Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.

Precise Tuning of Hollow and Pore Size of Bimetallic MOFs Derivate to Construct High-Performance Nanoscale Materials for Supercapacitors and Sodium-Ion Batteries.

Precise control of pore volume and size of carbon nanoscale materials is crucial for achieving high capacity and rate performances of charge/discharge. In this paper, starting from the unique mechanism of the role of In, Zn combination, and carboxyl functional groups in the formation of the lumen and pore size, the composition of InZn-MIL-68 is regulated to precisely tune the diameter and wall pore size of the hollow carbon tubes. The hollow carbon nanotubes (CNT) with high-capacity storage and fast exchange of Na+ ions and charges are prepared. The CNT possess ultra-high specific capacitance and ultra-long cycle life and also offer several times higher Na+ ion storage capacity and rate performance than the existing CNTs. Density functional theory calculations and tests reveal that these superior characteristics are attributed to the spacious hollow structure, which provides sufficient space for Na+ storage and the tube wall's distinctive porosity of tube wall as well as open ends for facilitating Na+ rapid desorption. It is believed that precise control of sub-nanopore volume and pore size by tuning the composition of the carbon materials derived from bimetallic metal-organic frameworks (MOFs) will establish the basis for the future development of high-energy density and high-power density supercapacitors and batteries.

Development of a Dual Fluorescence Signal-Enhancement Immunosensor Based on Substrate Modification for Simultaneous Detection of Interleukin-6 and Procalcitonin.

High-sensitivity detection of biomarkers is of great significance to improve the accuracy of disease diagnosis and the rate of occult disease diagnosis. Using a substrate modification and two-color quantum dot (QD) nanobeads (QBs), we have developed a dual fluorescence signal-enhancement immunosensor for sensitive, simultaneous detection of interleukin 6 (IL-6) and procalcitonin (PCT) at low volumes (∼20 µL). First, the QBs compatible with QDs with different surface ligands were prepared by optimizing surfactants based on the microemulsion method. Through the use of a fluorescence-linked immunosorbent assay (FLISA), the feasibility of a dual signal-enhancement immunosensor was verified, and a 5-fold enhancement of fluorescence intensity was achieved after the directional coating of the antibodies on sulfhydryl functionalization (-SH) substrates and the preparation of QBs by using a polymer and silica double-protection method. Next, a simple polydimethylsiloxane (HS-PDMS) immunosensor with a low volume consumption was prepared. Under optimal conditions, we achieved the simultaneous detection of IL-6 and PCT with a linear range of 0.05-50 ng/mL, and the limit of detection (LOD) was 24 and 32 pg/mL, respectively. The result is comparable to two-color QBs-FLISA with a sulfhydryl microplate, even though only 20% of its volume was used. Thus, the dual fluorescence signal-enhancement HS-PDMS immunosensor offers the capability of early microvolume diagnosis of diseases, while the detection of inflammatory factors is clinically important for assisting disease diagnosis and determining disease progression.

High-Temperature Phase Transition with Switchable Dielectric Behavior and Significant Photoluminescence Changes in a Zero-Dimensional Hybrid SbBr6 Perovskite.

In the past decade, metal halide materials have been favored by many researchers because of their excellent physical and chemical properties under thermal, electrical, and light stimuli, such as ferroelectricity, dielectric, nonlinearity, fluorescence, and semiconductors, greatly promoting their application in optoelectronic devices. In this study, we successfully constructed an unleaded organic-inorganic hybrid perovskite crystal: [Cl-C6H4-(CH2)2NH3]3SbBr6 (1), which underwent a high-temperature reversible phase transition near Tp = 368 K. The phase transition behavior of 1 was characterized by differential scanning calorimetry, accompanied by a thermal hysteresis of 6 K. In addition, variable-temperature Raman spectroscopy analysis and PXRD further verified the sensitivity of 1 to temperature and the phase transition from low symmetry to high symmetry. Temperature-dependent dielectric testing shows that 1 can be a sensitive switching dielectric constant switching material. Remarkably, 1 exhibits strong photoluminescence emission with a wavelength of 478 nm and a narrow band gap of 2.7 eV in semiconductors. As the temperature increases and decreases, fluorescence undergoes significant changes, especially near Tc, which further confirms the reversible phase transition of 1. All of these findings provide new avenues for designing and assembling new phase change materials with high Tp and photoluminescence properties.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Ochratoxin A-enhanced glycolysis induces inflammatory responses in human gastric epithelium cells through mTOR/HIF-1α signaling pathway.

