Suppression of AGRN enhances CD8+ T cell recruitment and inhibits breast cancer progression.

Breast cancer (BC) stands as a prominent contributor to global cancer-related mortality, with an increasing incidence annually. This study aims to investigate AGRN gene expression in BC, as well as explore its influence on the tumor immune microenvironment. AGRN displayed a pronounced upregulation in BC tissues relative to paracancerous tissues. Single-cell RNA analysis highlighted AGRN-specific elevation within cancer cell clusters and also showed expression expressed in stromal as well as immune cell clusters. AGRN upregulation was positively correlated with clinicopathological stage and negatively correlated with BC prognosis. As revealed by the in vitro experiment, AGRN knockdown effectively hinders BC cells in terms of proliferation, invasion as well as migration. AGRN protein, which may interact with EXT1, LRP4, RAPSN, etc., was primarily distributed in the cell cytoplasm. Notably, immune factors might interact with AGRN in BC, evidenced by its discernible associations with immunofactors like IL10, CD274, and PVRL2. Mass spectrometry and immunohistochemistry revealed that the reduction of AGRN led to an increase in CD8+ T cells with triple-negative breast cancer (TNBC). Mechanistically, the connection between TRIM7 and PD-L1 is improved by AGRN, acting as a scaffold, thereby facilitating the accelerated degradation of PD-L1 by TRIM7. Downregulation of AGRN inhibits BC progression and increases CD8+ T cell recruitment. Targeting AGRN may contribute to BC treatment. The biomarker AGRN, serving as a therapeutic target for BC, emerges as a prospective avenue for enhancing both diagnosis and prognosis in BC cases.

Robust Superhydrophobic Composite Fabric with Self-Healing and Chemical Durability.

Superhydrophobic fabrics with multiple functions have become a research hotspot. However, it is challenging to make self-healing mechanically robust and eco-friendly superhydrophobic fabrics, which are limited by complex fabrication processes and excessive use of environmentally unfriendly solvents during fabrication. Herein, inspired by the secretion of a waxy substance from the surface of lotus leaves to restore water repellency, self-healing superhydrophobic composite fabrics (as-synthesized PA66/6-PET@Tico) are obtained by constructing a papillary TiO2 and tentacle-like fluorinated acrylate polymer (FCB015) coating on polyester-nylon composite fabrics using two-step hydrothermal method. The result indicates that PA66/6-PET@Tico with hierarchical micro/nanostructure exhibits excellent superhydrophobic and self-healing properties. Compared with FCB015 coated fabric, the contact angles (CA) of water and soybean oil rise to 172.2° and 166.8° from 137.4° and 98.8°, respectively. After mechanical abrasion, PA66/6-PET@Tico recovers a water contact angle (WCA) of 165.6° at room temperature. The WCA remains higher than 155° after 18 h of chemical corrosion. Furthermore, the bacterial inhibition rates of PA66/6-PET@Tico for Staphylococcus Aureus and Escherichia Coli are 99.90 and 98.38%, respectively. In this work, a new idea is proposed for designing a simple and effective self-healing superhydrophobic coating, expecting to promote the large-scale industrial production and application of functional surfaces.

Role of Exosomes in Cardiovascular Diseases.

Exosomes (EXOs) are a subgroup of extracellular vesicles (EVs) that contain numerous biologically active molecules. They exhibit an essential mode of cell communication, primarily between distinct cell populations, for the maintenance of tissue homeostasis and coordination of adaptive responses to various stresses. These intercellular communications are vital for the complex, multicellular cardiovascular system. In the last ten years, their potential role as effective tissue-to-tissue communicators has received increasing attention in cardiovascular physiology and pathology. There is growing evidence that repair of the heart and regeneration can be promoted by EXOs derived from cardiomyocytes or stem/progenitor cells. However, the underlying mechanisms remain unclear. EVs derived from different stem/progenitor cell populations have been used as cell-free therapies in different preclinical models involving cardiovascular diseases and have shown promising results. In this review, we have summarized the recent developments in EXOs research, the impact of EXOs derived from different cells on the cardiovascular system, their potential therapeutic roles as well as new diagnostic biomarkers, and the possible clinical translational outcomes.

