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The interplay among frustrated lattice geometry, non-trivial band topology and correlation yields rich quantum states of matter in kagome systems1,2. A series of recent members in this family, AV3Sb5 (A = K, Rb or Cs), exhibit a cascade of symmetry-breaking transitions3, involving the 3Q chiral charge ordering4-8, electronic nematicity9,10, roton pair density wave11 and superconductivity12. The nature of the superconducting order is yet to be resolved. Here we report an indication of dynamic superconducting domains with boundary supercurrents in intrinsic CsV3Sb5 flakes. The magnetic field-free superconducting diode effect is observed with polarity modulated by thermal histories, suggesting that there are dynamic superconducting order domains in a spontaneous time-reversal symmetry-breaking background. Strikingly, the critical current exhibits double-slit superconductivity interference patterns when subjected to an external magnetic field. The characteristics of the patterns are modulated by thermal cycling. These phenomena are proposed as a consequence of periodically modulated supercurrents flowing along certain domain boundaries constrained by fluxoid quantization. Our results imply a time-reversal symmetry-breaking superconducting order, opening a potential for exploring exotic physics, for example, Majorana zero modes, in this intriguing topological kagome system.
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The newly discovered kagome superconductors represent a promising platform for investigating the interplay between band topology, electronic order and lattice geometry1-9. Despite extensive research efforts on this system, the nature of the superconducting ground state remains elusive10-17. In particular, consensus on the electron pairing symmetry has not been achieved so far18-20, in part owing to the lack of a momentum-resolved measurement of the superconducting gap structure. Here we report the direct observation of a nodeless, nearly isotropic and orbital-independent superconducting gap in the momentum space of two exemplary CsV3Sb5-derived kagome superconductors-Cs(V0.93Nb0.07)3Sb5 and Cs(V0.86Ta0.14)3Sb5-using ultrahigh-resolution and low-temperature angle-resolved photoemission spectroscopy. Remarkably, such a gap structure is robust to the appearance or absence of charge order in the normal state, tuned by isovalent Nb/Ta substitutions of V. Our comprehensive characterizations of the superconducting gap provide indispensable information on the electron pairing symmetry of kagome superconductors, and advance our understanding of the superconductivity and intertwined electronic orders in quantum materials.
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Mendelian randomization (MR), which utilizes genetic variants as instrumental variables (IVs), has gained popularity as a method for causal inference between phenotypes using genetic data. While efforts have been made to relax IV assumptions and develop new methods for causal inference in the presence of invalid IVs due to confounding, the reliability of MR methods in real-world applications remains uncertain. Instead of using simulated datasets, we conducted a benchmark study evaluating 16 two-sample summary-level MR methods using real-world genetic datasets to provide guidelines for the best practices. Our study focused on the following crucial aspects: type I error control in the presence of various confounding scenarios (e.g., population stratification, pleiotropy, and family-level confounders like assortative mating), the accuracy of causal effect estimates, replicability, and power. By comprehensively evaluating the performance of compared methods over one thousand exposure-outcome trait pairs, our study not only provides valuable insights into the performance and limitations of the compared methods but also offers practical guidance for researchers to choose appropriate MR methods for causal inference.
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Benchmarking , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Análise da Randomização Mendeliana/métodos , Humanos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Variação Genética , Causalidade , Polimorfismo de Nucleotídeo Único , Modelos GenéticosRESUMO
Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration.
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Neoplasias da Mama/patologia , Movimento Celular , Neoplasias da Próstata/patologia , Proteínas Quinases Associadas a Fase S/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Caseína Quinase I/metabolismo , Linhagem Celular Tumoral , Citoplasma/metabolismo , Modelos Animais de Doenças , Humanos , Lisina/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Neoplasias da Próstata/metabolismo , Processamento de Proteína Pós-Traducional , Sinais Direcionadores de Proteínas , Proteínas Quinases Associadas a Fase S/química , Proteínas Quinases Associadas a Fase S/genética , Alinhamento de Sequência , UbiquitinaçãoRESUMO
ABSTRACT: Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance. The G101V mutation in BCL2 is frequently observed in patients who relapsed treated with venetoclax and sufficient to confer resistance to venetoclax by interfering with compound binding. Therefore, the development of next-generation BCL2 inhibitors to overcome drug resistance is urgently needed. In this study, we discovered that sonrotoclax, a potent and selective BCL2 inhibitor, demonstrates stronger cytotoxic activity in various hematologic cancer cells and more profound tumor growth inhibition in multiple hematologic tumor models than venetoclax. Notably, sonrotoclax effectively inhibits venetoclax-resistant BCL2 variants, such as G101V. The crystal structures of wild-type BCL2/BCL2 G101V in complex with sonrotoclax revealed that sonrotoclax adopts a novel binding mode within the P2 pocket of BCL2 and could explain why sonrotoclax maintains stronger potency than venetoclax against the G101V mutant. In summary, sonrotoclax emerges as a potential second-generation BCL2 inhibitor for the treatment of hematologic malignancies with the potential to overcome BCL2 mutation-induced venetoclax resistance. Sonrotoclax is currently under investigation in multiple clinical trials.