Ochratoxin A (OTA) is a mycotoxin commonly found in several food commodities worldwide with potential nephrotoxic, hepatotoxic and carcinogenic effects. We previously showed for the first time that OTA treatment enhanced glycolysis in human gastric epithelium (GES-1) cells in vitro. Here, we found that OTA exposure activated inflammatory responses, evidenced by increasing of NF-κB signaling pathway-related protein (p-p65 and p-IκBα) expressions and elevating of inflammatory cytokine (IL-1ß and IL-6) mRNA expressions in GES-1 cells. To elucidate the role of glycolysis in inflammatory effects triggered by OTA, we pretreated GES-1 cells with glycolysis inhibitor (2-deoxy-D-glucose, 2-DG) before OTA exposure. The result showed that 2-DG reduced the protein expressions of p-p65 and p-IκBα and alleviated the mRNA expressions of inflammatory cytokines in OTA-treated GES-1 cells. Furthermore, OTA activated the mTOR/HIF-1α pathway by increasing the protein expressions of p-mTOR, p-eIF4E and HIF-1α, and inhibition of mTOR with rapamycin or silencing HIF-1α with siRNA significantly attenuated OTA-enhanced glycolysis by reducing glycolysis related genes and thereby decreasing inflammatory effects of GES-1 cells. These results demonstrate that OTA activates inflammatory responses in GES-1 cells and this is controlled by mTOR/HIF-1α pathway-mediated glycolysis enhancement. Our findings provide a novel mechanistic view into OTA-induced gastric cytotoxicity.

Efficient fluorescence coupling microlens integrated fiber magnetometer probe based on nitrogen vacancy centers.

The nitrogen vacancy (NV) centers in diamonds have gathered increasing interest as an emerging quantum sensing platform with high sensitivity and spatial resolution. Integration of micro-sized diamond and fiber is an essential method to build an NV center endoscope probe and enable NV center sensors for practical application. However, the low fluorescence collection efficiency of fibers due to their small numerical aperture (NA) has limited the sensitivity of the sensors. In this paper, a cone-shape microlens was fabricated using the photopolymerization process at the end of a multimode fiber to boost the laser excitation and fluorescence collection efficiency of NV centers. Experiments demonstrated that over 21 times fluorescence intensity enhancement and 12 times sensitivity improvement were achieved. This fiber-microlens magnetometer probe exhibited a 2.1-nT/Hz1/2 sensitivity over a bandwidth of 100 Hz with ∼80-µm diameter diamond. This research presented a robust and large NA diamond integrated fiber-microlens magnetometer probe, which can also be expanded to magnetic field scan and real-time monitoring.

Histone acetyltransferase 1 is a succinyltransferase for histones and non-histones and promotes tumorigenesis.

Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post-translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone acetyltransferase, regulating the acetylation of both histone and non-histone proteins. However, the role of HAT1 in succinylation modulation remains unclear. Here, we employ a quantitative proteomics approach to study succinylation in HepG2 cancer cells and find that HAT1 modulates lysine succinylation on various proteins including histones and non-histones. HAT1 succinylates histone H3 on K122, contributing to epigenetic regulation and gene expression in cancer cells. Moreover, HAT1 catalyzes the succinylation of PGAM1 on K99, resulting in its increased enzymatic activity and the stimulation of glycolytic flux in cancer cells. Clinically, HAT1 is significantly elevated in liver cancer, pancreatic cancer, and cholangiocarcinoma tissues. Functionally, HAT1 succinyltransferase activity and the succinylation of PGAM1 by HAT1 play critical roles in promoting tumor progression in vitro and in vivo. Thus, we conclude that HAT1 is a succinyltransferase for histones and non-histones in tumorigenesis.

