Screening optimal candidates with operable, early-stage triple-negative breast cancer benefitting from capecitabine maintenance: A post-hoc analysis of the SYSUCC-001 study.

BACKGROUND: To explore whether specific clinicopathological covariates are predictive for a benefit from capecitabine maintenance in early-stage triple-negative breast cancer (TNBC) in the SYSUCC-001 phase III clinical trial. METHODS: Candidate covariates included age, menstrual status, type of surgery, postoperative chemotherapy regimen, Ki-67 percentage, histologic grade, primary tumor size, lymphovascular invasion, node status, and capecitabine medication. Their nonlinear effects were modeled by restricted cubic spline. The primary endpoint was disease-free survival (DFS). A survival prediction model was constructed using Cox proportional hazards regression analysis. RESULTS: All 434 participants (306 in development cohort and 128 in validation cohort) were analyzed. The estimated 5-year DFS in development and validation cohorts were 77.8 % (95 % CI, 72.9%-82.7 %) and 78.2 % (95 % CI, 70.9%-85.5 %), respectively. Age and node status had significant nonlinear effects on DFS. The prediction model constructed using four covariates (node status, lymphovascular invasion, capecitabine maintenance, and age) demonstrated satisfactory calibration and fair discrimination ability, with C-index of 0.722 (95 % CI, 0.662-0.781) and 0.764 (95 % CI, 0.668-0.859) in development and validation cohorts, respectively. Moreover, patient classification was conducted according to their risk scores calculated using our model, in which, notable survival benefits were reported in low-risk subpopulations. An easy-to-use online calculator for predicting benefit of capecitabine maintenance was also designed. CONCLUSIONS: The evidence-based prediction model can be readily assessed at baseline, which might help decision making in clinical practice and optimize patient stratification, especially for those with low-risk, capecitabine maintenance might be a potential strategy in the early-disease setting.

Exposure to 6-PPD quinone causes damage on mitochondrial complex I/II associated with lifespan reduction in Caenorhabditis elegans.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) is an emerging pollutant transformed from 6-PPD. However, the effect of 6-PPDQ exposure on mitochondrion and underlying mechanism remains largely unclear. Using Caenorhabditis elegans as animal model, exposed to 6-PPDQ at 0.1-10 µg/L was performed form L1 larvae to adult day-1. Exposure to 6-PPDQ (1 and 10 µg/L) could increase oxygen consumption rate and decease adenosine 5'-triphosphate (ATP) content, suggesting induction of mitochondrial dysfunction. Activities of NADH dehydrogenase (complex I) and succinate dehydrogenase (complex II) were inhibited, accompanied by a decrease in expressions of gas-1, nuo-1, and mev-1. RNAi of gas-1 and mev-1 enhanced mitochondrial dysfunction and reduced lifespan of 6-PPDQ exposed nematodes. GAS-1 and MEV-1 functioned in parallel to regulate 6-PPDQ toxicity to reduce the lifespan. Insulin peptides and the insulin signaling pathway acted downstream of GAS-1 and MEV-1 to control the 6-PPDQ toxicity on longevity. Moreover, RNAi of sod-2 and sod-3, targeted genes of daf-16, caused susceptibility to 6-PPDQ toxicity in reducing lifespan and in causing reactive oxygen species (ROS) production. Therefore, 6-PPDQ at environmentally relevant concentrations (ERCs) potentially caused mitochondrial dysfunction by affecting mitochondrial complexes I and II, which was associated with lifespan reduction by affecting insulin signaling in organisms.

STING mediates LPS-induced acute lung injury by regulating ferroptosis.

