Screening and validation of atherosclerosis PAN-apoptotic immune-related genes based on single-cell sequencing.

Background: Carotid atherosclerosis (CAS) is a complication of atherosclerosis (AS). PAN-optosome is an inflammatory programmed cell death pathway event regulated by the PAN-optosome complex. CAS's PAN-optosome-related genes (PORGs) have yet to be studied. Hence, screening the PAN-optosome-related diagnostic genes for treating CAS was vital. Methods: We introduced transcriptome data to screen out differentially expressed genes (DEGs) in CAS. Subsequently, WGCNA analysis was utilized to mine module genes about PANoptosis score. We performed differential expression analysis (CAS samples vs. standard samples) to obtain CAS-related differentially expressed genes at the single-cell level. Venn diagram was executed to identify PAN-optosome-related differential genes (POR-DEGs) associated with CAS. Further, LASSO regression and RF algorithm were implemented to were executed to build a diagnostic model. We additionally performed immune infiltration and gene set enrichment analysis (GSEA) based on diagnostic genes. We verified the accuracy of the model genes by single-cell nuclear sequencing and RT-qPCR validation of clinical samples, as well as in vitro cellular experiments. Results: We identified 785 DEGs associated with CAS. Then, 4296 module genes about PANoptosis score were obtained. We obtained the 7365 and 1631 CAS-related DEGs at the single-cell level, respectively. 67 POR-DEGs were retained Venn diagram. Subsequently, 4 PAN-optosome-related diagnostic genes (CNTN4, FILIP1, PHGDH, and TFPI2) were identified via machine learning. Cellular function tests on four genes showed that these genes have essential roles in maintaining arterial cell viability and resisting cellular senescence. Conclusion: We obtained four PANoptosis-related diagnostic genes (CNTN4, FILIP1, PHGDH, and TFPI2) associated with CAS, laying a theoretical foundation for treating CAS.

CircSCNN1A inhibits the proliferation, migration and invasion of renal cell carcinoma cells by decreasing CLDN8 expression through miR-590-5p.

BACKGROUND: Increasing evidence suggests that circular RNA (circRNA) plays a regulatory role in the progression of renal cell carcinoma (RCC). However, the precise function and underlying mechanism of circSCNN1A in RCC progression still remain unclear. METHODS: The expression levels of circSCNN1A, microRNA-590-5p (miR-590-5p), claudin 8 (CLDN8), cyclin D1, matrix metalloprotein 2 (MMP2), MMP9, E-cadherin, N-cadherin and vimentin were detected by a quantitative real-time polymerase chain reaction and Western blotting analysis. Immunohistochemistry assay was performed to analyze the positive expression rate of CLDN8. Cell proliferation was investigated by cell colony formation, 5-Ethynyl-2'-deoxyuridine and DNA content quantitation assays. Cell migration and invasion were assessed by wound-healing and transwell invasion assays. Interactions among circSCNN1A, miR-590-5p and CLDN8 were identified by dual-luciferase reporter assay, RNA immunoprecipitation assay and RNA pull-down assay. Xenograft mouse model assay was conducted to verify the effect of circSCNN1A on tumor formation in vivo. RESULTS: CircSCNN1A and CLDN8 expression were significantly downregulated, while miR-590-5p was upregulated in both RCC tissues and cells. CircSCNN1A overexpression inhibited RCC cell proliferation, migration and invasion, accompanied by decreases of cyclin D1, MMP2, MMP9, N-cadherin and vimentin expression and an increase of E-cadherin expression. CircSCNN1A acted as a miR-590-5p sponge and regulated RCC cell processes by binding to miR-590-5p. CLDN8, a target gene of miR-590-5p, was involved in the regulation of the biological behaviors of RCC cells by miR-590-5p. In addition, circSCNN1A induced CLDN8 production by interacting with miR-590-5p. Further, circSCNN1A suppressed tumor formation in vivo. CONCLUSION: CircSCNN1A inhibited RCC cell proliferation, migration and invasion by regulating the miR-590-5p/CLDN8 pathway.

Knowledge level and health information-seeking behavior of people with diabetes in rural areas: a multicenter cross-sectional study.