Impact of volemia at admission on the effect of collateral status on functional outcomes in patients undergoing endovascular thrombectomy.

BACKGROUND AND PURPOSE: Having good collaterals is associated with better clinical outcomes in patients undergoing endovascular thrombectomy. This study aims to evaluate whether the effect of collateral status on functional outcomes is modified by volemia at admission. METHODS: This is a single-center, retrospective analysis of patients who had acute proximal anterior circulation occlusion and underwent endovascular thrombectomy between January 2019 and June 2022. Volemia at admission, evaluated by blood urea nitrogen-to-creatinine ratio, was used to dichotomize patients into dehydrated and hydrated groups. The primary outcome was functional independence (90-day modified Rankin Scale score = 0-2). Secondary outcomes were the rates of successful reperfusion, 24-h symptomatic intracranial hemorrhage, and 90-day all-cause mortality. Multivariable logistic regression analysis was used to assess the interaction between collateral status and volemia at admission on outcomes. RESULTS: A total of 290 patients were enrolled, among whom having good collaterals was associated with functional independence (adjusted odds ratio [OR] = 2.71, 95% confidence interval [CI] = 1.41-5.22, p = 0.003). Having good collaterals benefited dehydrated patients (adjusted OR = 3.33, 95% CI = 1.45-7.63, p = 0.004) but not hydrated patients (adjusted OR = 2.21, 95% CI = 0.73-6.68, p = 0.161). However, an interaction between collaterals and volemia at admission on functional independence was not observed (p = 0.319). The rates of successful reperfusion, symptomatic intracerebral hemorrhage, and all-cause mortality were similar between those with good and poor collaterals in both dehydrated and hydrated patients. CONCLUSIONS: The effect of collateral status on the functional independence of patients undergoing thrombectomy is not modified by volemia at admission.

Synthesis and Biological Evaluation of Phthalideisoquinoline Derivatives.

A photo and Cu-mediated radical-radical approach enabling the one-step synthesis of the phthalideisoquinoline skeleton has been reported. Under mild reaction conditions, a series of N-aryl phthalideisoquinolines containing various substituents were synthesized in moderate to good yields. Bioactivity data demonstrated that a new compound 4x can efficiently inhibit the growth of multiple tumor cell lines with enhancements of more than 10-fold by significantly increasing G2/M arrest compared with noscapine.

Postoperative blood glucose increase is associated with futile recanalization in patients with successful thrombectomy: a retrospective study.

BACKGROUND: Timely recognition of futile recanalization might enable a prompt response and an improved outcome in post-thrombectomy patients. This study aims to evaluate whether postoperative blood glucose increase (BGI) could act as an indicator of futile recanalization in patients receiving a successful thrombectomy. METHODS: This is a single-center, retrospective analysis of patients with anterior circulation large-vessel occlusion and successful thrombectomy between February 2019 and June 2022. BGI was defined as a higher level of blood glucose at the first postoperative morning than at admission. Futile recanalization was defined as patients with a modified Rankin Scale score of 3-6 at 90 days after onset. Multivariable binary logistic regression was used to assess the association of BGI with futile recanalization. RESULTS: A total of 276 patients were enrolled, amongst which 120 patients (43.5%) had BGI. Futile recanalization was more prevalent among patients with BGI compared to those without (70.0 vs. 49.4%, P = 0.001). After adjusting for potential confounders, BGI was associated with a higher likelihood of futile recanalization (adjusted OR: 2.97, 95%CI: 1.50-5.86, P = 0.002). This association was consistently observed regardless of diabetes history, occlusion site, time from symptom onset to groin puncture, or reperfusion status. CONCLUSION: Our findings support BGI serving as an indicator of futile recanalization in patients with anterior circulation large-vessel occlusion and successful thrombectomy.

Aspirin triggers ferroptosis in hepatocellular carcinoma cells through restricting NF-κB p65-activated SLC7A11 transcription.

