Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.

The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for ß-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

Evaluation of pharmacist-led medication reconciliation at county hospitals in China: A multicentre, open-label, assessor-blinded, nonrandomised controlled study.

Background: Due to a lack of related research, we aimed to determine the effectiveness of a pharmacist-led medication reconciliation intervention in China. Methods: We conducted a multicentre, prospective, open-label, assessor-blinded, cluster, nonrandomised controlled study at six county-level hospitals, with hospital wards serving as the clusters. We included patients discharged from the sampled hospitals who were aged ≥60 years; had ≥1 studied diagnoses; and were prescribed with ≥3 medications at discharge. Patients in the intervention group received a pharmacist-led medication reconciliation intervention and those in the control group received standard care. We assessed the incidence of medication discrepancies at discharge, patients' medication adherence, and health care utilisation within 30 days after discharge. Results: There were 429 patients in the intervention group (mean age = 72.5 years, standard deviation (SD) = 7.0) and 526 patients in the control group (mean age = 73.6 years, SD = 7.1). Of the 1632 medication discrepancies identified at discharge, fewer occurred in the intervention group (1.9 per patient on average) than the control group (2.6 per patient on average).The intervention significantly reduced the incidence of medication discrepancy by 9.6% (95% confidence interval (CI) = -15.6, -3.6, P = 0.002) and improved patients' medication adherence, with an absolute decrease in the mean adherence score of 2.5 (95% CI = -2.8, -2.2, P < 0.001). There was no significant difference in readmission rates between the intervention and control groups. Conclusions: Pharmacist-led medication reconciliation at discharge from Chinese county-level hospitals reduced medication discrepancies and improved patients' adherence among patients aged 60 years or above, though no impact on readmission after discharge was observed. Registration: ChiCTR2100045668.

High-Fidelity Sensitive Tracing Circulating Tumor Cell Telomerase Activity.

Dynamic tracing of intracellular telomerase activity plays a crucial role in cancer cell recognition and correspondingly in earlier cancer diagnosis and personalized precision therapy. However, due to the complexity of the required reaction system and insufficient loading of reaction components into cells, achieving a high-fidelity determination of telomerase activity is still a challenge. Herein, an Aptamer-Liposome mediated Telomerase activated poly-Molecular beacon Arborescent Nanoassembly(ALTMAN) approach was described for direct high-fidelity visualization of telomerase activity. Briefly, intracellular telomerase activates molecular beacons, causing their hairpin structures to unfold and produce fluorescent signals. Furthermore, multiple molecular beacons can self-assemble, forming arborescent nanostructures and leading to exponential amplification of fluorescent signals. Integrating the enzyme-free isothermal signal amplification successfully increased the sensitivity and reduced interference by leveraging the skillful design of the molecular beacon and the extension of the telomerase-activated TTAGGG repeat sequence. The proposed approach enabled ultrasensitive visualization of activated telomerase exclusively with a prominent detection limit of 2 cells·µL-1 and realized real-time imaging of telomerase activity in living cancer cells including blood samples from breast cancer patients and urine samples from bladder cancer patients. This approach opens an avenue for establishing a telomerase activity determination and in situ monitoring technique that can facilitate both telomerase fundamental biological studies and cancer diagnostics.

Targeting MEK/COX-2 axis improve immunotherapy efficacy in dMMR colorectal cancer with PIK3CA overexpression.

PURPOSE: PIK3CA mutation or overexpression is associated with immunotherapy resistance in multiple cancer types, but is also paradoxically associated with benefit of COX-2 inhibition on patient survival of colorectal cancer (CRC) with mismatch repair deficiency (dMMR). This study examined whether and how PIK3CA status affected COX-2-mediated tumor inflammation and immunotherapy response of dMMR CRC. METHODS: Murine colon cancer cells MC38, CT26, and CT26-Mlh1-KO were used to construct PIK3CA knockdown and overexpression models to mimic dMMR CRC with PIK3CA dysregulation, and xenograft models were used to evaluate how PIK3CA regulate COX-2 expression, CD8+ T cells infiltration, tumor growth, and therapy response to anti-PD-L1 treatment using immunocompetent mice. Western blot was carried out to delineate the signaling pathways in human and mouse cancer cells, and immunohistochemical analysis together with bioinformatics analysis using human patient samples. RESULTS: PIK3CA upregulates COX-2 expression through MEK/ERK signaling pathway independent of AKT signaling to promote tumor inflammation and immunosuppression. PIK3CA knockdown profoundly reduced CT26 tumor growth in a CD8+ T cell-dependent manner, while PIK3CA overexpression significantly inhibited CD8+ T cells infiltration and promoted tumor growth. Furthermore, MEK or COX-2 inhibition augmented the anti-tumor activity of anti-PD-L1 immunotherapy on dMMR CRC mouse models, accompanied with increased CD8+ T cells infiltration and activated tumor microenvironment. CONCLUSION: Our results identified that the PIK3CA hyperactivation in dMMR CRC upregulated COX-2 through MEK signaling, which inhibited CD8+ T cells infiltration and promoted tumor growth, together led to immunotherapy resistance. COX-2 or MEK inhibition may relieve therapy resistance and promote therapy efficacy of anti-PD-1/PD-L1 immunotherapy for treating dMMR CRC with PIK3CA overexpression or activating mutation.