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Antineoplásicos , Compostos Bicíclicos Heterocíclicos com Pontes , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hematológicas , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Animais , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Mutação , Apoptose/efeitos dos fármacosRESUMO
The high-valent cobalt-oxo species (Co(IV)=O) is being increasingly investigated for water purification because of its high redox potential, long half-life, and antiinterference properties. However, generation of Co(IV)=O is inefficient and unsustainable. Here, a cobalt-single-atom catalyst with N/O dual coordination was synthesized by O-doping engineering. The O-doped catalyst (Co-OCN) greatly activated peroxymonosulfate (PMS) and achieved a pollutant degradation kinetic constant of 73.12 min-1 g-2, which was 4.9 times higher than that of Co-CN (catalyst without O-doping) and higher than those of most reported single-atom catalytic PMS systems. Co-OCN/PMS realized Co(IV)=O dominant oxidation of pollutants by increasing the steady-state concentration of Co(IV)=O (1.03 × 10-10 M) by 5.9 times compared with Co-CN/PMS. A competitive kinetics calculation showed that the oxidation contribution of Co(IV)=O to micropollutant degradation was 97.5% during the Co-OCN/PMS process. Density functional theory calculations showed that O-doping influenced the charge density (increased the Bader charge transfer from 0.68 to 0.85 e), optimized the electron distribution of the Co center (increased the d-band center from -1.14 to -1.06 eV), enhanced the PMS adsorption energy from -2.46 to -3.03 eV, and lowered the energy barrier for generation of the key reaction intermediate (*O*H2O) during Co(IV)=O formation from 1.12 to 0.98 eV. The Co-OCN catalyst was fabricated on carbon felt for a flow-through device, which achieved continuous and efficient removal of micropollutants (degradation efficiency of >85% after 36 h operation). This study provides a new protocol for PMS activation and pollutant elimination through single-atom catalyst heteroatom-doping and high-valent metal-oxo formation during water purification.
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BACKGROUND: Single-cell RNA-Seq analysis can determine the heterogeneity of cells between different tissues at a single-cell level. Coronary artery endothelial cells (ECs) are important to coronary blood flow. However, little is known about the heterogeneity of coronary artery ECs, and cellular identity responses to flow. Identifying endothelial subpopulations will contribute to the precise localization of vascular endothelial subpopulations, thus enabling the precision of vascular injury treatment. METHODS: Here, we performed a single-cell RNA sequencing of 31â 962 cells and functional assays of 3 branches of the coronary arteries (right coronary artery/circumflex left coronary artery/anterior descending left coronary artery) in wild-type mice. RESULTS: We found a compendium of 7 distinct cell types in mouse coronary arteries, mainly ECs, granulocytes, cardiac myocytes, smooth muscle cells, lymphocytes, myeloid cells, and fibroblast cells, and showed spatial heterogeneity between arterial branches. Furthermore, we revealed a subpopulation of coronary artery ECs, CD133+TRPV4high ECs. TRPV4 (transient receptor potential vanilloid 4) in CD133+TRPV4high ECs is important for regulating vasodilation and coronary blood flow. CONCLUSIONS: Our study elucidates the nature and range of coronary arterial cell diversity and highlights the importance of coronary CD133+TRPV4high ECs in regulating coronary vascular tone.