Tai Chi-Induced Exosomal LRP1 is Associated With Memory Function and Hippocampus Plasticity in aMCI Patients.

OBJECTIVES: The study was designed to identify the potential peripheral processes of circulating exosome in response to Tai Chi (TC) exercise and the possibility of its loaded cargos in mediating the effects of TC training on cognitive function among older adults with amnestic mild cognitive impairment (aMCI). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter randomized controlled trial. One hundred community-dwelling old adults with aMCI were randomly assigned (1:1) to experimental (n = 50) and control groups (n = 50). INTERVENTION: The experimental group participated in TC exercise 5 times/week, with each session lasting 60 minutes for 12 weeks. Both experimental and control groups received health education every 4 weeks. MEASUREMENTS: The primary outcome was global cognitive function. Neurocognitive assessments, MRI examination, and large-scale proteomics analysis of peripheric exosome were conducted at baseline and after 12-week training. Outcome assessors and statisticians were blinded to group allocation. RESULTS: A total of 96 participants (96%) completed all outcome measurements. TC training improved global cognitive function (adjusted mean difference [MD] = 1.9, 95%CI 0.93-2.87, p <0.001) and memory (adjusted MD = 6.42, 95%CI 2.09-10.74, p = 0.004), increased right hippocampus volume (adjusted MD = 88.52, 95%CI 13.63-163.4, p = 0.021), and enhanced rest state functional connectivity (rsFC) between hippocampus and cuneus, which mediated the group effect on global cognitive function (bootstrapping CIs: [0.0208, 1.2826], [0.0689, 1.2211]) and verbal delay recall (bootstrapping CI: [0.0002, 0.6277]). Simultaneously, 24 differentially expressed exosomal proteins were detected in tandem mass tag-labelling proteomic analysis. Of which, the candidate protein low-density lipoprotein receptor-related protein 1 (LRP1) was further confirmed by parallel reaction monitoring and ELISA. Moreover, the up-regulated LRP1 was both positively associated with verbal delay recall and rsFC (left hippocampus-right cuneus). CONCLUSION: TC promotes LRP1 release via exosome, which was associated with enhanced memory function and hippocampus plasticity in aMCI patients. Our findings provided an insight into potential therapeutic neurobiological targets focusing on peripheric exosome in respond to TC exercise.

Inverse association between maternal serum concentrations of trace elements and risk of spontaneous preterm birth: a nested case-control study in China.

Few studies have evaluated the joint effect of trace elements on spontaneous preterm birth (SPTB). This study aimed to examine the relationships between the individual or mixed maternal serum concentrations of Fe, Cu, Zn, Se, Sr and Mo during pregnancy, and risk of SPTB. Inductively coupled plasma MS was employed to determine maternal serum concentrations of the six trace elements in 192 cases with SPTB and 282 controls with full-term delivery. Multivariate logistic regression, weighted quantile sum regression (WQSR) and Bayesian kernel machine regression (BKMR) were used to evaluate the individual and joint effects of trace elements on SPTB. The median concentrations of Sr and Mo were significantly higher in controls than in SPTB group (P < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted OR (aOR) of 0·432 (95 CI < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted aOR of 0·432 (95 % CI 0·247, 0·756), 0·386 (95 % CI 0·213, 0·701), 0·512 (95 % CI 0·297, 0·883) and 0·559 (95 % CI 0·321, 0·972), respectively. WQSR revealed the inverse combined effect of the trace elements mixture on SPTB (aOR = 0·368, 95 % CI 0·228, 0·593). BKMR analysis confirmed the overall mixture of the trace elements was inversely associated with the risk of SPTB, and the independent effect of Sr and Mo was significant. Our findings suggest that the risk of SPTB decreased with concentrations of the six trace elements, with Sr and Mo being the major contributors.

Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity.

Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.

Impact of Delirium Onset and Duration on Mortality in Patients With Cancer Admitted to the ICU.