Low shear stress exacerbates atherosclerosis by inducing the generation of neutrophil extracellular traps via Piezo1-mediated mechanosensation.

BACKGROUND AND AIMS: Atherosclerosis is a chronic lipid-driven inflammatory disease largely influenced by hemodynamics. Neutrophil extracellular trap (NET)-mediated inflammation plays an important role in atherosclerosis. However, little is known about the relationship between low shear stress (LSS) and NET generation, as well as the underlying mechanism. METHODS: We induced LSS by partial ligation of the left carotid artery in high-fat diet-fed male ApoE-/- mice. To further validate the direct relationship between LSS and NET formation invitro, differentiated human promyelocytic leukemia HL-60 cells and bone marrow-derived neutrophils were suspended in fluid flow under normal or low shear stress using a parallel-plate flow chamber system. RESULTS: Four weeks after surgery, ligated carotid arteries had more lipid deposition, larger plaque area, and increased NET formation than unligated arteries. Inhibition of NETosis could significantly reduce plaque formation in ApoE-/- mice. Invitro, LSS could promote NET generation directly through downregulation of Piezo1, a mechanosensitive ion channel. Downregulation of Piezol could activate neutrophils and promote NETosis in static conditions. Conversely, Yoda1-evoked activation of Piezo1 attenuated LSS-induced NETosis. Mechanistically, downregulation of Piezo1 resulted in decreased Ca2+ influx and increased histone deacetylase 2 (HDAC2), which increased reactive oxygen species levels and led to NETosis. LSS-induced NET generation also promoted apoptosis and adherence of endothelial cells. CONCLUSION: LSS directly promotes NETosis through the Piezo1-HDAC2 axis in atherosclerosis progression. This study uncovers the essential role of Piezo1-mediated mechanical signaling in NET generation and plaque formation, which provides a promising therapeutic strategy for atherosclerosis.

Salmonellosis outbreak archive in China: data collection and assembly.

Infectious disease outbreaks transcend the medical and public health realms, triggering widespread panic and impeding socio-economic development. Considering that self-limiting diarrhoea of sporadic cases is usually underreported, the Salmonella outbreak (SO) study offers a unique opportunity for source tracing, spatiotemporal correlation, and outbreak prediction. To summarize the pattern of SO and estimate observational epidemiological indicators, 1,134 qualitative reports screened from 1949 to 2023 were included in the systematic review dataset, which contained a 506-study meta-analysis dataset. In addition to the dataset comprising over 50 columns with a total of 46,494 entries eligible for inclusion in systematic reviews or input into prediction models, we also provide initial literature collection datasets and datasets containing socio-economic and climate information for relevant regions. This study has a broad impact on advancing knowledge regarding epidemic trends and prevention priorities in diverse salmonellosis outbreaks and guiding rational policy-making or predictive modeling to mitigate the infringement upon the right to life imposed by significant epidemics.

Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) are employed in immunotherapeutic applications for patients with weakened immune systems and can improve the ability of T cells to kill cancer cells. Although ICIs can potentially treat different types of cancers in various groups of patients, their effectiveness may differ among older individuals. The reason ICIs are less effective in older adults is not yet clearly understood, but age-related changes in the immune system, such as immunosenescence and inflammation, may play a role. Therefore, this review focuses on recent advances in understanding the effects of immunosenescence and inflammation on the efficacy of ICIs.

Climate change affects the spread of typhoid pathogens.

Typhoid fever is caused by Salmonella enterica serotype Typhi (Salmonella Typhi). Syndromes in patients vary from asymptomatic carriers to severe or death outcomes, which are frequently reported in African and Southeast Asian countries. It is one of the most common waterborne transmission agents, whose transmission is likely impacted by climate change. Here, we claimed the evidence and consequences of climate-related foodborne and waterborne diseases have increased and provided possible mitigations against Typhoidal Salmonella dissemination.