Introduction: There is a lack of research on the current level of diabetes knowledge and health information-seeking behaviors among patients with diabetes in rural areas of China's economically underdeveloped regions during COVID-19, as well as a lack of up-to-date evidence on glycemic control and the incidence of complications among rural patients with diabetes. Objectives: To investigate the prevalence of glycemic control and complications among patients with diabetes in rural areas, to explore the current status and correlation of diabetes knowledge level and health information-seeking behavior, and to analyze the factors affecting diabetes knowledge level. Methods: From January 2022 to July 2022, we conducted a screening on diabetic complications and a questionnaire survey among 2,178 patients with diabetes in 15 county hospitals in rural areas of Guangxi Zhuang Autonomous Region. The patients' knowledge level and health information-seeking behavior were investigated. Spearman correlation analysis was used to assess the correlation between diabetes knowledge and health information-seeking behavior. Multiple linear regression analysis was used to test how demographic information and health information-seeking behavior influenced the level of diabetes knowledge. Results: Of 2,178 patients with diabetes in rural areas, 1,684 (77.32%) had poor glycemic control, and the prevalence of diabetic complications was estimated to be 72.13%. Patients with diabetes had poor diabetes knowledge and health information-seeking behavior, and there is a strong positive correlation between them. Diabetes knowledge level was influenced by per capita household disposable income, occupational status, gender, age, ethnicity, family history of diabetes, insulin use, glycated hemoglobin, education level, number of complications and health information-seeking behavior. Conclusion: Patients with diabetes in rural areas have poor glycemic control and a high incidence of diabetic complications. Patients with diabetes in rural areas have poor knowledge and inadequate health information-seeking behavior. Systematic and standardized education should be provided to improve patients' diabetes knowledge and thus improve their self-management ability.

TRIM37 is a primate-specific E3 ligase for Huntingtin and accounts for the striatal degeneration in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by preferential neuronal loss in the striatum. The mechanism underlying striatal selective neurodegeneration remains unclear, making it difficult to develop effective treatments for HD. In the brains of nonhuman primates, we examined the expression of Huntingtin (HTT), the gene responsible for HD. We found that HTT protein is highly expressed in striatal neurons due to its slow degradation in the striatum. We also identified tripartite motif-containing 37 (TRIM37) as a primate-specific protein that interacts with HTT and is selectively reduced in the primate striatum. TRIM37 promotes the ubiquitination and degradation of mutant HTT (mHTT) in vitro and modulates mHTT aggregation in mouse and monkey brains. Our findings suggest that nonhuman primates are crucial for understanding the mechanisms of human diseases such as HD and support TRIM37 as a potential therapeutic target for treating HD.

HAP40 modulates mutant Huntingtin aggregation and toxicity in Huntington's disease mice.

Huntington's disease (HD) is a monogenic neurodegenerative disease, caused by the CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. The HTT gene encodes a large protein known to interact with many proteins. Huntingtin-associated protein 40 (HAP40) is one that shows high binding affinity with HTT and functions to maintain HTT conformation in vitro. However, the potential role of HAP40 in HD pathogenesis remains unknown. In this study, we found that the expression level of HAP40 is in parallel with HTT but inversely correlates with mutant HTT aggregates in mouse brains. Depletion of endogenous HAP40 in the striatum of HD140Q knock-in (KI) mice leads to enhanced mutant HTT aggregation and neuronal loss. Consistently, overexpression of HAP40 in the striatum of HD140Q KI mice reduced mutant HTT aggregation and ameliorated the behavioral deficits. Mechanistically, HAP40 preferentially binds to mutant HTT and promotes Lysine 48-linked ubiquitination of mutant HTT. Our results revealed that HAP40 is an important regulator of HTT protein homeostasis in vivo and hinted at HAP40 as a therapeutic target in HD treatment.

Discovery of a novel chemotype as DYRK1A inhibitors against Alzheimer's disease: Computational modeling and biological evaluation.

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) plays an essential role in Tau and Aß pathology closely related to Alzheimer's disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitor for clinical use as anti-AD therapy. This is somewhat due to the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried out in silico screening, in vitro assays and in vivo efficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. By in silico screening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compound Q17 (Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compound Q17 and two amino acid residues named GLU239 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compound Q17 could protect the SH-SY5Y human neuroblastoma cell line from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compound Q17 significantly improved cognitive dysfunction of 3 × Tg-AD mice, ameliorated pathological changes, and attenuated Tau hyperphosphorylation as well as Aß deposition. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compound Q17 in this study is worthy of further study.

Integrated and DC-powered superconducting microcomb.