A number of studies have shown that aspirin, as commonly prescribed drug, prevents the development of hepatocellular carcinoma (HCC). Ferroptosis as a dynamic tumor suppressor plays a vital role in hepatocarcinogenesis. In this study we investigated whether aspirin affected ferroptosis in liver cancer cells. RNA-seq analysis revealed that aspirin up-regulated 4 ferroptosis-related drivers and down-regulated 5 ferroptosis-related suppressors in aspirin-treated HepG2 cells. Treatment with aspirin (4 mM) induced remarkable ferroptosis in HepG2 and Huh7 cells, which was enhanced by the ferroptosis inducer erastin (10 µM). We demonstrated that NF-κB p65 restricted ferroptosis in HepG2 and Huh7 cells through directly binding to the core region of SLC7A11 promoter and activating the transcription of ferroptosis inhibitor SLC7A11, whereas aspirin induced ferroptosis through inhibiting NF-κB p65-activated SLC7A11 transcription. Overexpression of p65 rescued HepG2 and Huh7 cells from aspirin-induced ferroptosis. HCC patients with high expression levels of SLC7A11 and p65 presented lower survival rate. Functionally, NF-κB p65 blocked the aspirin-induced ferroptosis in vitro and in vivo, which was attenuated by erastin. We conclude that aspirin triggers ferroptosis by restricting NF-κB-activated SLC7A11 transcription to suppress the growth of HCC. These results provide a new insight into the mechanism by which aspirin regulates ferroptosis in hepatocarcinogenesis. A combination of aspirin and ferroptosis inducer may provide a potential strategy for the treatment of HCC in clinic.

Discovery of Fibrinogen γ-chain as a potential urinary biomarker for renal interstitial fibrosis in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is a major cause of chronic kidney disease (CKD). Renal interstitial fibrosis is a hallmark of CKD progression. Non-invasive biomarkers are needed to dynamically evaluate renal fibrosis. Data independent acquisition (DIA)-based liquid chromatography-mass spectrometry (DIA-MS) was used to identify candidate urinary biomarkers in IgAN patients with different renal interstitial fibrosis degrees. METHODS: Eighteen biopsy-proven IgAN patients and six healthy controls were recruited in a discovery cohort. Interstitial fibrosis changes were evaluated according to Oxford MEST-C scores. Urinary samples were analyzed with DIA-MS to identify hub proteins. Hub proteins were then confirmed by enzyme-linked immunosorbent assay (ELISA) in a validation cohort and the associated gene mRNA expression was analyzed using public gene expression omnibus (GEO) datasets. RESULTS: Complement and coagulation cascades pathway was the main KEGG pathway related to the over-expressed proteins. Fibrinogen γ-Chain (FGG) was selected as the potential urinary marker for further validation. Urinary FGG to creatinine ratio (uFGG/Cr) levels were higher in both disease controls and IgAN group than in healthy controls, but were not significantly different between IgAN and disease groups. uFGG/Cr was confirmed to be increased with the extent of renal fibrosis and presented moderate correlations with T score (r = 0.614, p < 0.01) and eGFR (r = -0.682, p < 0.01), and a mild correlation with UTP (r = 0.497, p < 0.01) in IgAN group. In disease control group, uFGG/Cr was higher in patients with T1 + 2 compared to those with T0. uFGG/Cr had a good discriminatory power to distinguish different fibrosis stages in IgAN: interstitial fibrosis ≤ 5% (minimal fibrosis) vs. interstitial fibrosis (mild fibrosis) > 5%, AUC 0.743; T0 vs. T1 + 2, AUC 0.839; T0 + 1 vs. T2, AUC 0.854. In disease control group, uFGG/Cr showed better performance of AUC than UTP between minimal and mild fibrosis (p = 0.038 for Delong's test). Moreover, GSE104954 dataset showed that FGG mRNA expression was up-regulated (fold change 1.20, p = 0.009) in tubulointerstitium of IgAN patients when compared to healthy living kidney donors. CONCLUSION: Urinary FGG is associated with renal interstitial fibrosis and could be used as a noninvasive biomarker for renal fibrosis in IgAN.