BACKGROUND: Little is known on the effects of delirium onset and duration on outcome in critically ill patients with cancer. OBJECTIVES: To determine the impact of delirium onset and duration on intensive care unit (ICU) and hospital mortality and length of stay (LOS) in patients with cancer. METHODS: Of the 915 ICU patients admitted in 2018, 371 were included for analysis after excluding for terminal disease, <24-h ICU stay, lack of active cancer and delirium. Delirium was defined as early if onset was within 2 days of ICU admission, late if onset was on day 3 or later, short if duration was 2 days or less, and long if duration was 3 days or longer. Patients were placed into 4 combination groups: early-short, early-long, late-short, and late-long delirium. Multivariate analysis controlling for sex, age, metastatic disease, and predelirium hospital LOS was performed to determine ICU and hospital mortality and LOS. Exploratory analysis of long-term survival was also performed. Restricted cubic splines were performed to confirm the use of 2 days to distinguish between early versus late onset and short versus long duration. RESULTS: A total of 32.9% (n = 122) patients had early-short, 39.1% (n = 145) early-long, 16.2% (n = 60) late-short, and 11.9% (n = 44) late-long delirium. Late-long delirium was independently associated with increased ICU (OR 4.45, CI 1.92-10.30; P < .001) and hospital (OR 2.91, CI 1.37-6.19; P = .005) mortality and longer ICU (OR 1.97, CI 1.58-2.47; P < .001) LOS compared to early-short delirium. Early delirium had better overall survival at 18 months than late delirium. Long-term survival further improved when delirium duration was 2 days or less. Prediction heatmaps confirm the use of a 2-day cutoff. CONCLUSION: Late delirium, especially with long duration, significantly worsens outcome in ICU patients with cancer and should be considered a harbinger of poor overall condition.

The altered hippocampal functional connectivity and serum brain-derived neurotrophic factor level predict cognitive decline in patients with knee osteoarthritis.

Patients with knee osteoarthritis (KOA) often suffer from cognitive decline and increased dementia risk, but the neurobiological mechanisms remain unclear. In this study, we evaluated cognitive performance and collected brain magnetic resonance imaging (MRI) data and blood samples from cognitively normal KOA patients at baseline sessions and reevaluated their cognition after 5 years. We also collected MRI data from matched healthy controls. Results showed that KOA patients exhibited dysregulated functional connectivities between the hippocampus and thalamus/superior frontal gyrus compared with healthy controls. The altered hippocampal functional connectivities were associated with serum brain-derived neurotrophic factor (BDNF) levels and spatial expression of genes enriched in synaptic plasticity. The hippocampus-thalamus functional connectivity was significantly correlated with patients' memory scores. Moreover, the baseline hippocampus-thalamus functional connectivity and BDNF levels significantly predicted the development of cognitive decline in KOA patients in the follow-up session. Our findings provide insight into the neurobiological underpinnings of KOA and cognitive decline.

Association of maternal phthalates exposure and metabolic gene polymorphisms with congenital heart diseases: a multicenter case-control study.

BACKGROUND: The majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring. METHODS: A multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-gene and gene-phthalates exposure interactions. RESULTS: There was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28-2.37; dominant: aOR = 1.86, 95% CI:1.25-2.78; recessive: aOR = 2.50, 95% CI: 1.26-4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54-121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed. CONCLUSIONS: The polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future.

Association between depression and infertility risk among American women aged 18-45 years: the mediating effect of the NHHR.

