Wrapping anisotropic microgel particles in lipid membranes: Effects of particle shape and membrane rigidity.

Cellular engulfment and uptake of macromolecular assemblies or nanoparticles via endocytosis can be associated to both healthy and disease-related biological processes as well as delivery of drug nanoparticles and potential nanotoxicity of pollutants. Depending on the physical and chemical properties of the system, the adsorbed particles may remain at the membrane surface, become wrapped by the membrane, or translocate across the membrane through an endocytosis-like process. In this paper, we address the question of how the wrapping of colloidal particles by lipid membranes can be controlled by the shape of the particles, the particle-membrane adhesion energy, the membrane phase behavior, and the membrane-bending rigidity. We use a model system composed of soft core-shell microgel particles with spherical and ellipsoidal shapes, together with phospholipid membranes with varying composition. Confocal microscopy data clearly demonstrate how tuning of these basic properties of particles and membranes can be used to direct wrapping and membrane deformation and the organization of the particles at the membrane. The deep-wrapped states are more favorable for ellipsoidal than for spherical microgel particles of similar volume. Theoretical calculations for fixed adhesion strength predict the opposite behavior-wrapping becomes more difficult with increasing aspect ratio. The comparison with the experiments implies that the microgel adhesion strength must increase with increasing particle stretching. Considering the versatility offered by microgels systems to be synthesized with different shapes, functionalizations, and mechanical properties, the present findings further inspire future studies involving nanoparticle-membrane interactions relevant for the design of novel biomaterials and therapeutic applications.

SlWRKY81 regulates Spd synthesis and Na+/K+ homeostasis through interaction with SlJAZ1 mediated JA pathway to improve tomato saline-alkali resistance.

Saline-alkali stress is an important abiotic stress factor affecting tomato (Solanum lycopersicum L.) plant growth. Although the involvement of the tomato SlWRKY gene family in responses to saline-alkali stress has been well established, the mechanism underlying resistance to saline-alkali stress remains unclear. In this study, we investigated the role of SlWRKY81 in conferring saline-alkali stress resistance by using overexpression and knockout tomato seedlings obtained via genetic modification. We demonstrated that SlWRKY81 improves the ability of tomato to withstand saline-alkali stress by enhancing antioxidant capacity, root activity, and proline content while reducing malondialdehyde levels. Saline-alkali stress induces an increase in jasmonic acid (JA) content in tomato seedlings, and the SlWRKY81 promoter responds to JA signaling, leading to an increase in SlWRKY81 expression. Furthermore, the interaction between SlJAZ1 and SlWRKY81 represses the expression of SlWRKY81. SlWRKY81 binds to W-box motifs in the promoter regions of SlSPDS2 and SlNHX4, thereby positively regulating their expression. This regulation results in increased spermidine (Spd) content and enhanced potassium (K+) absorption and sodium (Na+) efflux, which contribute to the resistance of tomato to saline-alkali stress. However, JA and SlJAZ1 exhibit antagonistic effects. Elevated JA content reduces the inhibitory effect of SlJAZ1 on SlWRKY81, leading to the release of additional SlWRKY81 protein and further augmenting the resistance of tomato to saline-alkali stress. In summary, the modulation of Spd synthesis and Na+/K+ homeostasis mediated by the interaction between SlWRKY81 and SlJAZ1 represents a novel pathway underlying tomato response to saline-alkali stress.

KIF23 promotes cervical cancer progression via inhibiting NLRP3-mediated pyroptosis.

BACKGROUND: Cervical cancer (CC), closely linked to persistent human papillomavirus infection, represents a major health problem for women worldwide. The objective of this study is to elucidate KIF23's role in the development of CC and its regulatory mechanism. METHODS: The bioinformatics methods were utilized to extract pyroptosis-associated differentially expressed genes (DEGs) and pivot genes from the GSE9750 and GSE63678 datasets, followed by immune infiltration analysis and quantification of these genes' expression. The effects of kinesin family member 23 (KIF23) were verified through functional experiments in vitro and a mouse xenograft model. The NLPR3 activator, nigericin, was applied for further analyzing the potential regulatory mechanism of KIF23 in CC. RESULTS: A total of 8 pyroptosis-related DEGs were screened out, among which 4 candidate core genes were identified as candidate hub genes and confirmed upregulation in CC tissues and cells. These genes respectively showed a positive correlation with the infiltration of distinct immune cells or tumor purity. Downregulation of KIF23 could suppress the proliferation, migration, and invasion abilities in CC cells and tumorigenesis through enhancing pyroptosis. Conversely, KIF23 overexpression accelerated the malignant phenotypes of CC cells and inhibited pyroptosis activation, which was blocked by nigericin treatment. CONCLUSIONS: KIF23 may play an oncogenic role in CC progression via inhibition of the NLRP3-mediated pyroptosis pathway.