Application of Transcranial Magnetic Stimulation with Electroencephalography in the Evaluation of Brain Function Changes after Stroke.

Objective: Based on transcranial magnetic stimulation (TMS) with electroencephalography technology, this study analyzed the rehabilitation mechanism of patients' motor function reconstruction and nerve remodeling after stroke. It revealed the function of the cerebral cortex network at a deeper level and established a set of prognostic marker evaluation indicators for the reconstruction of motor function after stroke. Methods: Twenty-one patients treated at the Beijing Rehabilitation Hospital of Capital Medical University because of ischemic stroke in the territory supplied by the middle cerebral artery were selected as the experimental group. Neurophysiological evaluation, motor function evaluation, and clinical evaluation were performed 30 and 180 d after the onset of ischemic stroke. In the control group, neurophysiological evaluation was also performed as a reference index to evaluate the changes in cortical patterns after stroke. Results: The brain topographic map showed the changes in energy or power spectral density (PSD) at 1,000 ms after stimulation as compared with before stimulation, but no difference was detected in these patients. The time-frequency analysis showed that when the left primary motor cortex (M1) area was stimulated using TMS, the PSD values of the left and right M1 and posterior occipital cortex areas produced an 8-40 Hz wave band in patients S1-S11. There was no significant energy change in patients S12-S16. Conclusions: For patients with different injury types, degrees of injury, and different onset periods, individualized intervention methods should be adopted. The evaluation methods should be as diverse as possible, and the rehabilitation effects of patients should be assessed from multiple perspectives to avoid the limitations of single factors. Possible mechanism: After brain injury, the nervous system can change its structure and function through different ways and maintain it for a certain period of time. This plasticity change will change with the course of the disease.

ZnO-NPs alleviate aflatoxin B1-induced hepatoxicity in ducklings by promoting hepatic metallothionein expression.

Aflatoxin B1 (AFB1) is a mycotoxin widely present in animal feed and human food, posing a serious threat to animal and human health. This study was aim to illustrate the mechanism of the protective role of MT against AFB1-induced hepatotoxicity, as well as to explore the feasibility of enhancing the tolerance of poultry to AFB1 by upregulating the expression of hepatic MT. After being exposed to AFB1 (50 ng/kg) primary duckling hepatocytes, the cell viability, the antioxidant index (SOD and GPx) and the mRNA levels of MT downstream genes (PTGR, p53, TrxR, AR and Bcl-2) significantly (p < 0.05) decreased, while the intracellular formation of (AFBO)-DNA adduct content, apoptosis, and MDA content significantly (p < 0.05) increased. Interestingly, overexpression of MT in primary duckling hepatocytes markedly (p < 0.05) reversed the detrimental impact of AFB1 and increased the expression of MT downstream genes. HepG2 cells were applied to study the mechanism how MT works to relieve the hepatic toxicity of AFB1. The ZnO-NPs (20 µg/mL) + AFB1 (20 µg/mL) group significantly (p < 0.05) increased the cell viability, the expression of NRF2, NQO1 and SOD, and expression of MT and MTF-1, as well as significantly (p < 0.05) decreased LDH, ROS and apoptotic rate, comparing with the AFB1 group. While joint treatment with AFB1 and ZnO-NPs, the hepatic toxicity exerted by AFB1 alone was reversed, along with the translocation of MTF-1 from the cytoplasm to the nucleus and upregulated its expression. Duckling trails were further carried out. A total number of 96 1-day-old healthy Cherry Valley commercial ducklings were randomly allocated according to a 2 by 2 factorial arrangement of treatments with the main factors including oral administration of AFB1 (0 vs. 40 µg/kg) and dietary supplementation of ZnO-NPs (0 vs. 60 mg/kg) for 7 days. It showed that AFB1 exposure caused body weight loss (p < 0.05), impaired liver structure and failure in hepatic function (activity of ALT, AST and concentration of TP and GLU) (p < 0.05), and decreases in antioxidant capacity(activity of SOD, CAT and concentration of GSH) (p < 0.05), along with the decrease in hepatic concentration of Zn, increase in expression of apoptosis-related genes and protein CAS3 and mRNA Bcl-2 expression (p < 0.05), and suppressed mRNA levels of antioxidant-related genes MT, SOD1, NRF2, and NQO1 (p < 0.05). In accordance with the cell test, dietary supplementation with ZnO-NPs mitigated the toxicity exerted by AFB1. In conclusion, ZnO-NPs has the protective effects against AFB1-induced hepatocyte injury by activating the expression of MTF-1 and the ectopic induction of MT expression, providing detailed information on the detoxification ability of MT on AFB1.