Novel small molecule-based organic nanoparticles for second near-infrared photothermal tumor ablation.

Second near-infrared (NIR-II,1000 âˆ¼ 1700 nm) therapeutic window presents an increased tissue penetration and elevated maximal permissible exposure in the application of photothermal therapy (PTT). However, the lack of NIR-II photothermal conversion agents (PCAs) limit their further development. In this work, we rationally designed and successfully developed three novel indolium-like heptamethine cyanine dyes (NFs) by installing N,N-diethylamino on the terminal ends of a conjugated polyene backbone and replacing the middle chlorine atom with o-mercapto benzoic acid and p-mercapto benzoic acid. Notably, NF2 with stronger rotating group encapsulated in organic nanoparticles (NF2 NPs) exhibited high photothermal conversion efficiency (PCE), which could come up to (61.3 %). Then we conducted serial experiments to further investigate PTT capability of NF2 NPs 4 T1 cell line and nude mice bearing 4 T1 tumor. As expected, the resulting NF2 NPs presented the excellent photothermal conversion ability and superb PTT effect both in vivo and in vitro. This study will inspire more work for future design and clinical applications of NIR-II therapeutic agents.

Mobilome-driven partitions of the resistome in Salmonella.

IMPORTANCE: Antimicrobial resistance (AMR) has become a significant global challenge, with an estimated 10 million deaths annually by 2050. The emergence of AMR is mainly attributed to mobile genetic elements (MGEs or mobilomes), which accelerate wide dissemination among pathogens. The interaction between mobilomes and AMR genes (or resistomes) in Salmonella, a primary cause of diarrheal diseases that results in over 90 million cases annually, remains poorly understood. The available fragmented or incomplete genomes remain a significant limitation in investigating the relationship between AMR and MGEs. Here, we collected the most extensive closed Salmonella genomes (n = 1,817) from various sources across 58 countries. Notably, our results demonstrate that resistome transmission between Salmonella lineages follows a specific pattern of MGEs and is influenced by external drivers, including certain socioeconomic factors. Therefore, targeted interventions are urgently needed to mitigate the catastrophic consequences of Salmonella AMR.

New Insights into Selective Singlet Oxygen Production via the Typical Electroactivation of Oxygen for Water Decontamination.

Selective production of singlet oxygen (1O2) as an electrophilic oxidant is crucial for the precise control of chemical targets in environmental fields. Herein, we proposed a strategy to construct a redox interface on electrodes, which can in situ produce inorganic metal hydroperoxides with appropriate oxidative ability during oxygen activation. Benefiting from atomic Cu sites (CuN4) in a copper-carbon aerogel electrode, almost complete production of 1O2 was achieved, thereby refraining the competitive formation of other reactive oxygen species. The fast electron transfer rate between CuN4 and electrogenerated H2O2 promoted the in situ formation of copper hydroperoxide (N4-Cu-OOH), thereby selectively and efficiently oxidizing intermediate O2•- to 1O2. The optimized production of 1O2 was up to 2583 µmol L-1 without additional chemical reagents. We further considered the high production of 1O2 for efficiently removing electron-rich organic pollutants from a complex water matrix. Fast kinetics was achieved and considered for removing various pollutants with electron-donating substituents in a nonradical oxidation pathway. The BPA degradation efficiency is less susceptible to the coexisting natural organic matter (NOM) and inorganic ions. Specifically, the kinetic constant for BPA removal is 34 times higher than that for a nanoparticle of a copper-carbon electrode while producing a hydroxyl radical. Our findings highlight the innovative interfacial surface engineering of an electrocatalytic O2 activation system to selectively generate 1O2 for future potential applications.

Bacterial cell sensing and signaling pathway for external polycyclic aromatic hydrocarbons (PAHs).

The mechanism by which a bacterial cell senses external nutrients remains largely unknown. In this study, we identified a bacterial cell sensing system for polycyclic aromatic hydrocarbons (PAHs) in a common marine PAH-using bacterium, Cycloclasticus. It consists of an outer membrane receptor (PahS) and a periplasmic protein (PahP) in combination with a two-component sensing system (TCS) that ensures a rapid response to PAH occurrence by directly controlling serial reactions including chemotactic sensing and movement, PAH uptake and intracellular PAH metabolism. PahS protrudes from the cell and acts as a PAH sensor, transducing the PAH signal across the outer membrane to its periplasmic partner PahP, which in turn transduces the PAH signal across the periplasm to a specialized TCS. This sensing system plays a critical role in sensing and promoting the metabolism of PAHs, which can be scavenged by various hydrocarbon-degrading bacteria.