Blood- and Urine-Based Liquid Biopsy for Early-Stage Cancer Investigation: Taken Clear Renal Cell Carcinoma as a Model.

Liquid biopsy is a noninvasive technique that can provide valuable information for disease characterization by using biofluids as a source of biomarkers. Proteins found in biofluids can offer a wealth of information for understanding pathological processes. In this study, we used early-stage clear cell renal cell carcinoma (ccRCC) as a model to explore the proteomic relationships among tissue, plasma, and urine. We analyzed samples of tumor tissue, plasma, and urine from a cohort of 27 ccRCC patients with T1-2 stage and 27 matched healthy controls, using liquid chromatography-mass spectrometry (LC-MS) for proteomic analysis. We integrated the differential proteins found in the three types of samples to explore ccRCC-associated molecular changes. Our results showed that both plasma and urine proteomes could reflect functional changes in tumor tissue. In plasma, cytoskeletal proteins and metabolic enzymes were differentially expressed, while in urine, adhesion molecules and defense proteins showed differential levels. The differential proteins found in plasma and urine both reflect the binding and catalytic activity of tumor tissue. Additionally, proteins only changed in biofluids could reflect body immune response changes, with plasma proteins involved in actin cytoskeleton and oxidative stress, and urine proteins involved in granulocyte adhesion and leukocyte extravasation signaling. Plasma and urine proteins could effectively distinguish RCC from control, with good performances (plasma/urine: 92.6%/92.6% specificity, 96.3%/92.6% sensitivity, and an area under the curve of 0.981/0.97). In conclusion, biofluids could not only reflect functional changes in tumor tissue but also reflect changes in the body's immune response. These findings will benefit the understanding of body biomarkers in tumors and the discovery of potential disease biomarkers.

Enabling Ultrafine Ru Nanoparticles with Tunable Electronic Structures via a Double-Shell Hollow Interlayer Confinement Strategy toward Enhanced Hydrogen Evolution Reaction Performance.

Engineering of the catalysts' structural stability and electronic structure could enable high-throughput H2 production over electrocatalytic water splitting. Herein, a double-shell interlayer confinement strategy is proposed to modulate the spatial position of Ru nanoparticles in hollow carbon nanoreactors for achieving tunable sizes and electronic structures toward enhanced H2 evolution. Specifically, the Ru can be anchored in either the inner layer (Ru-DSC-I) or the external shell (Ru-DSC-E) of double-shell nanoreactors, and the size of Ru is reduced from 2.2 to 0.9 nm because of the double-shell confinement effect. The electronic structures are efficiently optimized thereby stabilizing active sites and lowering the reaction barrier. According to finite element analysis results, the mesoscale mass diffusion can be promoted in the double-shell configuration. The Ru-DSC-I nanoreactor exhibits a much lower overpotential (η10 = 73.5 mV) and much higher stability (100 mA cm-2). Our work might shed light on the precise design of multishell catalysts with efficient refining electrostructures toward electrosynthesis applications.

Glycan-Imprinted Nanoparticle as Artificial Neutralizing Antibody for Efficient HIV-1 Recognition and Inhibition.

The HIV-1 envelope is a heavily glycosylated class 1 trimeric fusion protein responsible for viral entry into CD4+ immune cells. Developing neutralizing antibodies against the specific envelope glycans is an alternative method for antiviral therapies. This work presents the first-ever development and characterization of artificial neutralizing antibodies using molecular imprinting technology to recognize and bind to the envelope protein of HIV-1. The prepared envelope glycan-imprinted nanoparticles (GINPs) can successfully prevent HIV-1 from infecting target cells by shielding the glycans on the envelope protein. In vitro experiments showed that GINPs have strong affinity toward HIV-1 (Kd = 36.7 ± 2.2 nM) and possess high anti-interference and specificity. GINPs demonstrate broad inhibition activity against both tier 1 and tier 2 HIV-1 strains with a pM-level IC50 and exhibit a significant inhibitory effect on long-term viral replication by more than 95%. The strategy provides a promising method for the inhibition and therapy of HIV-1 infection.