BACKGROUND/OBJECTIVE: Depression and infertility are major medical and social problems. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) serves as an innovative and reliable lipid marker for cardiovascular disease risk assessment. Previous research has indicated a potential correlation among lipid metabolism, depression, and infertility. Nonetheless, the exact involvement of lipid metabolism in modulating the pathological mechanisms associated with depression-induced infertility remains to be fully elucidated. The aim of this study was to explore the connection between depression and infertility and to assess whether the NHHR mediates this association. METHODS: A cross-sectional analysis was performed utilizing data from there cycles (2013-2018) of the National Health and Nutrition Examination Survey (NHANES) database. Female infertility was assessed according to the responses to the RHQ074 question in the reproductive health questionnaire module. Depression states were evaluated using the Patient Health Questionnaire-9 and classified into three grades based on the total scores: no depression (0-4 points), minimal-to-mild depression (5-9 points) and moderate-to-severe depression (10 or more points). The NHHR was calculated from laboratory cholesterol test results. Baseline population characteristics were compared, and subgroup analyses were carried out based on the stratification of age and body mass index (BMI). Weighted multivariable logistic regression and linear regression models, with adjustments for various covariables, were employed to examine the associations among depression, infertility and the NHHR. Finally, mediation analysis was utilized to explore the NHHR's potential mediating role in depression states and female infertility. RESULTS: Within this cross-sectional study, 2,668 women aged 18 to 45 years residing in the United States were recruited, 305 (11.43%) of whom experienced infertility. The study revealed a markedly higher prevalence of depression (P = 0.040) and elevated NHHR (P < 0.001) among infertile women compared to the control cohort. Furthermore, moderate-to-severe depression states independently correlated with increased infertility risk, irrespective of adjustments for various covariables. Subgroup analysis indicated a positive association between depression and infertility risk within certain age categories, although no such relationship was observed within subgroups stratified by BMI. The findings from the weighted logistic regression analysis demonstrated that the elevated NHHR is positively associated with heightened infertility risk. Additionally, the weighted linear regression analysis indicated that moderate-to-severe depression is positively linked to the NHHR levels as well. Finally, the association between depression states and female infertility was partially mediated by the NHHR, with the mediation proportion estimated at 6.57%. CONCLUSION: In the United States, depression is strongly correlated with an increased likelihood of infertility among women of childbearing age, with evidence suggesting that this relationship is mediated by the NHHR. Subsequent research efforts should further explore the underlying mechanisms connecting depression and infertility.

Joint association of sedentary time and physical activity with abnormal heart rate recovery in young and middle-aged adults.

BACKGROUND: Abnormal heart rate recovery (HRR), representing cardiac autonomic dysfunction, is an important predictor of cardiovascular disease. Prolonged sedentary time (ST) is associated with a slower HRR. However, it is not clear how much moderate-to-vigorous physical activity (MVPA) is required to mitigate the adverse effects of sedentary behavior on HRR in young and middle-aged adults. This study aimed to examine the joint association of ST and MVPA with abnormal HRR in this population. METHODS: A cross-sectional analysis was conducted on 1253 participants (aged 20-50 years, 67.8% male) from an observational study assessing cardiopulmonary fitness in Fujian Province, China. HRR measured via cardiopulmonary exercise tests on a treadmill was calculated as the difference between heart rate at peak exercise and 2 min after exercise. When the HRR was ≤ 42 beats·minute-1 within this time, it was considered abnormal. ST and MVPA were assessed by the IPAQ-LF. Individuals were classified as having a low sedentary time (LST [< 6 h·day-1]) or high sedentary time (HST [≥ 6 h·day-1]) and according to their MVPA level (low MVPA [0-149 min·week-1], medium MVPA [150-299 min·week-1], high MVPA [≥ 300 min·week-1]). Finally, six ST-MVPA groups were derived. Associations between ST-MVPA groups with abnormal HRR incidence were examined using logistic regression models. RESULTS: 53.1% of the young and middle-aged adults had less than 300 min of MVPA per week. In model 2, adjusted for possible confounders (e.g. age, sex, current smoking status, current alcohol consumption, sleep status, body mass index), HST was associated with higher odds of an abnormal HRR compared to LST (odds ratio (OR) = 1.473, 95% confidence interval (CI) = 1.172-1.852). Compared with the reference group (HST and low MVPA), the HST and high MVPA groups have a lower chance of abnormal HRR (OR, 95% CI = 0.553, 0.385-0.795). Compared with individuals with HST and low MVPA, regardless of whether MVPA is low, medium, or high, the odds of abnormal HRR in individuals with LST is significantly reduced (OR, 95% CI = 0.515, 0.308-0.857 for LST and low MVPA; OR, 95% CI = 0.558, 0.345-0.902 for LST and medium MVPA; OR, 95% CI = 0.476, 0.326-0.668 for LST and high MVPA). CONCLUSION: Higher amounts of MVPA appears to mitigate the increased odds of an abnormal HRR associated with HST for healthy young and middle-aged adults.