The pathogenesis of acute lung injury is not fully understood. Stimulator of interferon genes (STING) and ferroptosis have been implicated in various pathological and physiological processes, including acute lung injury (ALI). However, the relationship between STING and ferroptosis in lipopolysaccharide (LPS)-induced ALI is unclear. We found that LPS stimulation activated STING and ferroptosis. Furthermore, STING knockout and ferroptosis inhibitor alleviated lung inflammation and epithelial cell damage. Also, STING knockout reduced inflammation injury and ferroptosis. Notably, the ferroptosis inducer reversed the alleviation of inflammation caused by STING knockout. These results show that STING participates in the inflammation injury of ALI by regulating ferroptosis. Results also showed that p-STAT3 levels increased after STING knockout, suggesting that STING negatively regulates STAT3 activation. Besides, STAT3 inhibitor aggravated ferroptosis after STING knockout, indicating that STING regulates ferroptosis through STAT3 signaling. In conclusion, STING mediates LPS-induced ALI by regulating ferroptosis, indicating that STING and ferroptosis may be new targets for ALI treatment.

Crocus genome reveals the evolutionary origin of crocin biosynthesis.

Crocus sativus (saffron) is a globally autumn-flowering plant, and its stigmas are the most expensive spice and valuable herb medicine. Crocus specialized metabolites, crocins, are biosynthesized in distant species, Gardenia (eudicot) and Crocus (monocot), and the evolution of crocin biosynthesis remains poorly understood. With the chromosome-level Crocus genome assembly, we revealed that two rounds of lineage-specific whole genome triplication occurred, contributing important roles in the production of carotenoids and apocarotenoids. According to the kingdom-wide identification, phylogenetic analysis, and functional assays of carotenoid cleavage dioxygenases (CCDs), we deduced that the duplication, site positive selection, and neofunctionalization of Crocus-specific CCD2 from CCD1 members are responsible for the crocin biosynthesis. In addition, site mutation of CsCCD2 revealed the key amino acids, including I143, L146, R161, E181, T259, and S292 related to the catalytic activity of zeaxanthin cleavage. Our study provides important insights into the origin and evolution of plant specialized metabolites, which are derived by duplication events of biosynthetic genes.

Advances and challenges of exosome-derived noncoding RNAs for hepatocellular carcinoma diagnosis and treatment.

Exosomes, also termed extracellular vesicles (EVs), are an important component of the tumor microenvironment (TME) and exert versatile effects on the molecular communications in the TME of hepatocellular carcinoma (HCC). Exosome-mediated intercellular communication is closely associated with the tumorigenesis and development of HCC. Exosomes can be extracted through ultracentrifugation and size exclusion, followed by molecular analysis through sequencing. Increasing studies have confirmed the important roles of exosome-derived ncRNAs in HCC, including tumorigenesis, progression, immune escape, and treatment resistance. Due to the protective membrane structure of exosomes, the ncRNAs carried by exosomes can evade degradation by enzymes in body fluids and maintain good expression stability. Thus, exosome-derived ncRNAs are highly suitable as biomarkers for the diagnosis and prognostic prediction of HCC, such as exosomal miR-21-5p, miR-221-3p and lncRNA-ATB. In addition, substantial studies revealed that the up-or down-regulation of exosome-derived ncRNAs had an important impact on HCC progression and response to treatment. Exosomal biomarkers, such as miR-23a, lncRNA DLX6-AS1, miR-21-5p, lncRNA TUC339, lncRNA HMMR-AS1 and hsa_circ_0004658, can reshape immune microenvironment by regulating M2-type macrophage polarization and then promote HCC development. Therefore, by controlling exosome biogenesis and modulating exosomal ncRNA levels, HCC may be inhibited or eliminated. In this current review, we summarized the recent findings on the role of exosomes in HCC progression and analyzed the relationship between exosome-derived ncRNAs and HCC diagnosis and treatment.

Effect of Particle Strength on SiCp/Al Composite Properties with Network Architecture Design.