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Células Endoteliais , Canais de Cátion TRPV , Camundongos , Animais , Células Endoteliais/metabolismo , Canais de Cátion TRPV/genética , Análise da Expressão Gênica de Célula Única , Vasodilatação/fisiologia , Endotélio Vascular/metabolismoRESUMO
Wearable sensors are experiencing vibrant growth in the fields of health monitoring systems and human motion detection, with comfort becoming a significant research direction for wearable sensing devices. However, the weak moisture-wicking capability of sensor materials leads to liquid retention, severely restricting the comfort of the wearable sensors. This study employs a pattern-guided alignment strategy to construct microhill arrays, endowing triboelectric materials with directional moisture-wicking capability. Within 2.25 s, triboelectric materials can quickly and directionally remove the droplets, driven by the Laplace pressure differences and the wettability gradient. The directional moisture-wicking triboelectric materials exhibit excellent pressure sensing performance, enabling rapid response/recovery (29.1/37.0 ms), thereby achieving real-time online monitoring of human respiration and movement states. This work addresses the long-standing challenge of insufficient moisture-wicking driving force in flexible electronic sensing materials, holding significant implications for enhancing the comfort and application potential of electronic skin and wearable electronic devices.
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Pressão , Dispositivos Eletrônicos Vestíveis , Molhabilidade , Humanos , Desenho de EquipamentoRESUMO
Two-dimensional (2D) Fe chalcogenides with their rich structures and properties are highly desirable for revealing the torturous transition mechanism of Fe chalcogenides and exploring their potential applications in spintronics and nanoelectronics. Hydrostatic pressure can effectively stimulate phase transitions between various ordered states, allowing one to successfully plot a phase diagram for a given material. Herein, the structural evolution and transport characteristics of 2D FeTe were systematically investigated under extreme conditions by comparing two distinct symmetries, i.e., tetragonal (t) and hexagonal (h) FeTe. We found that t-FeTe presented a pressure-induced transition from an antiferromagnetic state to a ferromagnetic state at â¼3 GPa, corresponding to the tetragonal collapse of the layered structure. Contrarily, the ferromagnetic order of h-FeTe was retained up to 15 GPa, which was evidently confirmed by electrical transport and Raman measurements. Furthermore, T-P phase diagrams for t-FeTe and h-FeTe were mapped under delicate critical conditions. Our results can provide a unique platform to elaborate the extraordinary properties of Fe chalcogenides and further develop their applications.
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PURPOSE: To report a case of a five-month-old Chinese infant who died of interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency presenting with rapid and progressive Pseudomonas aeruginosa sepsis. METHODS: The genetic etiology of IRAK-4 deficiency was confirmed through trio-whole exome sequencing and Sanger sequencing. Functional consequences were invested using an in vitro minigene splicing assay. RESULTS: Trio-whole exome sequencing of genomic DNA identified two novel compound heterozygous mutations, IRAK-4 (NM_016123.3): c.942-1G > A and c.644_651+ 6delTTGCAGCAGTAAGT in the proband, which originated from his symptom-free parents. These mutations were predicted to cause frameshifts and generate three truncated proteins without enzyme activity. CONCLUSIONS: Our findings expand the range of IRAK-4 mutations and provide functional support for the pathogenic effects of splice-site mutations. Additionally, this case highlights the importance of considering the underlying genetic defects of immunity when dealing with unusually overwhelming infections in previously healthy children and emphasizes the necessity for timely treatment with wide-spectrum antimicrobials.
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Quinases Associadas a Receptores de Interleucina-1 , Infecções por Pseudomonas , Pseudomonas aeruginosa , Sepse , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/deficiência , Pseudomonas aeruginosa/genética , Infecções por Pseudomonas/genética , Masculino , Lactente , Sepse/genética , Sepse/microbiologia , Doenças da Imunodeficiência Primária/genética , Mutação com Perda de Função , Heterozigoto , Sequenciamento do Exoma , Síndromes de Imunodeficiência/genéticaRESUMO
BACKGROUND: Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration.This experiment aims to explore how iron deficiency (ID) affects the function of vascular smooth muscle cell (VSMC) and participates in the occurrence and development of AD by regulating gene expression. METHODS: The relationship between iron and AD was proved by Western-blot (WB) and immunostaining experiments in human and animals. Transcriptomic sequencing explored the transcription factors that were altered downstream. WB, flow cytometry and immunofluorescence were used to demonstrate whether ID affected HIF1 expression through oxygen transport. HIF1 signaling pathway and phenotypic transformation indexes were detected in cell experiments. The use of the specific HIF1 inhibitor PX478 further demonstrated that ID worked by regulating HIF1. RESULTS: The survival period of ID mice was significantly shortened and the pathological staining results were the worst. Transcriptomic sequencing indicated that HIF1 was closely related to ID and the experimental results indicated that ID might regulate HIF1 expression by affecting oxygen balance. HIF1 activation regulates the phenotypic transformation of VSMC and participates in the occurrence and development of AD in vivo and in vitro.PX478, the inhibition of HIF1, can improve ID-induced AD exacerbation.
