of osteoprotegerin on the risk of acute myocardial infarction and coronary heart disease: A two-sample Mendelian randomization study.

Although since the 1980s, the mortality of coronary heart disease(CHD) has obviously decreased due to the rise of coronary intervention, the mortality and disability of CHD were still high in some countries. Etiological studies of acute myocardial infarction(AMI) and CHD were extremely important. In this study, we used two-sample Mendelian randomization(TSMR) method to collect GWAS statistics of osteoprotegerin (OPG), AMI and CHD to reveal the causal relationship between OPG and these two diseases. In total, we identified 7 genetic variants associated with AMI and 7 genetic variants associated with CHD that were not found to be in linkage disequilibrium(LD; r 2 < 0.001). Evidence of a positive effect of an OPG genetic susceptibility on AMI was discovered(IVW OR = 0.877; 95% CI = 0.787-0.977; p = 0.017; 7 SNPs) and CHD (IVW OR = 0.892; 95% CI = 0.803-0.991; p = 0.033; 7 SNPs). After removing the influence of rs1385492, we found that there was a correlation between OPG and AMI/CHD (AMI: weighted median OR = 0.818;95% CI = 0.724-0.950; p = 0.001; 6SNPs;CHD: weighted median OR = 0.842; 95% CI = 0.755-0.938; p = 1.893 × 10-3; 6SNPs). The findings of our study indicated that OPG had a tight genetic causation association with MI or CHD. This genetic causal relationship presented us with fresh ideas for the etiology of AMI and CHD, which is an area of research that will continue in the future.

2D Metal-Organic Frameworks as Competent Electrocatalysts for Water Splitting.

Hydrogen, a clean and flexible energy carrier, can be efficiently produced by electrocatalytic water splitting. To accelerate the sluggish hydrogen evolution reaction and oxygen evolution reaction kinetics in the splitting process, highly active electrocatalysts are essential for lowering the energy barriers, thereby improving the efficiency of overall water splitting. Combining the distinctive advantages of metal-organic frameworks (MOFs) with the physicochemical properties of 2D materials such as large surface area, tunable structure, accessible active sites, and enhanced conductivity, 2D MOFs have attracted intensive attention in the field of electrocatalysis. Different strategies, such as improving the conductivities of MOFs, reducing the thicknesses of MOF nanosheets, and integrating MOFs with conductive particles or substrates, are developed to promote the catalytic performances of pristine MOFs. This review summarizes the recent advances of pristine 2D MOF-based electrocatalysts for water electrolysis. In particular, their intrinsic electrocatalytic properties are detailly analyzed to reveal important roles of inherent MOF active centers, or other in situ generated active phases from MOFs responsible for the catalytic reactions. Finally, the challenges and development prospects of pristine 2D MOFs for the future applications in overall water splitting are discussed.

Delivery of nitric oxide with a pH-responsive nanocarrier for the treatment of renal fibrosis.

Fibrosis is an excessive accumulation of extracellular matrix (ECM) that may cause severe organ dysfunction. Nitric oxide (NO), a multifunctional gaseous signaling molecule, may inhibit fibrosis, and delivery of NO may serve as a potential antifibrotic strategy. However, major limitations in the application of NO to treat fibrotic diseases include its nonspecificity, short half-life and low availability in fibrotic tissue. Herein, we aimed to develop a stimuli-responsive drug carrier to deliver NO to halt kidney fibrosis. We manufactured a nanoparticle (NP) composed of pH-sensitive poly[2-(diisopropylamino)ethyl methacrylate (PDPA) polymers to encapsulate a NO donor, a dinitrosyl iron complex (DNIC; [Fe2(µ-SEt)2(NO)4]). The NPs were stable at physiological pH 7.4 but disintegrated at pH 4.0-6.0. The NPs showed significant cytotoxicity to cultured human myofibroblasts and were able to inhibit the activation of myofibroblasts, as indicated by a lower expression level of α-smooth muscle actin and the synthesis of a major ECM component, collagen I, in cultured human myofibroblasts. When given to mice treated with unilateral ureteral ligation/obstruction (UUO) to induce kidney fibrosis, these NPs remained in blood at a stable concentration for as long as 24 h and might enter the fibrotic kidneys to suppress myofibroblast activation and collagen I production, leading to a 70% reduction in the fibrotic area. In summary, our strategy to assemble a NO donor, the iron nitrosyl complex DNIC, into pH-responsive NPs proves effective in treating renal fibrosis and warrants further investigation for its therapeutic potential.