Recent works have experimentally proven that metal matrix composites (MMCs) with network architecture present improved strength-ductility match. It is envisaged that the performance of architecturally designed composites is particularly sensitive to reinforcement strength. Here, reinforcing particles with various fracture strengths were introduced in numerical models of composites with network particle distribution. The results revealed that a low particle strength (1 GPa) led to early-stage failure and brittle fracture. Nevertheless, a high particle strength (5 GPa) delayed the failure behavior and led to ductile fracture at the SiC/Al-Al macro-interface areas. Therefore, the ultimate tensile strengths (UTS) of the network SiC/Al composites increased from 290 to 385 MPa, with rising particle strength from 1 to 5 GPa. Based on the composite property, different particle fracture threshold strengths existed for homogeneous (~2.7 GPa) and network (~3.7 GPa) composites. The higher threshold strength in network composites was related to the increased stress concentration induced by network architecture. Unfortunately, the real fracture strength of the commercial SiC particle is 1-2 GPa, implying that it is possible to select a high-strength particle necessary for efficient network architecture design.

Lineage-Specific CYP80 Expansion and Benzylisoquinoline Alkaloid Diversity in Early-Diverging Eudicots.

Menispermaceae species, as early-diverging eudicots, can synthesize valuable benzylisoquinoline alkaloids (BIAs) like bisbenzylisoquinoline alkaloids (bisBIAs) and sinomenines with a wide range of structural diversity. However, the evolutionary mechanisms responsible for their chemo-diversity are not well understood. Here, a chromosome-level genome assembly of Menispermum dauricum is presented and demonstrated the occurrence of two whole genome duplication (WGD) events that are shared by Ranunculales and specific to Menispermum, providing a model for understanding chromosomal evolution in early-diverging eudicots. The biosynthetic pathway for diverse BIAs in M. dauricum is reconstructed by analyzing the transcriptome and metabolome. Additionally, five catalytic enzymes - one norcoclaurine synthase (NCS) and four cytochrome P450 monooxygenases (CYP450s) - from M. dauricum are responsible for the formation of the skeleton, hydroxylated modification, and C-O/C-C phenol coupling of BIAs. Notably, a novel leaf-specific MdCYP80G10 enzyme that catalyzes C2'-C4a phenol coupling of (S)-reticuline into sinoacutine, the enantiomer of morphinan compounds, with predictable stereospecificity is discovered. Moreover, it is found that Menispermum-specific CYP80 gene expansion, as well as tissue-specific expression, has driven BIA diversity in Menispermaceae as compared to other Ranunculales species. This study sheds light on WGD occurrences in early-diverging eudicots and the evolution of diverse BIA biosynthesis.

A NiFe PBA/AuNPs nanocomposite sensitive immunosensor for electrochemical detection of PSA.

In this paper, a label-free electrochemical immunosensor for sensitive detection of prostate antigen (PSA) was developed based on a NiFe PBA/AuNPs composite. The prostate antigen antibody was immobilized and the immunosensor was constructed by using a glassy carbon electrode modified with a nanocomposite consisting of nickel-iron Prussian blue analog (NiFe PBA) and gold nanoparticles (AuNPs). Due to the good biological affinity of AuNPs for biomolecules, as well as the porous nanostructure and regular shape of NiFe PBA, NiFe PBA/AuNPs nanocomposites significantly improve the electron transport rate, while achieving excellent performance for the sensor. Due to the interaction between the antibody and the antigen on the modified electrode, the current signal of the NiFe PBA itself is reduced due to the redox changes in Fe2+ and Fe3+, which can be determined by differential pulse voltammetry (DPV). Therefore, the monitoring of prostate antigen detection is realized. Under optimal experimental conditions, the immunosensor exhibited excellent detection performance with a dynamic response range from 0.5 pg mL-1 to 1000 pg mL-1 for the PSA concentration and a detection limit of 0.23 pg mL-1 (S/N = 3). In addition, the PSA aptasensor has good selectivity, high stability, and satisfactory reproducibility and has broad potential in clinical research and diagnostic applications.

Advances in antitumor activity and mechanism of natural steroidal saponins: A review of advances, challenges, and future prospects.