Value Added Conversion of Ethanol on Morphologically Controlled and Defect-Engineered Titanium Dioxide Nanorods.

Developing an environmentally benign and highly effective strategy for the value-added conversion of biomass platform molecules such as ethanol has emerged as a significant challenge and opportunity. This challenge stems from the need to harness renewable solar energy and conduct thermodynamically unfavorable reactions at room temperature. To tackle this challenge, one-dimensional titanium dioxide photocatalysts have been designed and fabricated to achieve a remarkable photocatalytic selectivity of almost 100 % for transforming ethanol into value-added 1,1-diethoxyethane, contrasting the primary production of acetaldehyde in titanium dioxide nanoparticles. By incorporating a Pt co-catalyst and infusing oxygen vacancies into the one-dimensional catalyst, the ethanol transformation rate was doubled to 128.8 mmol g-1 h-1 with respect to that of its unmodified counterpart (about 66.7 mmol g-1 h-1 ). The underlying mechanism for this high conversion and selectivity resides in the narrowed bandgap of the catalyst and the prolonged lifetime of the photo-generated carriers. This is a promising strategy for the photocatalytic transformation of essential biomass platform molecules that intertwines morphological control and defect engineering.

A smart TESTER for reliable discrimination of cancer-derived small extracellular vesicles.

Cancer-derived small extracellular vesicles (csEVs) are crucial liquid biopsy indicators that reflect the presence and progression of many malignancies. However, reliable discrimination of csEVs remains a great challenge owing to the interference from normal sEVs (nsEVs) and low abundance in the early stages of cancer. In this work, we developed a Two-Elements Selectively Triggered csEVs Recognization (TESTER) strategy for selective identification of csEVs from the complex clinical body fluid samples. This method was based on the MNAzyme-controlled synchronous recognition to EpCAM and CD63 proteins on the membrane of csEVs. Efficient recognition to csEVs via EpCAM aptamer and CD63 aptamer prompted the release of Partzyme A and Partzyme B probes to induce a MNAzyme structure formation, resulting in the cyclic cleavage of substrate chain to produce cascade fluorescence signal amplification. The detection threshold of the developed TESTER approach for csEVs in complicated biological samples was 72 particles µL-1, accomplishing the highly sensitive and selective quantification of csEVs. At the same time, we successfully constructed a new platform for bimolecular simultaneous recognition, which provides a good idea for the construction of bimolecular-activated detection switch in the future.

A Nanovaccine Based on Adjuvant Peptide FK-13 and l-Phenylalanine Poly(ester amide) Enhances CD8+ T Cell-Mediated Antitumor Immunity.

Cancer vaccines have shown promise as effective means of antitumor immunotherapy by inducing tumor antigen-specific T cell immunity. In this study, a novel peptide-based tumor nanovaccine that boosts antigen presentation and elicits effective antitumor immunity is developed. The adjuvant characteristics of an antimicrobial peptide-derived core peptide, FK-13, are investigated and used it to generate a fusion peptide named FK-33 with tumor antigen epitopes. l-phenylalanine-based poly(ester amide) (Phe-PEA), 8p4, is also identified as a competent delivery vehicle for the fusion peptide FK-33. Notably, the vaccination of 8p4 + FK-33 nanoparticles (8FNs) in vivo induces dendritic cell activation in the lymph nodes and elicits robust tumor antigen-specific CD8+ T cell response. The nanovaccine 8FNs demonstrate significant therapeutic and prophylactic efficacy against in situ tumor growth, effectively inhibit tumor metastasis, and significantly prolong the survival of tumor-bearing mice. Moreover, 8FNs can incorporate different tumor antigens and exhibit a synergistic therapeutic effect with antiprogrammed cell death protein 1 (PD-1) therapy. In summary, 8FNs represent a promising platform for personalized cancer vaccines and may serve as a potential combinational modality to improve current immunotherapy.

Genetic variants influenced the risk of bleeding and pharmacodynamics of rivaroxaban in patients with nonvalvular atrial fibrillation: A multicentre prospective cohort study.