Frequency combs, specialized laser sources emitting multiple equidistant frequency lines, have revolutionized science and technology with unprecedented precision and versatility. Recently, integrated frequency combs are emerging as scalable solutions for on-chip photonics. Here, we demonstrate a fully integrated superconducting microcomb that is easy to manufacture, simple to operate, and consumes ultra-low power. Our turnkey apparatus comprises a basic nonlinear superconducting device, a Josephson junction, directly coupled to a superconducting microstrip resonator. We showcase coherent comb generation through self-started mode-locking. Therefore, comb emission is initiated solely by activating a DC bias source, with power consumption as low as tens of picowatts. The resulting comb spectrum resides in the microwave domain and spans multiple octaves. The linewidths of all comb lines can be narrowed down to 1 Hz through a unique coherent injection-locking technique. Our work represents a critical step towards fully integrated microwave photonics and offers the potential for integrated quantum processors.

Ketamine induces insomnia-like symptom of zebrafish at environmentally relevant concentrations by mediating GABAergic synapse.

Although the stimulative effects on the normal behaviors of fish posed by ketamine (KET) were well-studied, the adverse effects on the behavioral functions induced by KET at nighttime were unknown. Here, we used zebrafish larvae as a model exposed to KET (10, 50, 100, and 250 ng/L) at environmental levels for 21 days. The behavioral functions at nighttime, morphological changes during exposure stage, and alterations on the associated genes transcriptional levels of fish were determined. The difficultly initiating sleep was found in the fish exposed to KET, while the sleep duration of the animals was at the normal levels in exposure groups. The significant suppressions of the developmentally relevant genes, including bmp2, bmp4, and pth2ra were consistent with the developmental abnormalities of fish found in exposure groups. Moreover, the expression of γ-aminobutyric acid (GABA) receptor increased and melatonin (MTN) receptor decreased while the levels of GABA and MTN remained unchanged after exposure, by gene expression analysis and molecular docking. In addition, the transcriptional expression of apoptotic genes, including tp53, aifm1, and casp6, was significantly upregulated by KET. After a 7-day recovery, the insomnia-like behaviors (shorter sleep duration) were observed in zebrafish from the 250 ng/L-KET group. Accordingly, the adverse outcome pathway framework of KET was constructed by prognostic assessment of zebrafish larvae. This study suggested that the adverse outcomes of KET on the sleep health of organisms at environmentally relevant concentrations should be concerned.

Combining T1rho and advanced diffusion MRI for noninvasively staging liver fibrosis: an experimental study in rats.

PURPOSE: To investigate the value of imaging parameters derived from T1 relaxation times in the rotating frame (T1ρ or T1rho), diffusion kurtosis imaging (DKI) and intravoxel incoherent motion (IVIM) in assessment of liver fibrosis in rats and propose an optimal diagnostic model based on multiparametric MRI. METHODS: Thirty rats were divided into one control group and four fibrosis experimental groups (n = 6 for each group). Liver fibrosis was induced by administering thioacetamide (TAA) for 2, 4, 6, and 8 weeks. T1ρ, mean kurtosis (MK), mean diffusivity (MD), perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were measured and compared among different fibrosis stages. An optimal diagnostic model was established and the diagnostic efficiency was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: The mean AUC values, sensitivity, and specificity of T1ρ and MD derived from DKI across all liver fibrosis stages were comparable but much higher than those of other imaging parameters (0.954, 92.46, 91.85 for T1ρ; 0.949, 92.52, 91.24 for MD). The model combining T1ρ and MD exhibited better diagnostic performance with higher AUC values than any individual method for staging liver fibrosis (≥ F1: 1.000 (0.884-1.000); ≥ F2: 0.935 (0.782-0.992); ≥ F3: 0.982 (0.852-1.000); F4: 0.986 (0.859-1.000)). CONCLUSION: Among the evaluated imaging parameters, T1ρ and MD were superior for differentiating varying liver fibrosis stages. The model combining T1ρ and MD was promising to be a credible diagnostic biomarker to detect and accurately stage liver fibrosis.

Salvia miltiorrhiza ameliorates endometritis in dairy cows by relieving inflammation, energy deficiency and blood stasis.