BACKGROUND: Cancer, the second leading cause of death worldwide following cardiovascular diseases, presents a formidable challenge in clinical settings due to the extensive toxic side effects associated with primary chemotherapy drugs employed for cancer treatment. Furthermore, the emergence of drug resistance against specific chemotherapeutic agents has further complicated the situation. Consequently, there exists an urgent imperative to investigate novel anticancer drugs. Steroidal saponins, a class of natural compounds, have demonstrated notable antitumor efficacy. Nonetheless, their translation into clinical applications has remained unrealized thus far. In light of this, we conducted a comprehensive systematic review elucidating the antitumor activity, underlying mechanisms, and inherent limitations of steroidal saponins. Additionally, we propose a series of strategic approaches and recommendations to augment the antitumor potential of steroidal saponin compounds, thereby offering prospective insights for their eventual clinical implementation. PURPOSE: This review summarizes steroidal saponins' antitumor activity, mechanisms, and limitations. METHODS: The data included in this review are sourced from authoritative databases such as PubMed, Web of Science, ScienceDirect, and others. RESULTS: A comprehensive summary of over 40 steroidal saponin compounds with proven antitumor activity, including their applicable tumor types and structural characteristics, has been compiled. These steroidal saponins can be primarily classified into five categories: spirostanol, isospirostanol, furostanol, steroidal alkaloids, and cholestanol. The isospirostanol and cholestanol saponins are found to have more potent antitumor activity. The primary antitumor mechanisms of these saponins include tumor cell apoptosis, autophagy induction, inhibition of tumor migration, overcoming drug resistance, and cell cycle arrest. However, steroidal saponins have limitations, such as higher cytotoxicity and lower bioavailability. Furthermore, strategies to address these drawbacks have been proposed. CONCLUSION: In summary, isospirostanol and cholestanol steroidal saponins demonstrate notable antitumor activity and different structural categories of steroidal saponins exhibit variations in their antitumor signaling pathways. However, the clinical application of steroidal saponins in cancer treatment still faces limitations, and further research and development are necessary to advance their potential in tumor therapy.

Classification, biosynthesis, and biological functions of triterpene esters in plants.

Triterpene esters comprise a class of secondary metabolites that are synthesized by decorating triterpene skeletons with a series of oxidation, glycosylation, and acylation modifications. Many triterpene esters with important bioactivities have been isolated and identified, including those with applications in the pesticide, pharmaceutical, and cosmetic industries. They also play essential roles in plant defense against pests, diseases, physical damage (as part of the cuticle), and regulation of root microorganisms. However, there has been no recent summary of the biosynthetic pathways and biological functions of plant triterpene esters. Here, we classify triterpene esters into five categories based on their skeletons and find that C-3 oxidation may have a significant effect on triterpenoid acylation. Fatty acid and aromatic moieties are common ligands present in triterpene esters. We further analyze triterpene ester synthesis-related acyltransferases (TEsACTs) in the triterpene biosynthetic pathway. Using an evolutionary classification of BAHD acyltransferases (BAHD-ATs) and serine carboxypeptidase-like acyltransferases (SCPL-ATs) in Arabidopsis thaliana and Oryza sativa, we classify 18 TEsACTs with identified functions from 11 species. All the triterpene-skeleton-related TEsACTs belong to BAHD-AT clades IIIa and I, and the only identified TEsACT from the SCPL-AT family belongs to the CP-I subfamily. This comprehensive review of the biosynthetic pathways and bioactivities of triterpene esters provides a foundation for further study of their bioactivities and applications in industry, agricultural production, and human health.

Garlic-Derived Exosome-like Nanovesicles-Based Wound Dressing for Staphylococcus aureus Infection Visualization and Treatment.