INTRODUCTION: Individual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF). MATERIALS AND METHODS: From June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti-Factor Xa (anti-FXa) level 3 h after rivaroxaban administration as peak concentration. Whole-exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496). RESULTS: The bleeding events within 12 months were significantly related to the peak anti-FXa level (p = .027). SUSD3 rs76292544 was associated with 12-month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17-8.14, p = 6.43×10-5 ). Five SNPs including NCMAP rs4553122 (p = 2.29×10-5 ), PRF1 rs885821 (p = 7.02×10-5 ), PRKAG2 rs12703159 (p = 7.97×10-5 ), PRKAG2 rs13224758 (p = 8.70×10-5 ), and POU2F3 rs2298579 (p = 8.24×10-5 ) were associated with peak anti-FXa level. Genetic variants of 52 SNPs from 36 genes including GOT2 rs14221 and MMP13 rs640198 were potentially related to 12-month bleeding events caused by rivaroxaban's efficacy. CONCLUSIONS: Peak anti-FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban. SUSD3 rs76292544 was suggestively associated with 12-month bleeding events and five SNPs (NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, rs13224758 and POU2F3 rs2298579) were suggestively associated with peak anti-FXa level.

[Omics Analysis of Ferroptosis and Establishment of Prognostic Model for multiple myeloma Patients].

OBJECTIVE: To explore the role of ferroptosis-related genes in multiple myeloma(MM) through TCGA database and FerrDb, and build a prognostic model of ferroptosis-related genes for MM patients. METHODS: Using the TCGA database containing clinical information and gene expression profile data of 764 patients with MM and the FerrDb database including ferroptosis-related genes, the differentially expressed ferroptosis-related genes were screened by wilcox.test function. The prognostic model of ferroptosis-related genes was established by Lasso regression, and the Kaplan-Meier survival curve was drawn. Then COX regression analysis was used to screen independent prognostic factors. Finally, the differential genes between high-risk and low-risk patients were screened, and enrichment analysis was used to explore the mechanism of the relationship between ferroptosis and prognosis in MM. RESULTS: 36 differential genes related to ferroptosis were screened out from bone marrow samples of 764 MM patients and 4 normal people, including 12 up-regulated genes and 24 down-regulated genes. Six prognosis-related genes (GCLM, GLS2, SLC7A11, AIFM2, ACO1, G6PD) were screened out by Lasso regression and the prognostic model with ferroptosis-related genes of MM was established. Kaplan-Meier survival curve analysis showed that the survival rate between high risk group and low risk group was significantly different(P<0.01). Univariate COX regression analysis showed that age, sex, ISS stage and risk score were significantly correlated with overall survival of MM patients(P<0.05), while multivariate COX regression analysis showed that age, ISS stage and risk score were independent prognostic indicators for MM patients (P<0.05). GO and KEGG enrichment analysis showed that the ferroptosis-related genes was mainly related to neutrophil degranulation and migration, cytokine activity and regulation, cell component, antigen processing and presentation, complement and coagulation cascades, haematopoietic cell lineage and so on, which may affect the prognosis of patients. CONCLUSION: Ferroptosis-related genes change significantly during the pathogenesis of MM. The prognostic model of ferroptosis-related genes can be used to predict the survival of MM patients, but the mechanism of the potential function of ferroptosis-related genes needs to be confirmed by further clinical studies.

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.

As the key component of host innate antiviral immunity, type I interferons (IFN-Is) exert multiple antiviral effects by inducing hundreds of IFN-stimulated genes. However, the precise mechanism involved in host sensing of IFN-I signaling priming is particularly complex and remains incompletely resolved. This research identified F-box protein 11 (FBXO11), a component of the E3-ubiquitin ligase SKP/Cullin/F-box complex, acted as an important regulator of IFN-I signaling priming and antiviral process against several RNA/DNA viruses. FBXO11 functioned as an essential enhancer of IFN-I signaling by promoting the phosphorylation of TBK1 and IRF3. Mechanistically, FBXO11 facilitated the assembly of TRAF3-TBK1-IRF3 complex by mediating the K63 ubiquitination of TRAF3 in a NEDD8-dependent manner to amplify the activation of IFN-I signaling. Consistently, the NEDD8-activating enzyme inhibitor MLN4921 could act as a blocker for FBXO11-TRAF3-IFN-I axis of signaling. More significantly, examination of clinical samples of chronic hepatitis B virus (HBV) infection and public transcriptome database of severe acute respiratory syndrome coronavirus-2-, HBV-, and hepatitis C virus-infected human samples revealed that FBXO11 expression was positively correlated with the stage of disease course. Taken together, these findings suggest that FBXO11 is an amplifier of antiviral immune responses and might serve as a potential therapeutic target for a number of different viral diseases.