Silencing the odorant co-receptor (Orco) in Anoplophora glabripennis disrupts responses to pheromones and host volatiles.

Insects rely primarily on a robust and precise olfactory recognition system to detect chemicals and environmental signals. Olfaction is mediated mainly by various odorant receptors (ORs) expressed on olfactory neurons. The odorant co-receptor (Orco) is a highly conserved and obligatory subunit of ORs, and its combination with conventional ORs to form ligand-gated ion channel heterodimeric complexes plays a crucial role in odor recognition. Anoplophora glabripennis Is a major quarantinable pest that affects broadleaved tree species worldwide. Odorant binding proteins (OBPs) and ORs have been identified in the A. glabripennis genome and the binding properties of some OBPs and their cognate ligands have been clarified. The role of the OR-mediated recognition pathway, however, remains largely uncharacterized. Here, we cloned and sequenced the full-length Orco gene sequence of A. glabripennis and performed structural characterization of the protein. We found that AglaOrco has high sequence homology with Orco from other orders of insects, and that it is highly conserved. Spatio-temporal differential expression analysis revealed that AglaOrco is highly expressed in adult antennae, and that expression at the sexually mature stage is significantly higher than at other developmental stages. There was no significant difference in expression between sexes. Silence AglaOrco using RNAi revealed that expression levels of AglaOrco mRNA fell significantly in both males and females at 72 h post-injection of 5 µg of dsOrco, with no obvious effect on expression of most other olfactory-related genes; however, some were up-or downregulated. For example, silenced Orco-expressing males and females showed a significant reduction in antennal potential responses to the odorants 3-carene, Ocimene, and 4-heptyloxy-1-butanol. Overall, the data suggest that AglaOrco plays an important role in mediating olfactory perception in A. glabripennis, and also identifies potential target genes for environmentally friendly pest control strategies.

Transcriptome analysis reveals the pheromone synthesis mechanism and mating response in Monochamus saltuarius (Coleoptera, Cerambycidae).

The pinewood nematode Bursaphelenchus xylophilus (Steiner and Buhrer 1934) causes pine wilt disease, which severely affects the biodiversity and economy of Eurasian coniferous forests. Monochamus saltuarius (Coleoptera, Cerambycidae) was first identified as nematode vectors in Liaoning Province, China, in 2017. M. saltuarius has high mating efficiency and reproductive capabilities, pheromones are crucial in these processes. However, the mechanisms of pheromone synthesis in M. saltuarius are unclear. This study performed morphometric and transcriptomic analyses of the internal reproductive systems of males and females at different developmental stages and analyzed mate selection behavior. We found a significant difference in the morphology of internal reproductive systems between sexually immature and mature insects. A total of 58 and 64 pheromone biosynthesis genes were identified in females and males, respectively. The expression of the analyzed genes differed between males and females in the initial and subsequent synthesis processes. Interference experiment indicated that knocking down SDR1 gene in male M. saltuarius reduces the content of pheromones. Behavioral analyses found that males preferred virgin females. This study identified key pheromone genes and synthesis pathway that could serve as potential targets for disrupting mating in M. saltuarius through the development of novel biological agents using genetic engineering techniques.

Functional and Compositional Changes in Sirex noctilio Gut Microbiome in Different Habitats: Unraveling the Complexity of Invasive Adaptation.