Introduction: According to traditional Chinese veterinary medicine, endometritis is caused by a combination of Qi deficiency, blood stasis, and external evil invasion. Salvia miltiorrhiza is a traditional Chinese medicine that counteracts blood stasis and has additional demonstrated effects in boosting energy and restraining inflammation. Salvia miltiorrhiza has been employed in many traditional Chinese prescriptions that have proven effective in healing clinical dairy cow endometritis. Methods: the in vivo effect of Salvia miltiorrhiza in treating endometritis was evaluated in dairy cows. In addition, bovine endometrial epithelium cell inflammation and rat blood stasis models were employed to demonstrate the crosstalk between energy, blood circulation and inflammation. Network analysis, western blotting, qRT-PCR and ELISA were performed to investigate the molecular mechanism of Salvia miltiorrhiza in endometritis treatment. Results: The results demonstrate that treatment with Salvia miltiorrhiza relieves uterine inflammation, increases blood ATP concentrations, and prolongs blood clotting times. Four of the six Salvia miltiorrhiza main components (SMMCs) (tanshinone IIA, cryptotanshinone, salvianolic acid A and salvianolic acid B) were effective in reversing decreased ATP and increased IL-1ß, IL-6, and IL-8 levels in an in vitro endometritis model, indicating their abilities to ameliorate the negative energy balance and external evil invasion effects of endometritis. Furthermore, in a blood stasis rat model, inflammatory responses were induced in the absence of external infection; and all six SMMCs inhibited thrombin-induced platelet aggregation. Network analysis of SMMC targets predicted that Salvia miltiorrhiza may mediate anti-inflammation via the Toll-like receptor signaling pathway; anti-aggregation via the Platelet activation pathway; and energy balance via the Thermogenesis and AMPK signaling pathways. Multiple molecular targets within these pathways were verified to be inhibited by SMMCs, including P38/ERK-AP1, a key molecular signal that may mediate the crosstalk between inflammation, energy deficiency and blood stasis. Conclusion: These results provide mechanistic understanding of the therapeutic effect of Salvia miltiorrhiza for endometritis achieved through Qi deficiency, blood stasis, and external evil invasion.

Evolutionary patterns of DNA base composition at polymorphic sites highlight the role of the environment in shaping barley and rice genomes.

Insights into changes in genome base composition underlying crop domestication can be gained by using comparative genomics. With this approach, previous studies have reported that crop genomes during domestication accumulate more nucleotides adenine (A) and thymine (T) (termed as [AT]-increase) across polymorphic sites. However, the potential influence of the environment or its factors, for example, solar ultraviolet (UV) radiation and temperature, on the [AT]-increase has not been well elucidated. Here, we investigated the [AT]-increase in barley (Hordeum vulgare L.) and rice (Oryza sativa L.) and the association with natural environments, where accessions are distributed. With 12,798,376 and 2,861,535 single-nucleotide polymorphisms from 368 barley and 1375 rice accessions, respectively, we discovered that [AT] increases from wild accessions to improved cultivars, and genomic regions with larger [AT]-increase tend to have higher UV-related motif frequencies, suggesting solar UV radiation as a potential factor in driving genome variation. To link [AT] change with the geographic distribution, we gathered georeferenced accessions and examined their local environments. Interestingly, negative correlations between [AT] and environmental factors were observed (r = -0.39 ∼ -0.75) and modern accessions with higher [AT] values, as compared with wild relatives, are from the environments with lower solar UV radiation or lower temperature. With [AT] and environmental factors as phenotypes, genome-wide association mapping identified three candidate genes that have the potential to contribute to [AT] variation under the effect of environmental conditions. Our findings provide genomic and environmental insights into evolutionary pattern of DNA base composition and underlying mechanisms.

A hemodynamic model of artery bypass graft considering microcirculation function.

BACKGROUND: The incidence of arterial stenosis is increasing year by year. In order to better diagnose and treat arterial stenosis, numerical simulation technology has become a popular method. OBJECTIVE: A novel model is constructed to investigate the influence of microcirculation on the hemodynamics of artery bypass graft. METHODS: In this paper, a severely narrow artery bypass graft model is considered. The geometric shape includes a narrow artery tube and a bypass graft of the same diameter with a 45° suture angle. The fluid-structure interaction model is considered by finite element numerical calculation, and the flow is simulated with microcirculation as the outlet boundary condition. The changes of blood flow velocity, pressure and wall shear stress are analyzed. RESULTS: The results show that blood almost entirely flows into the graft tube and there is no recirculation area at the anastomosis. CONCLUSION: The artery bypass graft model considering microcirculation function could simulate the physiological characteristics of blood flow more reasonably, and it provide helps for clinicians to diagnose and treat arterial stenosis.

A multi-omics investigation of the lung injury induced by PM2.5 at environmental levels via the lung-gut axis.