Equivariant score-based generative diffusion framework for 3D molecules.

BACKGROUND: Molecular biology is crucial for drug discovery, protein design, and human health. Due to the vastness of the drug-like chemical space, depending on biomedical experts to manually design molecules is exceedingly expensive. Utilizing generative methods with deep learning technology offers an effective approach to streamline the search space for molecular design and save costs. This paper introduces a novel E(3)-equivariant score-based diffusion framework for 3D molecular generation via SDEs, aiming to address the constraints of unified Gaussian diffusion methods. Within the proposed framework EMDS, the complete diffusion is decomposed into separate diffusion processes for distinct components of the molecular feature space, while the modeling processes also capture the complex dependency among these components. Moreover, angle and torsion angle information is integrated into the networks to enhance the modeling of atom coordinates and utilize spatial information more effectively. RESULTS: Experiments on the widely utilized QM9 dataset demonstrate that our proposed framework significantly outperforms the state-of-the-art methods in all evaluation metrics for 3D molecular generation. Additionally, ablation experiments are conducted to highlight the contribution of key components in our framework, demonstrating the effectiveness of the proposed framework and the performance improvements of incorporating angle and torsion angle information for molecular generation. Finally, the comparative results of distribution show that our method is highly effective in generating molecules that closely resemble the actual scenario. CONCLUSION: Through the experiments and comparative results, our framework clearly outperforms previous 3D molecular generation methods, exhibiting significantly better capacity for modeling chemically realistic molecules. The excellent performance of EMDS in 3D molecular generation brings novel and encouraging opportunities for tackling challenging biomedical molecule and protein scenarios.

Protein O-GlcNAcylation impairment caused by N-acetylglucosamine phosphate mutase deficiency leads to growth variations in Arabidopsis thaliana.

As an essential enzyme in the uridine diphosphate (UDP)-GlcNAc biosynthesis pathway, the significant role of N-acetylglucosamine phosphate mutase (AGM) remains unknown in plants. In the present study, a functional plant AGM (AtAGM) was identified from Arabidopsis thaliana. AtAGM catalyzes the isomerization of GlcNAc-1-P and GlcNAc-6-P, and has broad catalytic activity on different phosphohexoses. UDP-GlcNAc contents were significantly decreased in AtAGM T-DNA insertional mutants, which caused temperature-dependent growth defects in seedlings and vigorous growth in adult plants. Further analysis revealed that protein O-GlcNAcylation but not N-glycosylation was dramatically impaired in Atagm mutants due to UDP-GlcNAc shortage. Combined with the results from O-GlcNAcylation or N-glycosylation deficient mutants, and O-GlcNAcase inhibitor all suggested that protein O-GlcNAcylation impairment mainly leads to the phenotypic variations of Atagm plants. In conclusion, based on the essential role in UDP-GlcNAc biosynthesis, AtAGM is important for plant growth mainly via protein O-GlcNAcylation-level regulation.

Suppressing Metal Leaching and Sintering in Hydroformylation Reaction by Modulating the Coordination of Rh Single Atoms with Reactants.

Hydroformylation reaction is one of the largest homogeneously catalyzed industrial processes yet suffers from difficulty and high cost in catalyst separation and recovery. Heterogeneous single-atom catalysts (SACs), on the other hand, have emerged as a promising alternative due to their high initial activity and reasonable regioselectivity. Nevertheless, the stability of SACs against metal aggregation and leaching during the reaction has rarely been addressed. Herein, we elucidate the mechanism of Rh aggregation and leaching by investigating the structural evolution of Rh1@silicalite-1 SAC in response to different adsorbates (CO, H2, alkene, and aldehydes) by using diffuse reflectance infrared Fourier transform spectroscopy, X-ray adsorption fine structure, and scanning transmission electron microscopy techniques and kinetic studies. It is discovered that the aggregation and leaching of Rh are induced by the strong adsorption of CO and aldehydes on Rh, as well as the reduction of Rh3+ by CO/H2 which weakens the binding of Rh with support. In contrast, alkene effectively counteracts this effect by the competitive adsorption on Rh atoms with CO/aldehyde, and the disintegration of Rh clusters. Based on these results, we propose a strategy to conduct the reaction under conditions of high alkene concentration, which proves to be able to stabilize Rh single atom against aggregation and/or leaching for more than 100 h time-on-stream.