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Dissecção Aórtica , Músculo Liso Vascular , Miócitos de Músculo Liso , Oxigênio , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Dissecção Aórtica/metabolismo , Dissecção Aórtica/etiologia , Dissecção Aórtica/genética , Dissecção Aórtica/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Fator 1 Induzível por Hipóxia/metabolismo , Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Deficiências de Ferro , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Oxigênio/metabolismo , FenótipoRESUMO
Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.
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Aquaporina 4 , Astrócitos , Eixo Encéfalo-Intestino , Hiperamonemia , Encefalopatia Associada a Sepse , Animais , Camundongos , Aquaporina 4/metabolismo , Aquaporina 4/genética , Aquaporina 4/biossíntese , Astrócitos/metabolismo , Hiperamonemia/metabolismo , Encefalopatia Associada a Sepse/metabolismo , Masculino , Eixo Encéfalo-Intestino/fisiologia , Camundongos Endogâmicos C57BL , Amônia/metabolismo , Amônia/sangue , Encéfalo/metabolismo , Transplante de Microbiota FecalRESUMO
Floating gate memory (FGM), composed of van der Waals (vdW) junctions with an atomically thin floating layer for charge storage, is widely employed to develop logic-in memories and in-sensor computing devices. Most research efforts of FGM are spent on achieving long-term charge storage and fast reading/writing for flash and random-access memory. However, dynamic modulation of memory time via a tunneling barrier and vdW interfaces, which is critical for synaptic computing and machine vision, is still lacking. Here, a van der Waals short-term memory with tunable memory windows and retention times from milliseconds to thousands of seconds is reported, which is approximately exponentially proportional to the thickness h-BN (hexagonal boron nitride) barrier. The specific h-BN barrier with fruitful gap states provides charge release channels for trapped charges, making the vdW device switchable between positive photoconductance and negative photoconductance with a broadband light from IR to UV range. The dynamic short-term memory with tunable photo response highlights the design strategy of novel vdW memory vis interface engineering for further intelligent information storage and optoelectronic detection.
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Tree peony (Paeonia suffruticosa) undergoes bud endodormancy, and gibberellin (GA) pathway plays a crucial role in dormancy regulation. Recently, a key DELLA protein PsRGL1 has been identified as a negative regulator of bud dormancy release. However, the mechanism of GA signal to break bud dormancy remains unknown. In this study, yeast two-hybrid screened PsSOC1 interacting with PsRGL1 through its MADS domain, and interaction was identified using pull-down and luciferase complementation imaging assays Transformation in tree peony and hybrid poplar confirmed that PsSOC1 facilitated bud dormancy release. Transcriptome analysis of PsSOC1-overexpressed buds indicated PsCYCD3.3 and PsEBB3 were its potential downstream targets combining with promoter survey, and they also accelerated bud dormancy release verified by genetic analysis. Yeast one-hybrid, electrophoretic mobility shifts assays, chromatin immunoprecipitation quantitative PCR, and dual luciferase assays confirmed that PsSOC1 could directly bind to the CArG motif of PsCYCD3.3 and PsEBB3 promoters via its MADS domain. PsRGL1-PsSOC1 interaction inhibited the DNA-binding activity of PsSOC1. Additionally, PsCYCD3.3 promoted bud dormancy release by rebooting cell proliferation. These findings elucidated a novel GA pathway, GA-PsRGL1-PsSOC1-PsCYCDs, which expanded our understanding of the GA pathway in bud dormancy release.