Long-term exposure to fine particulate matter (PM2.5) posed injury for gastrointestinal and respiratory systems, ascribing with the lung-gut axis. However, the cross-talk mechanisms remain unclear. Here, we attempted to establish the response networks of lung-gut axis in mice exposed to PM2.5 at environmental levels. Male Balb/c mice were exposed to PM2.5 (dose of 0.1, 0.5, and 1.0 mg/kg) collected from Chengdu, China for 10 weeks, through intratracheally instillation, and examined the effect of PM2.5 on lung functions of mice. The changes of lung and gut microbiota and metabolic profiles of mice in different groups were determined. Furthermore, the results of multi-omics were conjointly analyzed to elucidate the primary microbes and the associated metabolites in lung and gut responsible for PM2.5 exposure. Accordingly, the cross-talk network and key pathways between lung-gut axis were established. The results indicated that exposed to PM2.5 0.1 mg/kg induced obvious inflammations in mice lung, while emphysema was observed at 1.0 mg/kg. The levels of metabolites guanosine, hypoxanthine, and hepoxilin B3 increased in the lung might contribute to lung inflammations in exposure groups. For microbiotas in lung, PM2.5 exposure significantly declined the proportions of Halomonas and Lactobacillus. Meanwhile, the metabolites in gut including L-tryptophan, serotonin, and spermidine were up-regulated in exposure groups, which were linked to the decreasing of Oscillospira and Helicobacter in gut. Via lung-gut axis, the activations of pathways including Tryptophan metabolism, ABC transporters, Serotonergic synapse, and Linoleic acid metabolism contributed to the cross-talk between lung and gut tissues of mice mediated by PM2.5. In summary, the microbes including Lactobacillus, Oscillospira, and Parabacteroides, and metabolites including hepoxilin B3, guanosine, hypoxanthine, L-tryptophan, and spermidine were the main drivers. In this lung-gut axis study, we elucidated some pro- and pre-biotics in lung and gut microenvironments contributed to the adverse effects on lung functions induced by PM2.5 exposure.

SOCS5-RBMX stimulates SREBP1-mediated lipogenesis to promote metastasis in steatotic HCC with HBV-related cirrhosis.

Abnormal lipid metabolism promotes hepatocellular carcinoma (HCC) progression, which engenders therapeutic difficulties owing to unclear mechanisms of the phenomenon. We precisely described a special steatotic HCC subtype with HBV-related cirrhosis and probed its drivers. Hematoxylin-eosin (HE) staining of 245 HCC samples revealed a special HCC subtype (41 cases) characterized by HBV-related cirrhosis and intratumoral steatosis without fatty liver background, defined as steatotic HCC with HBV-related cirrhosis (SBC-HCC). SBC-HCC exhibits a larger tumor volume and worse prognosis than non-SBC-HCC. Screening for driver genes promoting fatty acid (FA) biosynthesis in the Gao's HBV-related cirrhosis HCC cases and GSE121248' HBV-related HCC cases revealed that high expression of SOCS5 predicts increased FA synthesis and that SOCS5 is upregulated in SBC-HCC. Through proteomics, metabolomics, and both in vivo and in vitro experiments, we demonstrated that SOCS5 induces lipid accumulation to promote HCC metastasis. Mechanistically, through co-IP and GST-pulldown experiments, we found that the SOCS5-SH2 domain, especially the amino acids Y413 and D443, act as critical binding sites for the RBMX-RRM domain. SOCS5-RBMX costimulates the promoter of SREBP1, inducing de novo lipogenesis, while mutations in the SH2 domain, Y413, and D443 reverse this effect. These findings precisely identified SBC-HCC as a special steatotic HCC subtype and highlighted a new mechanism by which SOCS5 promotes SBC-HCC metastasis.

DIA-Based Proteomic Analysis Reveals MYOZ2 as a Key Protein Affecting Muscle Growth and Development in Hybrid Sheep.

Hybridization of livestock can be used to improve varieties, and different hybrid combinations produce unique breeding effects. In this study, male Southdown and Suffolk sheep were selected to hybridize with female Hu sheep to explore the effects of male parentage on muscle growth and the development of offspring. Using data-independent acquisition technology, we identified 119, 187, and 26 differentially abundant proteins (DAPs) between Hu × Hu (HH) versus Southdown × Hu (NH), HH versus Suffolk × Hu (SH), and NH versus SH crosses. Two DAPs, MYOZ2 and MYOM3, were common to the three hybrid groups and were mainly enriched in muscle growth and development-related pathways. At the myoblast proliferation stage, MYOZ2 expression decreased cell viability and inhibited proliferation. At the myoblast differentiation stage, MYOZ2 expression promoted myoblast fusion and enhanced the level of cell fusion. These findings provide new insights into the key proteins and metabolic pathways involved in the effect of male parentage on muscle growth and the development of hybrid offspring in sheep.