Garlic-derived exosome-like nanovesicles (GELNs) could function in interspecies communication and may serve as natural therapeutics to regulate the inflammatory response or as nanocarriers to efficiently deliver specific drugs. Staphylococcus aureus (S. aureus) is able to hide within host cells to evade immune clearance and antibiotics, leading to life-threatening infections. On-site detection and efficient treatment of intracellular S. aureus infection in wounds remain challenging. Herein, we report a thermosensitive, injectable, visible GELNs-based wound dressing, Van@GELNs/F127 hydrogel (gel Van@GELNs), which is H2O2-responsive and can slowly release vancomycin into host cells forS. aureus infection visualization and treatment in wounds. GELNs show inherent antibacterial activity, which is significantly enhanced after loading vancomycin. Both GELNs and Van@GELNs have the ability to be internalized by cells, so Van@GELNs are more effective than free vancomycin in killing S. aureus in RAW 264.7 macrophages. When applied to an S. aureus-infected wound on a mouse, the colorless HRP&ABTS/Van@GELNs/F127 solution immediately changes to a green hydrogel and shows better therapeutic effect than vancomycin. Thus, direct visualization by the naked eye and effective treatment of S. aureus infection in wounds are achieved by gel Van@GELNs. We anticipate gel Van@GELNs be applied for the theranostics of S. aureus infection diseases in the clinic in the near future.

Polyethylene nanoparticles at environmentally relevant concentrations enhances neurotoxicity and accumulation of 6-PPD quinone in Caenorhabditis elegans.

The exposure risk of 6-PPD quinone (6-PPDQ) has aroused increasing concern. In the natural environment, 6-PPDQ could interact with other pollutants, posing more severe environmental problems and toxicity to organisms. We here examined the effect of polyethylene nanoplastic (PE-NP) on 6-PPDQ neurotoxicity and the underling mechanisms in Caenorhabditis elegans. In nematodes, PE-NP (1 and 10 µg/L) decreased locomotion behavior, but did not affect development of D-type neurons. Exposure to PE-NP (1 and 10 µg/L) strengthened neurotoxicity of 6-PPDQ (10 µg/L) on the aspect of locomotion and neurodegeneration induction of D-type motor neurons. Exposure to PE-NPs (10 µg/L) caused increase in expressions of mec-4, asp-3, and asp-4 governing neurodegeneration in 10 µg/L 6-PPDQ exposed nematodes. Moreover, exposure to PE-NP (10 µg/L) increased expression of some neuronal genes (daf-7, dbl-1, jnk-1, and mpk-1) in 6-PPDQ exposed nematodes, and RNAi of these genes resulted in susceptibility to neurotoxicity of PE-NP and 6-PPDQ. 6-PPDQ could be adsorbed by PE-NPs, and resuspension of PE-NP and 6-PPDQ after adsorption equilibrium exhibited similar neurotoxicity to co-exposure of PE-NP and 6-PPDQ. In addition, exposure to PE-NP (1 and 10 µg/L) increased 6-PPDQ accumulation in body of nematodes and increased defecation cycle length in 6-PPDQ exposed nematodes. Therefore, 6-PPDQ could be adsorbed on nanoplastics (such as PE-NPs) and enhance both neurotoxicity and accumulation of 6-PPDQ in organisms.

Comparison of reproductive toxicity between pristine and aged polylactic acid microplastics in Caenorhabditis elegans.

Caenorhabditis elegans was employed as model to compare reproductive toxicity between pristine and aged polylactic acid microplastics (PLA-MPs). Aged PLA-MPs induced by UV irradiation showed degradation reflected by decrease in size and alteration in morphological surface. Aged PLA-MPs also exhibited some certain changes of chemical properties compared to pristine PLA-MP. Compared with pristine PLA-MPs, more severe toxicity on reproductive capacity and gonad development was detected in 1-100 µg/L aged PLA-MPs. Meanwhile, aged PLA-MPs caused more severe enhancement in germline apoptosis and alterations in expressions of ced-9, ced-4, ced-3, and egl-1 governing cell apoptosis. In addition, aged PLA-MPs resulted in more severe increase in expression of DNA damage related genes (cep-1, mrt-2, hus-1, and clk-2) compared to pristine PLA-MPs, and the alterations in expression of ced-9, ced-4, ced-3, and egl-1 in pristine and aged PLA-MPs could be reversed by RNAi of cep-1, mrt-2, hus-1, and clk-2. Besides this, enhanced germline apoptosis in pristine and aged PLA-MPs exposed animals was also suppressed by RNAi of cep-1, mrt-2, hus-1, and clk-2. Therefore, our results suggested the more severe exposure risk of aged PLA-MPs than pristine PLA-MPs in causing reproductive toxicity, which was associated with the changed physicochemical properties and DNA damage induced germline apoptosis.