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Proliferação de Células , Regulação da Expressão Gênica de Plantas , Giberelinas , Proteínas de Plantas , Regiões Promotoras Genéticas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Giberelinas/metabolismo , Regiões Promotoras Genéticas/genética , Dormência de Plantas/genética , Transdução de Sinais , Ligação ProteicaRESUMO
BACKGROUND: "Disulfide death," a form of cellular demise, is triggered by the abnormal accumulation of intracellular disulfides under conditions of glucose deprivation. However, its role in the prognosis of glioma remains undetermined. Therefore, the main objective of this study is to establish prognostic signature based on disulfide death-related genes (DDRGs) and to provide new solutions in choosing the effective treatment of glioma. METHODS: The RNA transcriptome, clinical information, and mutation data of glioma samples were sourced from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), while normal samples were obtained from the Genotype-Tissue Expression (GTEx). DDRGs were compiled from previous studies and selected through differential analysis and univariate Cox regression analysis. The molecular subtypes were determined through consensus clustering analysis. Further, LASSO analysis was employed to select characteristic genes, and subsequently, a risk model comprising seven DDRGs was constructed based on multivariable Cox analysis. Kaplan-Meier survival curves were employed to assess survival differences between high and low-risk groups. Additionally, functional analyses (GO, KEGG, GSEA) were conducted to explore the potential biological functions and signaling pathways of genes associated with the model. The study also explored immune checkpoint (ICP) genes, immune cell infiltration levels, and immune stromal scores. Finally, the effect of Importin-4(IPO4) on glioma has been further confirmed through RT-qPCR, Western blot, and cell functional experiments. RESULTS: 7 genes associated with disulfide death were obtained and two subgroups of patients with different prognosis and clinical characteristics were identified. Risk signature was subsequently developed and proved to serve as an prognostic predictor. Notably, the high-risk group exhibited an immunosuppressive microenvironment characterized by a high concentration of M2 macrophages and regulatory T cells (Tregs). In contrast, the low-risk group showed lower half-maximal inhibitory concentration (IC50) values. Therefore, patients in the high-risk group may benefit more from immunotherapy, while patients in the low-risk group may benefit more from chemotherapy. In addition, in vitro experiments have shown that inhibition of the expression of IPO4 leads to a significant reduction in the proliferation, migration, and invasion of glioma cells. CONCLUSION: This study identified two glioma subtypes and constructed a prognostic signature based on DDRGs. The signature has the potential to optimize the selection of patients for immune- and chemotherapy and provided a potential therapeutic target for glioma.
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Small extracellular vesicles (sEVs) are cell-derived, nanometer-sized particles enclosed by a lipid bilayer. All kinds of biological molecules, including proteins, DNA fragments, RNA, lipids, and metabolites, can be selectively loaded into sEVs and transmitted to recipient cells that are near and distant. Growing shreds of evidence show the significant biological function and the clinical significance of sEVs in cancers. Numerous recent studies have validated that sEVs play an important role in tumor progression and can be utilized to diagnose, stage, grading, and monitor early tumors. In addition, sEVs have also served as drug delivery nanocarriers and cancer vaccines. Although it is still infancy, the field of basic and translational research based on sEVs has grown rapidly. In this review, we summarize the latest research on sEVs in gliomas, including their role in the malignant biological function of gliomas, and the potential of sEVs in non-invasive diagnostic and therapeutic approaches, i.e., as nanocarriers for drug or gene delivery and cancer vaccines.
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It has been theoretically predicted that perturbation of the Berry curvature by electromagnetic fields gives rise to intrinsic nonlinear anomalous Hall effects that are independent of scattering. Two types of nonlinear anomalous Hall effects are expected. The electric nonlinear Hall effect has recently begun to receive attention, while very few studies are concerned with the magneto-nonlinear Hall effect. Here, we combine experiment and first-principles calculations to show that the kagome ferromagnet Fe_{3}Sn_{2} displays such a magneto-nonlinear Hall effect. By systematic field angular and temperature-dependent transport measurements, we unambiguously identify a large anomalous Hall current that is linear in both applied in-plane electric and magnetic fields, utilizing a unique in-plane configuration. We clarify its dominant orbital origin and connect it to the magneto-nonlinear Hall effect. The effect is governed by the intrinsic quantum geometric properties of Bloch electrons. Our results demonstrate the significance of the quantum geometry of electron wave functions from the orbital degree of freedom and open up a new direction in Hall transport effects.
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Developing efficient nanostructured electrocatalysts for N2 reduction to NH3 under mild conditions remains a major challenge. The Fe-Mo cofactor serves as the archetypal active site in nitrogenase. Inspired by nitrogenase, we designed a series of heteronuclear dual-atom catalysts (DACs) labeled as FeMoN6-a Xa (a=1, 2, 3; X=B, C, O, S) anchored on the pore of g-C3 N4 to probe the impact of coordination on FeMo-catalyzed nitrogen fixation. The stability, reaction paths, activity, and selectivity of 12 different FeMoN6-a Xa DACs have been systematically studied using density functional theory. Of these, four DACs (FeMoN5 B1 , FeMoN5 O1 , FeMoN4 O2 , and FeMoN3 C3 ) displayed promising nitrogen reduction reaction (NRR) performance. Notably, FeMoN5 O1 stands out with an ultralow limiting potential of -0.11â V and high selectivity. Analysis of the density of states and charge/spin changes shows FeMoN5 O1 's high activity arises from optimal N2 binding on Fe initially and synergy of the FeMo dimer enabling protonation in NRR. This work contributes to the advancement of rational design for efficient NRR catalysts by regulating atomic coordination environments.