Ethylene Methoxycarbonylation over Heterogeneous Pt1/MoS2 Single-Atom Catalyst: Metal-Support Concerted Catalysis.

Ethylene methoxycarbonylation (EMC) to methyl propanoate (MP) is an industrially important reaction and commercially uses a homogeneous Pd-phosphine organometallic complex as the catalyst and corrosive strong acid as the promoter. In this work, we develop a Pt1/MoS2 heterogeneous single-atom catalyst (SAC) which exhibits high activity, selectivity, and good recyclability for EMC reaction without need of any liquid acid. The production rate of MP achieves 0.35 gMP gcat-1 h-1 with MP selectivity of 91.1% at 1 MPa CO, 1 MPa C2H4, and 160 °C, which can be doubled at 2 MPa CO and corresponds to 320.1 molMP molPt-1 h-1, at least 1 order of magnitude higher than the earlier reported heterogeneous catalyst and even comparable to some of homogeneous catalyst. Advanced characterizations and DFT calculations reveal that all the Pt single atoms are located at the Mo vacancies along the Mo edge of the MoS2 nanosheets, forming pocket-like Mo-S-Pt1-S-Mo ensembles with uniform and well-defined structure. Methanol is first adsorbed and dissociated on Mo sites, and the produced H spillovers to the adjacent Pt site forming Pt-H species which then activate ethylene, forming Pt-ethyl species. Meanwhile, CO adsorbed on the other Mo site reacts with the Pt-ethyl species, yielding propionyl species, and this carbonylation is the rate-determining step. The final methoxylation step proceeds via the nucleophilic attack of propionyl species by -OCH3 affording the final product MP. Such a metal-support concerted catalysis enabled by the Mo-S-Pt1-S-Mo multisite ensemble opens a new avenue for SACs to promote the multimolecular reactions that prevail in homogeneous catalysis.

Dual-Atom Catalyst with N-Colligated Zn1Co1 Species as Dominant Active Sites for Propane Dehydrogenation.

Dual-atom catalysts (DACs) with paired active sites can provide unique intrinsic properties for heterogeneous catalysis, but the synergy of the active centers remains to be elucidated. Here, we develop a high-performance DAC with Zn1Co1 species anchored on nitrogen-doped carbon (Zn1Co1/NC) as the dominant active site for the propane dehydrogenation (PDH) reaction. It exhibits several times higher turnover frequency (TOF) of C3H8 conversion and enhanced C3H6 selectivity compared to Zn1/NC or Co1/NC with only a single-atom site. Various experimental and theoretical studies suggest that the enhanced PDH performance stems from the promoted activation of the C-H bond of C3H8 triggered by the electronic interaction between Zn1 and Co1 colligated by N species. Moreover, the dynamic sinking of the Zn1 site and rising of the Co1 site, together with the steric effect of the dissociated H species at the bridged N during the PDH reaction, provides a feasible channel for C3H6 desorption through the more exposed Co1 site, thereby boosting the selectivity. This work provides a promising strategy for designing robust hetero DACs to simultaneously increase activity and selectivity in the PDH reaction.

Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer.

R-loops are prevalent three-stranded nucleic acid structures, comprising a DNA-RNA hybrid and a displaced single-stranded DNA, that frequently form during transcription and may be attributed to genomic stability and gene expression regulation. It was recently discovered that RNA modification contributes to maintain the stability of R-loops such as N6-methyladenosine (m6A). Yet, m6A-modified R-loops in regulating gene transcription remains poorly understood. Here, we demonstrated that insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) recognize R-loops in an m6A-dependent way. Consequently, IGF2BPs overexpression leads to increased overall R-loop levels, cell migration inhibition, and cell growth retardation in prostate cancer (PCa) via precluding the binding of DNA methyltransferase 1(DNMT1) to semaphorin 3 F (SEMA3F) promoters. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A-containing R-loops and are required for tumor suppressor functions. Overexpression of SEMA3F markedly enhanced docetaxel chemosensitivity in prostate cancer via regulating Hippo pathway. Our findings point to a distinct R-loop resolution pathway mediated by IGF2BPs, emphasizing the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology.The manuscript summarizes the new role of N6-methyladenosine in epigenetic regulation, we introduce the distinct R-loop resolution mediated by IGF2BP proteins in an m6A-dependent way, which probably lead to the growth retardation and docetaxel chemotherapy resistance in prostate cancer. Moreover, our findings first emphasized the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology. In addition, our research provides a novel RBM15/IGF2BPs/DNMT1 trans-omics regulation m6A axis, indicating the new crosstalk between RNA m6A methylation and DNA methylation in prostate cancer.