Chronic neurotoxicity of Tetrabromobisphenol A: Induction of oxidative stress and damage to neurons in Caenorhabditis elegans.

Tetrachlorobisphenol A (TCBPA) has been used as an alternative flame retardant in various fields. However, the long-term effects of TCBPA on the nervous system remain unclear. Thus, Caenorhabditis elegans (L4 larvae) were selected as a model animal to investigate the neurotoxic effects and underlying mechanisms after 10 d of TCBPA exposure. Exposure to TCBPA (0.01-100 µg/L) decreased locomotive behavior in a concentration-dependent manner. In addition, reactive oxygen species (ROS) formation and lipofuscin accumulation were significantly increased, and the expression of sod-3 was upregulated in the exposed nematodes, indicating that TCBPA exposure induced oxidative damage. Furthermore, 100 µg/L TCBPA exposure caused a reduction in dopamine and serotonin levels, and damage in dopaminergic and serotoninergic neurons, which was further confirmed by the downregulated expression of related genes (e.g., dop-1, dop-3, cat-1, and mod-1). Molecular docking analysis demonstrated the potential of TCBPA to bind to the neurotransmitter receptor proteins DOP-1, DOP-3, and MOD-1. These results indicate that chronic exposure to TCBPA induces neurotoxic effects on locomotive behavior, which is associated with oxidative stress and damage to dopaminergic and serotoninergic neurons.

The extraction of buckwheat protein and its interaction with kappa-carrageenan: Textural, rheological, microstructural, and chemical properties.

Current plant-based foods use plant proteins as a key structuring and texturing ingredient. The use of water for extraction can replace conventional protein extraction methods. Water extraction of protein is environmentally friendly and could prevent the loss of protein functionality due to extreme pH changes. This study demonstrates an aqueous extraction method, coupled with ultrasound as pre-treatment, to obtain buckwheat protein (BWPE) and assess its gelling property and composited gel with kappa-carrageenan (k-carr). Textural and rheological analyses showed that the hardness and storage modulus of the composited gel containing 1 % w/w BWPE and 1 % w/w k-carr was 4.2-fold and 100-fold, respectively, higher than k-carr gel at 1 % w/w. Light microscopy showed a mixed bi-continuous gel system, with k-carr reinforcing the protein gel network. Besides volume exclusion effects, chemical bond and FTIR analyses revealed that adding k-carr to BWPE altered the protein's secondary structure and mediated protein denaturation during heating. This results in greater ß-sheet content, which creates a more organised gel structure. These results demonstrated that ultrasound-assisted water-extracted BWPE, together with varying concentrations of k-carr, can be used to develop composited gels of tailorable textural and rheological properties to suit different food applications.

Application of Global Leadership Initiative on Malnutrition criteria in patients with liver cirrhosis.