The mutualistic symbiosis relationship between the gut microbiome and their insect hosts has attracted much scientific attention. The native woodwasp, Sirex nitobei, and the invasive European woodwasp, Sirex noctilio, are two pests that infest pines in northeastern China. Following its encounter with the native species, however, there is a lack of research on whether the gut microbiome of S. noctilio changed, what causes contributed to these alterations, and whether these changes were more conducive to invasive colonization. We used high-throughput and metatranscriptomic sequencing to investigate S. noctilio larval gut and frass from four sites where only S. noctilio and both two Sirex species and investigated the effects of environmental factors, biological interactions, and ecological processes on S. noctilio gut microbial community assembly. Amplicon sequencing of two Sirex species revealed differential patterns of bacterial and fungal composition and functional prediction. S. noctilio larval gut bacterial and fungal diversity was essentially higher in coexistence sites than in separate existence sites, and most of the larval gut bacterial and fungal community functional predictions were significantly different as well. Moreover, temperature and precipitation positively correlate with most of the highly abundant bacterial and fungal genera. Source-tracking analysis showed that S. noctilio larvae at coexistence sites remain dependent on adult gut transmission (vertical transmission) or recruitment to frass (horizontal transmission). Meanwhile, stochastic processes of drift and dispersal limitation also have important impacts on the assembly of S. noctilio larval gut microbiome, especially at coexistence sites. In summary, our results reveal the potential role of changes in S. noctilio larval gut microbiome in the successful colonization and better adaptation of the environment.

Electroacupuncture improves vascular cognitive impairment no dementia: A Randomized Clinical Trial.

BACKGROUND: Electroacupuncture (EA) could represent a clinically effective treatment strategy for patients with vascular cognitive impairment no dementia (VCIND). This randomized trial aims to explore the underlying mechanism of EA in VCIND patients through cognitive function assessment and neuroimaging assessment. METHODS: 140 eligible patients with VCIND were recruited and randomly divided into EA group (n = 70) and Control group (n = 70). The Montreal Cognitive Assessment (MoCA), and the Auditory Verbal Learning Test (AVLT), the Stroop color-naming task (STROOP), and the resting-state functional magnetic resonance imaging assessment. The EA group received treatment for 30 min/day, 5 times/week, for 8 weeks. RESULTS: EA intervention could increase the MoCA score and improve the neutral and consistency response of the STROOP test in VCIND patients (P < 0.05). fMRI functional connectivity analysis showed that, after EA, the default mode network (DMN) function of the posterior cingulate gyrus, left middle frontal gyrus, left anterior cingulate gyrus, left and right superior temporal gyrus, right insula, left precentral gyrus and other brain regions were significantly higher than that in the control group. The functional connectivity between the posterior cingulate gyrus-left middle frontal gyrus and the posterior cingulate gyrus-right superior temporal gyrus was positively correlated with cognitive function (P < 0.05). Gray Matter Volume increased in VCIND after EA(P < 0.05). CONCLUSIONS: EA can increase the functional connectivity between posterior cingulate gyrus-other gyri in VCIND patients. The functional connectivity is positively correlated with cognitive function.

[Astragali Radix-Curcumae Rhizoma inhibits colon cancer progression and enhances 5-FU efficacy by regulating hypoxia-inducible factors and tumor stem cells].

The animal and cell models were used in this study to investigate the mechanism of Astragali Radix-Curcumae Rhizoma(HQEZ) in inhibiting colon cancer progression and enhancing the efficacy of 5-fluorouracil(5-FU) by regulating hypoxia-inducible factors and tumor stem cells. The animal model was established by subcutaneous transplantation of colon cancer HCT116 cells in nude mice, and 24 successfully modeled mice were randomized into model, 5-FU, HQEZ, and 5-FU+HQEZ groups. The tumor volume was measured every two days. Western blot was employed to measure the protein levels of epidermal growth factor receptor(EGFR), dihydropyrimidine dehydrogenase(DPYD), and thymidylate synthase(TYMS), the key targets of the hypoxic core region, as well as the hypoxia-inducible factors HIF-1α and HIF-2α and the cancer stem cell surface marker CD133 and SRY-box transcription factor 2(SOX2). The results of animal experiments showed that HQEZ slowed down the tumor growth and significantly increased the tumor inhibition rate of 5-FU. Compared with the model group, HQEZ significantly down-regulated the protein levels of EGFR and DPYD, and 5-FU+HQEZ significantly down-regulated the protein levels of EGFR and TYMS in tumors. Compared with the model group, HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, SOX2, and CD133 in the hypoxic core region. Compared with the 5-FU group, 5-FU+HQEZ lowered the protein levels of HIF-1α, HIF-2α, and SOX2. The cell experiments showed that the protein le-vels of HIF-1α and HIF-2α in HCT116 cells elevated significantly after low oxygen treatment. Compared with 5-FU(1.38 µmol·L~(-1)) alone, HQEZ(40 mg·mL~(-1)) and 5-FU+HQEZ significantly down-regulated the protein levels of HIF-1α, HIF-2α, and TYMS. In conclusion, HQEZ can inhibit the expression of hypoxia-responsive molecules in colon cancer cells and reduce the properties of cancer stem cells, thereby enhancing the therapeutic effect of 5-FU on colon cancer.