Quantitative Characterization of Protein N-Linked Core-Fucosylation by an Efficient Glycan Truncation Strategy.

Dysregulation of protein core-fucosylation plays a pivotal role in the onset, progression, and immunosuppression of cancer. However, analyzing core-fucosylation, especially the accurate determination of the core-fucosylation (CF) site occupancy ratio, remains challenging. To address these problems, we developed a truncation strategy that efficiently converts intact glycopeptides with hundreds of different glycans into two truncated forms, i.e., a monosaccharide HexNAc and a disaccharide HexNAc+core-fucose. Further combination with data-independent analysis to form an integrated platform allowed the measurement of site-specific core-fucosylation abundances and the determination of the CF occupancy ratio with high reproducibility. Notably, three times CF sites were identified using this strategy compared to conventional methods based on intact glycopeptides. Application of this platform to characterize protein core-fucosylation in two breast cancer cell lines, i.e., MDA-MB-231 and MCF7, yields a total of 1615 unique glycosites and about 900 CF sites from one single LC-MS/MS analysis. Differential analysis unraveled the distinct glycosylation pattern for over 201 cell surface drug targets between breast cancer subtypes and provides insights into developing new therapeutic strategies to aid precision medicine. Given the robust performance of this platform, it would have broad application in discovering novel biomarkers based on the CF glycosylation pattern, investigating cancer mechanisms, as well as detecting new intervention targets.

The protease caspase-1: Activation pathways and functions.

Caspase-1 is one of the main mediators of inflammatory caspases and has become a correspondent with inflammation, cell death, and several inflammatory diseases. In this review, we systematically summarize both original and recent advances in caspase-1 to provide references for a better understanding of the molecular mechanisms in its activation and functions. This study investigates and summarizes the published articles concerning caspase-1, inflammation, pyroptosis, apoptosis, and cell death by searching academic search systems, including the PubMed, Web of Science, and Google Scholar. Caspase-1 is one of the main mediators of inflammatory caspases and has become a correspondent with inflammation and cell death. In cell death, caspase-1 was originally found to cause apoptosis in fibroblasts. Importantly, caspase-1 was later reported to execute programmed cell death, including pyroptosis and apoptosis, in many immune cells in response to diverse stimuli. It is widely established that different pathways can activate caspase-1 and subsequently mediate cell death and inflammation. It has become increasingly clear that caspase-1 is responsible for the initiation and control of pyroptosis, apoptosis, and inflammation in addition to its well-known function in cleaving IL-1ß. The significant advancement in the understanding of caspase-1-controlled cell death and novel substrates inspires new therapeutic approaches in the future.

Sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production.

To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2-8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G-CSF-inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario.

Transcriptome analysis of Pennisetum americanum × Pennisetum purpureum and Pennisetum americanum leaves in response to high-phosphorus stress.

Excessive phosphorus (P) levels can disrupt nutrient balance in plants, adversely affecting growth. The molecular responses of Pennisetum species to high phosphorus stress remain poorly understood. This study examined two Pennisetum species, Pennisetum americanum × Pennisetum purpureum and Pennisetum americanum, under varying P concentrations (200, 600 and 1000 µmol·L- 1 KH2PO4) to elucidate transcriptomic alterations under high-P conditions. Our findings revealed that P. americanum exhibited stronger adaption to high-P stress compared to P. americanum× P. purpureum. Both species showed an increase in plant height and leaf P content under elevated P levels, with P. americanum demonstrating greater height and higher P content than P. americanum× P. purpureum. Transcriptomic analysis identified significant up- and down-regulation of key genes (e.g. SAUR, GH3, AHP, PIF4, PYL, GST, GPX, GSR, CAT, SOD1, CHS, ANR, P5CS and PsbO) involved in plant hormone signal transduction, glutathione metabolism, peroxisomes, flavonoid biosynthesis, amino acid biosynthesis and photosynthesis pathways. Compared with P. americanum× P. purpureum, P. americanum has more key genes in the KEGG pathway, and some genes have higher expression levels. These results contribute valuable insights into the molecular mechanisms governing high-P stress in Pennisetum species and offer implications for broader plant stress research.