Effect of peroxiredoxin 1 on the regulation of trophoblast function by affecting autophagy and oxidative stress in preeclampsia.

PURPOSE: PE is a pregnancy-specific syndrome and one of the main causes of maternal, fetal, and neonatal mortality. PRDX1 is an antioxidant that regulates cell proliferation, differentiation, and apoptosis. The aim of this study is to investigate the effect of PRDX1 on the regulation of trophoblast function by affecting autophagy and oxidative stress in preeclampsia. METHODS: Western blotting, RT-qPCR, and immunofluorescence were used to examine the expression of PRDX1 in placentas. PRDX1-siRNA was transfected to knockdown PRDX1 in HTR-8/SVneo cells. The biological function of HTR-8/SVneo cells was detected by wound healing, invasion, tube formation, CCK-8, EdU, flow cytometry, and TUNEL assays. Western blotting was used to detect the protein expression of cleaved-Caspase3, Bax, LC3II, Beclin1, PTEN, and p-AKT. DCFH-DA staining was used to detect ROS levels by flow cytometry. RESULTS: PRDX1 was significantly decreased in placental trophoblasts in PE patients. Following the exposure of HTR-8/SVneo cells to H2O2, PRDX1 expression was significantly decreased, LC3II and Beclin1 expression was notably increased, and ROS level was also markedly increased. PRDX1 knockdown impaired migration, invasion, and tube-formation abilities and promoted apoptosis, which was accompanied by an increased expression of cleaved-Caspase3 and Bax. PRDX1 knockdown induced a significant decrease in LC3II and Beclin1 expression, along with an elevated p-AKT expression and a decreased PTEN expression. PRDX1 knockdown increased intracellular ROS levels, and NAC attenuated PRDX1 knockdown-induced apoptosis. CONCLUSION: PRDX1 regulated trophoblast function through the PTEN/AKT signaling pathway to affect cell autophagy and ROS level, which provided a potential target for the treatment of PE.

Exploring Health Literacy Categories in Patients With Heart Failure: A Latent Class Analysis.

BACKGROUND: Although a growing number of studies have demonstrated that patients' health literacy is associated with health outcomes, the exact relationship between them is not clear. AIMS AND OBJECTIVES: The aim of this study was to explore latent classes of health literacy in patients with heart failure and analyze the differences among different groups. DESIGN AND METHODS: This is a cross-sectional survey. Patients diagnosed with heart failure were selected from 3 tertiary hospitals in Tianjin, China, from March 2019 to November 2019. We measured patients' health literacy using the Health Literacy Scale for Chronic Patients. Latent class analysis was carried out based on the patients' Health Literacy Scale for Chronic Patients scores. Multinomial logistic regression was used to identify the predictive indicators of the latent classes. RESULTS: The health literacy of patients with heart failure was divided into 3 different latent classes, named "high health literacy group," "low literacy high dependence group," and "moderate literacy high willingness group." There were statistically significant differences in gender, age, smoking history, marital status, education level, household income level, and quality of life among different health literacy classes. Low education level and household income level predicted poor health literacy. CONCLUSION: There were 3 latent classes for the health literacy of patients with heart failure. Different health literacy classes exhibited their own distinctive characteristics. Patients in the "moderate literacy high willingness group" had the worst quality of life. Understanding the specific types of health literacy in patients with heart failure facilitates targeted nursing interventions to improve their quality of life.