Hierarchically Responsive Alternating Nano-Copolymers with Tailored Interparticle Bonds.

Self-assembly of inorganic nanoparticles (NPs) is an essential tool for constructing structured materials with a wide range of applications. However, achieving ordered assembly structures with externally programmable properties in binary NP systems remains challenging. In this work, we assemble binary inorganic NPs into hierarchically pH-responsive alternating copolymer-like nanostructures in an aqueous medium by engineering the interparticle electrostatic interactions. The polymer-grafted NPs bearing opposite charges are viewed as nanoscale monomers ("nanomers"), and copolymerized into alternating nano-copolymers (ANCPs) driven by the formation of interparticle "bonds" between nanomers. The resulting ANCPs exhibit reversibly responsive "bond" length (i.e., the distance between nanomers) in response to the variation of pH in a range of ~7-10, allowing precise control over the surface plasmon resonance of ANCPs. Moreover, specific interparticle "bonds" can break up at pH≥11, leading to the dis-assembly of ANCPs into molecule-like dimers and trimers. These dimeric and trimeric structures can reassemble to form ANCPs owing to the resuming of interparticle "bonds", when the pH value of the solution changes from 11 to 7. The hierarchically responsive nanostructures may find applications in such as biosensing, optical waveguide, and electronic devices.

Twin Proliferation and Prolongation under Kinetic Control: Pd-Au Janus Icosahedra versus Pd@Au Core-Shell Starfishes.

Heterogeneous bimetallic nanocrystals featuring explicit spatial configurations and abundant twin defects can simultaneously enable geometric and ligand effects to enhance catalytic and photonic applications. Herein, we report two growth patterns of Au atoms on penta-twinned Pd decahedra, involving twin proliferation to generate asymmetric Pd-Au Janus icosahedra and twin elongation to produce anisotropic Pd@Au core-shell starfishes, respectively. Mechanistic analysis indicates that the injection rate determines the lower-limit number (nlow) of Au(III) ions in the steady state and thus controls the growth pattern. When nlow ≤ 5.5, the kinetic rate is slow enough to initiate asymmetrical one-side growth but fast enough to outpace surface diffusion; Au tetrahedral subunits are successively proliferated along the axial ⟨110⟩ direction of Pd decahedra to form Pd-Au Janus icosahedra. Composed of five Pd and 15 Au tetrahedral subunits, such a heterogeneous icosahedron supports high (2.2 GPa) tensile strain and high strain difference up to +21.9%. In contrast, when nlow > 5.5, the fast reduction kinetics promotes symmetric growth with inadequate surface diffusion. As such, Au atoms are laterally deposited along five high-indexed ⟨211⟩ ridges of Pd decahedra to generate concave Pd@Au core-shell starfishes with tunable sizes (28-40 nm), twin elongation ratios (33.82-162.08%), and lattice expansion ratios (8.82-20.10%).

RIPK1 polymorphisms and expression levels: impact on genetic susceptibility and clinical outcome of epithelial ovarian cancer.