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) criteria were published to build a global consensus on nutritional diagnosis. Reduced muscle mass is a phenotypic criterion with strong evidence to support its inclusion in the GLIM consensus criteria. However, there is no consensus regarding how to accurately measure and define reduced muscle mass in clinical settings. This study aimed to investigate the optimal reference values of skeletal muscle mass index for diagnosing sarcopenia and GLIM-defined malnutrition, as well as the prevalence of GLIM-defined malnutrition in hospitalized cirrhotic patients. METHODS: This retrospective study was conducted on 1002 adult patients with liver cirrhosis between January 1, 2018, and February 28, 2022, at Beijing You-An Hospital, Capital Medical University. Adult patients with a clinical diagnosis of liver cirrhosis and who underwent an abdominal computed tomography (CT) examination during hospitalization were included in the study. These patients were randomly divided into a modeling group (cohort 1, 667 patients) and a validation group (cohort 2, 335 patients). In cohort 1, optimal cut-off values of skeletal muscle index at the third lumbar skeletal muscle index (L3-SMI) were determined using receiver operating characteristic analyses against in-hospital mortality in different gender groups. Next, patients in cohort 2 were screened for nutritional risk using the Nutritional Risk Screening 2002 (NRS-2002), and malnutrition was diagnosed by GLIM criteria. Additionally, the reference values of reduced muscle mass in GLIM criteria were derived from the L3-SMI values from cohort 1. Multivariate logistic regression analysis was used to analyze the association between GLIM-defined malnutrition and clinical outcomes. RESULTS: The optimal cut-off values of L3-SMI were 39.50 cm 2 /m 2 for male patients and 33.06 cm 2 /m 2 for female patients. Based on the cut-off values, 31.63% (68/215) of the male patients and 23.3% (28/120) of the female patients had CT-determined sarcopenia in cohort 2. The prevalence of GLIM-defined malnutrition in cirrhotic patients was 34.3% (115/335) and GLIM-defined malnutrition was an independent risk factor for in-hospital mortality in patients with liver cirrhosis ( Wald = 6.347, P  = 0.012). CONCLUSIONS: This study provided reference values for skeletal muscle mass index and the prevalence of GLIM-defined malnutrition in hospitalized patients with liver cirrhosis. These reference values will contribute to applying the GLIM criteria in cirrhotic patients.

Ni Single-Atoms Based Memristors with Ultrafast Speed and Ultralong Data Retention.

Memristor with low-power, high density, and scalability fulfills the requirements of the applications of the new computing system beyond Moore's law. However, there are still nonideal device characteristics observed in the memristor to be solved. The important observation is that retention and speed are correlated parameters of memristor with trade off against each other. The delicately modulating distribution and trapping level of defects in electron migration-based memristor is expected to provide a compromise method to address the contradictory issue of improving both switching speed and retention capability. Here, high-performance memristor based on the structure of ITO/Ni single-atoms (NiSAs/N-C)/Polyvinyl pyrrolidone (PVP)/Au is reported. By utilizing well-distributed trapping sites , small tunneling barriers/distance and high charging energy, the memristor with an ultrafast switching speed of 100 ns, ultralong retention capability of 106  s, a low set voltage (Vset ) of ≈0.7 V, a substantial ON/OFF ration of 103 , and low spatial variation in cycle-to-cycle (500 cycles) and device-to-device characteristics (128 devices) is demonstrated. On the premise of preserving the strengths of a fast switching speed, this memristor exhibits ultralong retention capability comparable to the commercialized flash memory. Finally, a memristor ratioed logic-based combinational memristor array to realize the one-bit full adder is further implemented.

Targeting the cGAS-STING Pathway Inhibits Peripheral T-cell Lymphoma Progression and Enhances the Chemotherapeutic Efficacy.

Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous group of mature T-cell malignancies. The efficacy of current first-line treatment is dismal, and novel agents are urgently needed to improve patient outcomes. A close association between the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and tumor promotion exists, revealing prospective therapeutic targets. This study, investigates the role of the cGAS-STING pathway and its underlying mechanisms in PTCL progression. Single-cell RNA sequencing showes that the cGAS-STING pathway is highly expressed and closely associated with PTCL proliferation. cGAS inhibition suppresses tumor growth and impaires DNA damage repair. Moreover, Cdc2-like kinase 1 (CLK1) is critical for residual tumor cell survival after treatment with cGAS inhibitors, and CLK1 suppression enhances sensitivity to cGAS inhibitors. Single-cell dynamic transcriptomic analysis indicates reduced proliferation-associated nascent RNAs as the underlying mechanism. In first-line therapy, chemotherapy-triggered DNA damage activates the cGAS-STING pathway, and cGAS inhibitors can synergize with chemotherapeutic agents to kill tumors. The cGAS-STING pathway is oncogenic in PTCL, whereas targeting cGAS suppresses tumor growth, and CLK1 may be a sensitivity indicator for cGAS inhibitors. These findings provide a theoretical foundation for optimizing therapeutic strategies for PTCL, especially in patients with relapsed/refractory disease.