Chromosome-level genome provides new insight into the overwintering process of Korla pear (Pyrus sinkiangensis Yu).

Korla pear has a unique taste and aroma and is a breeding parent of numerous pear varieties. It is susceptible to Valsa mali var. pyri, which invades bark wounded by freezing injury. Its genetic relationships have not been fully defined and could offer insight into the mechanism for freezing tolerance and disease resistance. We generated a high-quality, chromosome-level genome assembly for Korla pear via the Illumina and PacBio circular consensus sequencing (CCS) platforms and high-throughput chromosome conformation capture (Hi-C). The Korla pear genome is ~ 496.63 Mb, and 99.18% of it is assembled to 17 chromosomes. Collinearity and phylogenetic analyses indicated that Korla might be derived from Pyrus pyrifolia and that it diverged ~ 3.9-4.6 Mya. During domestication, seven late embryogenesis abundant (LEA), two dehydrin (DHN), and 54 disease resistance genes were lost from Korla pear compared with P. betulifolia. Moreover, 21 LEA and 31 disease resistance genes were common to the Korla pear and P. betulifolia genomes but were upregulated under overwintering only in P. betulifolia because key cis elements were missing in Korla pear. Gene deletion and downregulation during domestication reduced freezing tolerance and disease resistance in Korla pear. These results could facilitate the breeding of novel pear varieties with high biotic and abiotic stress resistance.

Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system. METHODS: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB-/- mice were generated, and relevant in vivo experiments were performed. RESULTS: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage. CONCLUSION: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.

Characterization of the proteome of stable and unstable carotid atherosclerotic plaques using data-independent acquisition mass spectrometry.

BACKGROUND: Currently, noninvasive imaging techniques and circulating biomarkers are still insufficient to accurately assess carotid plaque stability, and an in-depth understanding of the molecular mechanisms that contribute to plaque instability is still lacking. METHODS: We established a clinical study cohort containing 182 patients with carotid artery stenosis. After screening, 39 stable and 49 unstable plaques were included in the discovery group, and quantitative proteomics analysis based on data independent acquisition was performed for these plaque samples. Additionally, 35 plaques were included in the validation group to validate the proteomics results by immunohistochemistry analysis. RESULTS: A total of 397 differentially expressed proteins were identified in stable and unstable plaques. These proteins are primarily involved in ferroptosis and lipid metabolism-related functions and pathways. Plaque validation results showed that ferroptosis- and lipid metabolism-related proteins had different expression trends in stable plaques versus unstable fibrous cap regions and lipid core regions. Ferroptosis- and lipid metabolism-related mechanisms in plaque stability were discussed. CONCLUSIONS: Our results may provide a valuable strategy for revealing the mechanisms affecting plaque stability and will facilitate the discovery of specific biomarkers to broaden the therapeutic scope.

High quantum efficiency of hydrogen production from methanol aqueous solution with PtCu-TiO2 photocatalysts.

Methanol with 12.5 wt% H2 content is widely considered a liquid hydrogen medium. Taking into account water with 11.1 wt% H2 content, H2 synthesis from the mixture of water and methanol is a promising method for on-demand hydrogen production. We demonstrate an atomic-level catalyst design strategy using the synergy between single atoms and nanodots for H2 production. The PtCu-TiO2 sandwich photocatalyst achieves a remarkable H2 formation rate (2,383.9 µmol h-1) with a high apparent quantum efficiency (99.2%). Furthermore, the oxidation product is a high-value chemical formaldehyde with 98.6% selectivity instead of CO2, leading to a nearly zero-carbon-emission process. Detailed investigations indicate a dual role of the copper atoms: an electron acceptor to facilitate photoelectron transfer to Pt, and a hole acceptor for the selective oxidation of methanol to formaldehyde, thus avoiding over-oxidation to CO2. The synergy between Pt nanodots and Cu single atoms together reduces the activation energy of this process to 13.2 kJ mol-1.