BACKGROUND: The aim of this study was to explore the associations of RIPK1 polymorphisms, plasma levels and mRNA expression with susceptibility to epithelial ovarian cancer (EOC) and clinical outcome. METHODS: Three hundred and nineteen EOC patients included in a 60-month follow-up program and 376 controls were enrolled. Two tag SNPs (rs6907943 and rs9392453) of RIPK1 were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Plasma levels of RIPK1 and RIPK1 mRNA expression in white blood cells were determined by ELISA and qPCR, respectively. RESULTS: For rs9392453, significantly increased EOC risk was found to be associated with C allele (P = 0.002, OR = 1.49, 95%CI 1.15-1.92), and with CT/CC genotypes in the dominant genetic model (P = 0.006, OR = 1.54, 95%CI 1.12-2.08). CC haplotype (rs6907943-rs9392453) was associated with increased EOC susceptibility. CC genotype of rs6907943 and CT/CC genotypes of rs9392453 were associated with early onset (age ≤ 50 years) of EOC (OR = 2.5, 95%CI 1.03-5.88, and OR = 1.64, 95%CI 1.04-2.63, respectively). AC genotype of rs6907943 was associated with better overall survival of EOC patients in the over-dominant genetic model (P = 0.035, HR = 0.41, 95%CI 0.18-0.94). Multivariate survival analysis identified the AC genotype of rs6907943 as an independent protective factor for survival of early onset patients (P = 0.044, HR = 0.12, 95%CI 0.02-0.95). Compared to controls, significantly increased plasma levels of RIPK1 and reduced RIPK1 mRNA expression were observed in patients. CONCLUSIONS: Our results suggest that tag SNPs of RIPK1, increased plasma levels of RIPK1 protein and reduced RIPK1 mRNA expression in white blood cells, may influence the susceptibility to EOC. SNP rs6907943 may be a useful marker to distinguish EOC patients with high risk of death.

Elevated random glucose levels at admission are associated with all-cause mortality and cardiogenic shock during hospitalisation in patients with acute myocardial infarction and without diabetes: A retrospective cohort study.

BACKGROUND: Elevated glucose levels at admission are associated with a worse prognosis in patients with acute myocardial infarction (AMI); additionally, such elevation has a higher prognostic value for patients without diabetes. METHODS: We retrospectively recruited 2412 AMI patients without diabetes from 1 August 2011 to 10 January 2022. The primary outcome was all-cause mortality during hospitalisation, and the secondary outcomes were cardiogenic shock, ventricular tachycardia, ventricular fibrillation, atrioventricular block and new stroke. RESULTS: The mean age of participants was 65 years and 78.6% were male. Of the 2412 patients, all-cause mortality occurred in 236 patients (9.8%) during hospitalisation. In multivariate-adjusted models that corrected for variable weights, the risk of all-cause mortality increased with an increase in random glucose levels at admission; specifically, the risk of all-cause mortality increased per 1 mg/dL (odds ratio [OR] 1.006, 95% confidence interval [CI]: 1.004-1.008), per 9 mg/dL (OR: 1.06, 95% CI: 1.04-1.08), and per 18 mg/dL (OR: 1.12, 95% CI: 1.07-1.16) increases in admission glucose levels. When admission glucose levels were expressed as a categorical variable, increased levels of glucose (relative to the reference glucose value <140 mg/dL) led to an increased risk of all-cause mortality; specifically, the OR of all-cause mortality for 140-200 mg/dL glucose was 1.55 (95% CI: 1.09-2.17) and the OR for glucose >200 mg/dL was 3.08 (95% CI: 2.00-4.62) (P for trend <0.001). The risk of cardiogenic shock also increased with glucose levels with an OR of 1.68 (95% CI: 1.21-2.31) for 140-200 mg/dL glucose and an OR of 3.72 (95% CI: 2.50-5.46) for >200 mg/dL, compared with that of glucose <140 mg/dL. In multivariate-adjusted spline regression models, an increased risk of all-cause mortality was observed in patients with glucose ≥122 mg/dL (OR: 1.81, 95% CI: 1.38-2.38, p < 0.001) compared with the reference cohort. Furthermore, patients with glucose ≥111 mg/dL (OR: 2.36, 95% CI: 1.80-3.12) had a higher risk of cardiogenic shock than patients with glucose <111 mg/dL. CONCLUSIONS: Patients with AMI and without diabetes who had elevated random glucose levels at admission had a higher risk of all-cause mortality and cardiogenic shock during hospitalisation. In particular, patients with glucose ≥122 mg/dL had an increased risk of all-cause mortality, and those with glucose ≥111 mg/dL had an increased risk of cardiogenic shock.