Numerical investigation of quantitative pulmonary pressure ratio in different degrees of stenosis.

BACKGROUND: Pulmonary artery stenosis endangers people's health. Quantitative pulmonary pressure ratio (QPPR) is very important for clinicians to quickly diagnose diseases and develop treatment plans. OBJECTIVE: Our purpose of this paper is to investigate the effects of different degrees (50% and 80%) of pulmonary artery stenosis on QPPR. METHODS: An idealized model is established based on the normal size of human pulmonary artery. The hemodynamic governing equations are solved using fluid-structure interaction. RESULTS: The results show that the QPPR decreases with the increase of stenosis degree, and it is closely related to the pressure drop at both ends of stenosis. Blood flow velocity and wall shear stress are sensitive to the stenosis degree. When the degree of stenosis is 80%, the amplitude of changes of blood flow velocity and wall shear stress at both ends of stenosis is lower. CONCLUSIONS: The results suggest that the degree of pulmonary artery stenosis has a significant impact on QPPR and hemodynamic changes. This study lays a theoretical foundation for further study of QPPR.

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Intracranial hemorrhage risk in patients with cerebral microbleeds after mechanical thrombectomy for acute ischemic stroke: a systematic review and meta-analysis.

Background and purpose intracranial hemorrhage risk in patients with cerebral microbleeds (CMBs) after mechanical thrombectomy for acute ischemic stroke (AIS) was investigated. We searched PubMed and Embase from inception to 29 August 2023 for relevant studies, calculated pooled odds ratio (ORs) of intracerebral hemorrhage (ICH) subtypes in AIS patients with CMB presence, 1-4 or ≥ 5 CMBs versus CMB absence, and with different CMB locations after mechanical thrombectomy. ICH subtypes included any ICH, symptomatic and asymptomatic ICH, hemorrhage outside infarct (including subarachnoid hemorrhage), hemorrhagic infarction, and parenchymal hemorrhage after mechanical thrombectomy. Five eligible studies enrolling 2051 patients were included. No significant association was shown between CMB locations (lobar, deep, infratentorial or mixed) and ICH risk. CMB presence or 1-4 CMBs did not significantly increase the risk of any ICH, symptomatic or asymptomatic ICH, ICH outside infarct, subarachnoid hemorrhage, hemorrhagic infarction, or parenchymal hemorrhage. CMBs ≥ 5 increased the risk of any ICH (OR 2.58, 95% CI 1.16-5.72), parenchymal hemorrhage (OR 3.38, 95% CI 1.43-7.97) and parenchymal hemorrhage-2 (OR 5.33, 2.05-13.86), without increasing hemorrhagic infarction or parenchymal haemorrhage-1 risk. After adjusted for possible confounding factors, increases in CMB burden were associated with hemorrhagic complications but not with symptomatic ICH. In AIS patients who received mechanical thrombectomy, no association was shown between CMB location and ICH risk. ICH risk was not significantly increased by CMB presence or 1-4 CMBs. ICH risk in patients with ≥ 5 CMBs requires further study.

Single-nucleus RNA sequencing reveals that macrophages and smooth muscle cells promote carotid atherosclerosis progression through mitochondrial autophagy.

Carotid atherosclerotic plaques are the manifestation of atherosclerosis in the carotid arteries and can significantly increase the incidence of cerebrovascular disease. Macrophages and smooth muscle cells are crucial for their development. To reveal the mechanism of carotid atherosclerotic plaque formation, we performed single-nucleus RNA sequencing of the carotid plaque tissue and identified 11 cell types, and the macrophages were divided into 5 different macrophage subpopulations. The macrophages and smooth muscle cells in the patients with symptomatic carotid atherosclerotic plaques caused intraplaque cell death via the mitochondrial autophagic pathway, resulting in plaque instability and rupture, which in turn led to clinical cardiovascular and cerebrovascular events. The findings provide new insights into carotid atherosclerosis formation, and this may provide new directions for the prevention and treatment of carotid atherosclerosis.