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Abdominal aortic aneurysm (AAA) is a dangerous condition affecting the aorta. Macrophage pyroptosis, phenotypic transformation, and apoptosis of aortic smooth muscle cells (ASMCs) are pivotal mechanisms in AAA pathogenesis. This study explores how Gasdermin B (GSDMB) regulates macrophage non-canonical pyroptosis and its impact on the phenotypic transformation and apoptosis of ASMCs, thereby unveiling the role of GSDMB in AAA pathogenesis. Immunofluorescence analysis was used to assess the expression levels and localization of GSDMB, cysteinyl aspartate-specific protease-4 (Caspase-4), and N-terminal of cleaved GSDMD (N-GSDMD) in AAA tissues. A cell model that mimics macrophage non-canonical pyroptosis was established by treating THP-1 cells with lipopolysaccharide (LPS). THP-1 cells with reduced or increased GSDMB were generated using small interfering RNA (siRNA) or plasmids. Co-culture experiments involving THP-1 cells and HASMCs were conducted to explore the impact of GSDMB on HASMCs. The mitochondrial reactive oxygen species (mtROS) scavenger Mito-TEMPO lowered mtROS levels in THP-1 cells. Our findings revealed that GSDMB was significantly upregulated in AAA macrophages, which was accompanied by robust non-canonical pyroptosis. THP-1 cells showed non-canonical pyroptosis in response to LPS, which was accompanied by an increase in GSDMB. Further research demonstrated that altering GSDMB, either by knockdown or overexpression, can affect macrophage non-canonical pyroptosis as well as the phenotypic transformation and apoptosis of HASMCs. LPS-induced non-canonical pyroptosis in THP-1 cells was associated with an increase in mtROS, whereas Mito-TEMPO effectively decreased non-canonical pyroptosis and the expression of GSDMB. These findings suggest that GSDMB plays a role in AAA macrophage non-canonical pyroptosis, which influences the phenotypic transformation and apoptosis of HASMCs. The mtROS-Dynamin-Related Protein 1 (Drp1) axis is likely to regulate the GSDMB-mediated non-canonical pyroptosis.
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BACKGROUND: Ovarian cancer is one of the most common gynecological malignancies due to the lack of early symptoms, early diagnosis and limited screening. Therefore, it is necessary to understand the molecular mechanism underlying the occurrence and progression of ovarian cancer and to identify a basic biomarker for the early diagnosis and clinical treatment of ovarian cancer. METHODS: The association between FBXO28 and ovarian cancer prognosis was analyzed using KaplanâMeier survival analysis. The difference in FBXO28 mRNA expression between normal ovarian tissues and ovarian tumor tissues was obtained from The Cancer Genome Atlas (TCGA), and Genotype-Tissue Expression (GTEx) cohorts. The expression levels of the FBXO28 protein in ovarian cancer tissues and normal ovarian tissues were measured via immunohistochemical staining. Western blotting was used to determine the level of FBXO28 expression in ovarian cancer cells. The CCK-8, the colony formation, Transwell migration and invasion assays were performed to evaluate cell proliferation and motility. RESULTS: We found that a higher expression level of FBXO28 was associated with poor prognosis in ovarian cancer patients. Analysis of the TCGA and GTEx cohorts showed that the FBXO28 mRNA level was lower in normal ovarian tissue samples than in ovarian cancer tissue samples. Compared with that in normal ovarian tissues or cell lines, the expression of FBXO28 was greater in ovarian tumor tissues or tumor cells. The upregulation of FBXO28 promoted the viability, proliferation, migration and invasion of ovarian cancer cells. Finally, we demonstrated that FBXO28 activated the TGF-beta1/Smad2/3 signaling pathway in ovarian cancer. CONCLUSIONS: In conclusion, FBXO28 enhanced oncogenic function via upregulation of the TGF-beta1/Smad2/3 signaling pathway in ovarian cancer.