Research on Robot Screwing Skill Method Based on Demonstration Learning.

A robot screwing skill learning framework based on teaching-learning is proposed to improve the generalization ability of robots for different scenarios and objects, combined with the experience of a human operation. This framework includes task-based teaching, learning, and summarization. We teach a robot to twist and gather the operation's trajectories, define the obstacles with potential functions, and counter the twisting of the robot using a skill-learning-based dynamic movement primitive (DMP) and Gaussian mixture model-Gaussian mixture regression (GMM-GMR). The hole-finding and screwing stages of the process are modeled. In order to verify the effectiveness of the robot tightening skill learning model and its adaptability to different tightening scenarios, obstacle avoidance trends and tightening experiments were conducted. Obstacle avoidance and tightening experiments were conducted on the robot tightening platform for bolts, plastic bottle caps, and faucets. The robot successfully avoided obstacles and completed the twisting task, verifying the effectiveness of the robot tightening skill learning model and its adaptability to different tightening scenarios.

Disulfiram/Cu Kills and Sensitizes BRAF-Mutant Thyroid Cancer Cells to BRAF Kinase Inhibitor by ROS-Dependently Relieving Feedback Activation of MAPK/ERK and PI3K/AKT Pathways.

BRAFV600E, the most common genetic alteration, has become a major therapeutic target in thyroid cancer. Vemurafenib (PLX4032), a specific inhibitor of BRAFV600E kinase, exhibits antitumor activity in patients with BRAFV600E-mutated thyroid cancer. However, the clinical benefit of PLX4032 is often limited by short-term response and acquired resistance via heterogeneous feedback mechanisms. Disulfiram (DSF), an alcohol-aversion drug, shows potent antitumor efficacy in a copper (Cu)-dependent way. However, its antitumor activity in thyroid cancer and its effect on cellular response to BRAF kinase inhibitors remain unclear. Antitumor effects of DSF/Cu on BRAFV600E-mutated thyroid cancer cells and its effect on the response of these cells to BRAF kinase inhibitor PLX4032 were systematically assessed by a series of in vitro and in vivo functional experiments. The molecular mechanism underlying the sensitizing effect of DSF/Cu on PLX4032 was explored by Western blot and flow cytometry assays. DSF/Cu exhibited stronger inhibitory effects on the proliferation and colony formation of BRAFV600E-mutated thyroid cancer cells than DSF treatment alone. Further studies revealed that DSF/Cu killed thyroid cancer cells by ROS-dependent suppression of MAPK/ERK and PI3K/AKT signaling pathways. Our data also showed that DSF/Cu strikingly increased the response of BRAFV600E-mutated thyroid cancer cells to PLX4032. Mechanistically, DSF/Cu sensitizes BRAF-mutant thyroid cancer cells to PLX4032 by inhibiting HER3 and AKT in an ROS-dependent way and subsequently relieving feedback activation of MAPK/ERK and PI3K/AKT pathways. This study not only implies potential clinical use of DSF/Cu in cancer therapy but also provides a new therapeutic strategy for BRAFV600E-mutated thyroid cancers.

Bioactive Components of Lycium barbarum and Deep-Processing Fermentation Products.

Lycium barbarum, a homology of medicine and food, contains many active ingredients including polysaccharides, polyphenol, betaine, and carotenoids, which has health benefits and economic value. The bioactive components in Lycium barbarum exhibit the effects of antioxidation, immune regulation, hypoglycemic effects, and vision improvement. Recently, the development of nutrition and health products of Lycium barbarum has been paid more and more attention with the increase in health awareness. A variety of nutrients and bioactive components in wolfberry can be retained or increased using modern fermentation technology. Through fermentation, the products have better flavor and health function, which better meet the needs of market diversification. The main products related to wolfberry fermentation include wolfberry fruit wine, wolfberry fruit vinegar, and lactic acid fermented beverage. In this review, the mainly bioactive components of Lycium barbarum and its deep-processing products of fermentation were summarized and compared. It will provide reference for the research and development of fermented and healthy products of Lycium barbarum.