Controlled fabrication of Ag@clay nanomaterials for ultrasensitive and rapid surface-enhanced Raman spectroscopic detection.

The nanostructure of Ag nanoparticles (NPs) plays a critical role in their surface-enhanced Raman scattering (SERS) activity. Despite many efforts to tune the nanostructure of Ag NPs, it remains a great challenge as Ag NPs tend to agglomerate and their nanostructure is difficult to control. Herein, newly-discovered clay-surfactant-Ag+ materials and interfacial processes were developed and used to prepare uniform spherical Ag@synthetic hectorite (Ag@Hct) nanomaterials for ultrasensitive SERS assay. Sodium dodecyl sulfate (SDS), an anionic surfactant, acted as a bridge to conjugate the positively charged edge of Hct NPs and Ag+via electrostatic interaction to form the bridging nanostructure of Hct-SDS-Ag+, which promoted the uniform dispersion of Hct NPs. Following this, Ag+ was reduced to Ag0 by the reductant, and Ag0 grew on the surface of disc-like Hct NPs to form spherical Ag@Hct nanomaterials with an average particle size of ∼24 nm. The prepared Ag@Hct nanomaterials showed an ultrasensitive SERS response to methylene blue (MB) with a detection limit of 10-12 M. The detection limit of MB in sewage was 10-11 M. The prepared Ag@Hct nanomaterials also exhibited great SERS enhancement for malachite green and crystal violet. This work provides a novel and simple approach to prepare Ag@Hct nanomaterials with uniform spheres and adjustable particle size, allowing more sensitive and reproducible detection of MB.

Screening and characterization of inhibitory vNAR targeting nanodisc-assembled influenza M2 proteins.

Influenza A virus poses a constant challenge to human health. The highly conserved influenza matrix-2 (M2) protein is an attractive target for the development of a universal antibody-based drug. However, screening using antigens with subphysiological conformation in a nonmembrane environment significantly reduces the generation of efficient antibodies. Here, M2(1-46) was incorporated into nanodiscs (M2-nanodiscs) with M2 in a membrane-embedded tetrameric conformation, closely resembling its natural physiological state in the influenza viral envelope. M2-nanodisc generation, an antigen, was followed by Chiloscyllium plagiosum immunization. The functional vNARs were selected by phage display panning strategy from the shark immune library. One of the isolated vNARs, AM2H10, could specifically bind to tetrameric M2 instead of monomeric M2e (the ectodomain of M2 protein). Furthermore, AM2H10 blocked ion influx through amantadine-sensitive and resistant M2 channels. Our findings indicated the possibility of developing functional shark nanobodies against various influenza viruses by targeting the M2 protein.

PTPRN mediates endocytosis of NaV1.2 sodium chan-nels and suppresses epileptogenesis in mice / 中国药理学与毒理学杂志

Epilepsy is a disorder of the brain charac-terized by abnormal neuron excitability.However,the underlying molecular mechanism of neuron excitability modulation remains elusive.With the help of bioinformatic methods,we have identified receptor-type tyrosine-pro-tein phosphatase-like N(PTPRN)as a critical gene dur-ing epileptogenesis.PTPRN recruits NEDD4L ubiquitin E3 ligase to NaV1.2 sodium channels,facilitating NEDD4L-mediated ubiquitination and endocytosis.Knockout of PTPRN endows hippocampal granule cells with augmented depolarization currents and higher intrinsic excitability,which is reflected by increased seizure susceptibility of transgenic mice.On the contrary,reduced neuron excit-ability and decreased seizure susceptibility are observed after PTPRN overexpression.Meanwhile,we find that a 133 aa fragment recaptures modulation effect of PTPRN full-length,and this fragment shows therapeutic potential towards epilepsy caused by NaV1.2 gain of function vari-ants.In brief,our results demonstrate PTPRN playsa criti-calroleinregulatingneuronexcitability,providing a poten-tial therapeutic approach for epilepsy.

ORP8 acts as a lipophagy receptor to mediate lipid droplet turnover

Lipophagy, the selective engulfment of lipid droplets (LDs) by autophagosomes for lysosomal degradation, is critical to lipid and energy homeostasis. Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes. This function of ORP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs. Upon lipophagy induction, ORP8 has increased localization on LDs and is phosphorylated by AMPK, thereby enhancing its affinity for LC3/GABARAPs. Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride. Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice, and Osbpl8-/- mice exhibit liver lipid clearance defects. Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism.