Ainsliadimer A induces ROS-mediated apoptosis in colorectal cancer cells via directly targeting peroxiredoxin 1 and 2.

The peroxiredoxin (PRDX) family is a class of antioxidant enzymes with peroxidase activity. Human PRDXs currently have six members (PRDX1-6), which are gradually becoming potential therapeutic targets for major diseases such as cancer. In this study, we reported ainsliadimer A (AIN), a sesquiterpene lactone dimer with antitumor activity. We found that AIN directly targets Cys173 of PRDX1 and Cys172 of PRDX2 and then inhibits their peroxidase activities. As a result, the level of intracellular ROS increases, causing oxidative stress damage in mitochondria, inhibiting mitochondrial respiration, and significantly inhibiting ATP production. AIN inhibits the proliferation and induces apoptosis of colorectal cancer cells. Additionally, it inhibits tumor growth in mice and the growth of tumor organoid models. Therefore, AIN can be one of the natural compounds targeting PRDX1 and PRDX2 in the treatment of colorectal cancer.

A multifunctional nanocomposite coated with a BSA membrane for cascaded nitric oxide therapy.

Gas therapy based on nitric oxide (NO) has emerged as a potential therapeutic approach for cancer, and in conjunction with multi-mode combination therapy, offers new possibilities for achieving significant hyperadditive effects. In this study, an integrated AI-MPDA@BSA nanocomposite for diagnosis and treatment was constructed for PDA based photoacoustic imaging (PAI) and cascade NO release. Natural NO donor L-arginine (L-Arg) and photosensitizer (PS) IR780 were loaded into mesoporous polydopamine (MPDA). Bovine serum albumin (BSA) was conjugated to the MPDA to increase the dispersibility and biocompatibility of the nanoparticles, as well as to serve as a gatekeeper controlling IR780 release from the MPDA pores. The AI-MPDA@BSA produced singlet oxygen (1O2) and converted it into NO through a chain reaction based on L-Arg, enabling a combination of photodynamic therapy and gas therapy. Moreover, due to the photothermal properties of MPDA, the AI-MPDA@BSA performed good photothermal conversion, which allowed photoacoustic imaging. As expected, both in vitro and in vivo studies have confirmed that the AI-MPDA@BSA nanoplatform has a significant inhibitory effect on cancer cells and tumors, and no apparent systemic toxicity or side effects were detected during the treatment period.

Design of Proactive Interaction for In-Vehicle Robots Based on Transparency.

Based on the transparency theory, this study investigates the appropriate amount of transparency information expressed by the in-vehicle robot under two channels of voice and visual in a proactive interaction scenario. The experiments are to test and evaluate different transparency levels and combinations of information in different channels of the in-vehicle robot, based on a driving simulator to collect subjective and objective data, which focuses on users' safety, usability, trust, and emotion dimensions under driving conditions. The results show that appropriate transparency expression is able to improve drivers' driving control and subjective evaluation and that drivers need a different amount of transparency information in different types of tasks.

Long Noncoding RNA HOTAIRM1 Promotes Immunosuppression in Sepsis by Inducing T Cell Exhaustion.

Sepsis is an acute life-threatening disorder associated with multiorgan dysfunction that remains the leading cause of death in intensive care units. As sepsis progresses, it causes prolonged immunosuppression, which results in sustained mortality, morbidity, and susceptibility to secondary infections. Using a mouse model of sepsis, we found that the long noncoding RNA HOTAIRM1 (HOXA transcript antisense RNA myeloid-specific 1) was highly expressed in mice during the late phase of sepsis. The upregulation of HOTAIRM1 was induced by Notch/Hes1 activation and, moreover, was critical for the formation of an immunosuppressive microenvironment. HOTAIRM1 induced T cell exhaustion by increasing the percentage of PD-1+ T cells and regulatory T cells, accompanied by elevated PD-L1. Blockade of either Notch/Hes1 signaling or HOTAIRM1 inhibited T cell exhaustion in late sepsis, having alleviated lung injury and improved survival of mice. Further mechanistic studies identified HOXA1 as a key transcription factor targeted by HOTAIRM1 to regulate PD-L1 expression in lung alveolar epithelial cells. These results implicated that the Notch/Hes1/HOTAIRM1/HOXA1/PD-L1 axis was critical for sepsis-induced immunosuppression and could be a potential target for sepsis therapies.

Biomarkers for predicting the efficacy of immune checkpoint inhibitors.

Immune checkpoint blockade has vastly changed the landscape of cancer treatment and showed a promising prognosis for cancer patients. However, there is still a large portion of patients who have no response to this therapy. Therefore, it's essential to investigate biomarkers to predict the efficacy of immune checkpoint inhibitors. This article summarizes the predictive value of established biomarkers, including programmed cell death ligand 1(PD-L1) expression level, tumor mutational burden, tumor-infiltrating lymphocytes, and mismatch repair deficiency. It also addresses the predictive value of tumorous mutations, circulation factors, immune-related factors, and gut microbiome with immunotherapy treatment. Furthermore, some of the emerging novel biomarkers, and potential markers for hyper progressive disease are discussed, which should be validated in clinical trials in the future.

Detection and significance of main anchoring villus in early pregnancy.

OBJECTIVE: To find and explore the relationship among the length of the embryo's main anchoring villus and the week of gestation, embryonic crown-rump length (CRL), and maternal blood human chorionic gonadotropin (hCG) during early pregnancy using ultrasound. METHODS: A total of 108 women with singleton pregnancies underwent ultrasound examination of the fetus during the early months of their pregnancy (5+5 -13+6  weeks of pregnancy). The main anchoring villus was detected using HD-Flow and SlowflowHD mode ultrasound. The detection rate and length of the main anchoring villus were recorded. The correlations among main anchoring villus with gestational weeks, CRL, and blood hCG were obtained. RESULTS: The main anchoring villus was detected in all women (108/108). It could be found throughout the early gestational weeks from as early as 4+6  weeks. The length of the main anchoring villus increased with gestational age, and was positively correlated with CRL and the logarithm of hCG (P < 0.05). CONCLUSION: Our results showed that the detection rate of the main anchoring villus was 100% and the length of the main anchoring villus was correlated with gestational week, CRL, and blood hCG. The main anchoring villus could represent where the embryo implanted.

Multimodal Warnings Design for In-Vehicle Robots under Driving Safety Scenarios.

In case of dangerous driving, the in-vehicle robot can provide multimodal warnings to help the driver correct the wrong operation, so the impact of the warning signal itself on driving safety needs to be reduced. This study investigates the design of multimodal warnings for in-vehicle robots under driving safety warning scenarios. Based on transparency theory, this study addressed the content and timing of visual and auditory modality warning outputs and discussed the effects of different robot speech and facial expressions on driving safety. Two rounds of experiments were conducted on a driving simulator to collect vehicle data, subjective data, and behavioral data. The results showed that driving safety and workload were optimal when the robot was designed to use negative expressions for the visual modality during the comprehension (SAT 2) phase and speech at a rate of 345 words/minute for the auditory modality during the comprehension (SAT 2) and prediction (SAT 3) phases. The design guideline obtained from the study provides a reference for the interaction design of driver assistance systems with robots as the interface.

A bioluminescence reporter mouse strain for in vivo imaging of CD8+ T cell localization and function.

CD8+ T cells play a critical role during adaptive immune response, which often change locations and expand or contract in numbers under different states. In the past, many attempts to develop CD8+T cells that express luciferase in vivo have involved the use of viral transduction, which has drawbacks of hardly tracked via detection of luciferase signal in untouched natural states. Here, we generate a transgenic mouse model via CRISPR-mediated genome editing, C57BL/6-CD8aem(IRES-AkaLuci-2A-EGFP) knock-in mice(CD8a-Aka mice), as a novel tool for non-invasive imaging of CD8+ T cells, which expressed a highly sensitive luciferase-Akaluciferase. Our study offers a convenient and robust tool for understanding fundamental CD8+ T cell biology in experimental applications and preclinical translational studies.

Robot Transparency and Anthropomorphic Attribute Effects on Human-Robot Interactions.

Anthropomorphic robots need to maintain effective and emotive communication with humans as automotive agents to establish and maintain effective human-robot performances and positive human experiences. Previous research has shown that the characteristics of robot communication positively affect human-robot interaction outcomes such as usability, trust, workload, and performance. In this study, we investigated the characteristics of transparency and anthropomorphism in robotic dual-channel communication, encompassing the voice channel (low or high, increasing the amount of information provided by textual information) and the visual channel (low or high, increasing the amount of information provided by expressive information). The results showed the benefits and limitations of increasing the transparency and anthropomorphism, demonstrating the significance of the careful implementation of transparency methods. The limitations and future directions are discussed.

Anatomic evidence shows that lymphatic drainage exists in the pituitary to loop the cerebral lymphatic circulation.

Respiratory infections can result in intracranial infections and unknown neurological symptoms. The central nervous system lacks classical meningeal lymphatic (circulation) drainage, and the exact underlying mechanisms of how immune cells from the peripheral lymphatic system enter the central nervous system (CNS) remain unknown. To determine whether the perinasal lymphatic system or lymphatic vessels are involved in cerebral immune defence and play a role in causing CNS infections (especially respiratory tract-related infections), we performed an anatomic study to investigate the drainage differences between the perinasal and intracerebral lymphatic systems by using injection of Evans blue and anatomic surgery, together with immunohistochemistry and immunofluorescence assays. Surprisingly, we found that (1) the pituitary (adenohypophysis) is involved and is rich in lymphatic vessels and (2) perinasal tissue could communicate with central pituitary lymphatic vessels in a specific and unidirectional manner. Taken together, our study may be the first to anatomically demonstrate the existence of novel lymphatic vessel structures in the pituitary, as well as their communication with the perinasal (lymphatic) tissue. Our findings suggest the existence of an ultimate loop for "classical" meningeal lymphatic drainage and are relevant to cerebral infection and immune defence.

Fault diagnosis in a current sensor and its application to fault-tolerant control for an air supply subsystem of a 50 kW-Grade fuel cell engine.

The safety, reliability and stability of air supply subsystems are still problems for the commercial applications of fuel cells; therefore, engine fault diagnosis and fault-tolerant control are essential to protect the fuel cell stack. In this study, a fault diagnosis and fault-tolerant control method based on artificial neural networks (ANNs) has been proposed. The offline ANN modification model was trained with a Levenberg-Marquardt (LM) algorithm based on other sensors' signals relevant to the current sensor of a 50 kW-grade fuel cell engine test bench. The output current was predicted via the ANN identification model according to other relevant sensors and compared with the sampled current sensor signal. The faults in the current sensor were detected immediately once the difference exceeded the given threshold value, and the invalid signals of the current sensor were substituted with the predictive output value of the ANN identification model. Finally, the reconstructed current sensor signals were sent back to a fuel cell controller unit (FCU) to adjust the air flow and rotate speeds of the air compressor. Experimental results show that the typical faults in the current sensor can be diagnosed and distinguished within 0.5 s when the threshold value is 15 A. The invalid signal of current sensor can be reconstructed within 0.1 s. Which ensures that the air compressor operate normally and avoids oxygen starvation. The proposed method can protect the fuel cell stack and enhance the fault-tolerant performance of air supply subsystem used in the fuel cell engine, and it is promising to be utilized in the fault diagnosis and fault-tolerant control of various fuel cell engines and multiple sensor systems.

Serum Calprotectin Levels and Outcome Following Percutaneous Coronary Intervention in Patients with Diabetes and Acute Coronary Syndrome.

BACKGROUND A retrospective study of data from a prospective clinical registry was conducted to evaluate the prognostic role of serum calprotectin in patients with diabetes who underwent percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). MATERIAL AND METHODS Data were retrieved for 273 patients with diabetes mellitus who underwent PCI for primary ACS in a single center. Serum calprotectin levels were measured before PCI. Baseline clinical data included the Global Registry of Acute Coronary Events (GRACE) risk score for ACS. All patients underwent regular follow-up for major adverse cardiovascular events (MACE) during 12 months after PCI, including target vessel revascularization (TVR), defined as the need for an unplanned repeat PCI or coronary artery procedure. The predictive value of serum calprotectin for MACE was analyzed by using univariate and multivariate analysis and receiver operating characteristic (ROC) curve analysis. RESULTS At the final follow-up, 47 of the 273 patients studies experienced MACE. Optimal cutoff values for serum calprotectin levels predictive for MACE stratified patients into a high calprotectin group and a low calprotectin group. The incidence of MACE and TVR in the high calprotectin group was significantly greater than in the low calprotectin group (21.9% vs. 11.5%; P=0.02). Multivariate analysis, adjusted for confounders, showed that the serum level of calprotectin was an independent risk factor for MACE (HR, 1.56; 95% CI, 1.08-4.62; P=0.01). CONCLUSIONS In patients with diabetes and the co-morbidity of ACS, a high serum level of calprotectin was associated with a significantly increased risk for MACE following PCI.

Methane and Nitrous Oxide Flux after Biochar Application in Subtropical Acidic Paddy Soils under Tobacco-Rice Rotation.

Biochar amendment is a good means of mitigating methane (CH4) and nitrous oxide (N2O) emissions. However, the effects of biochar amendment on N2O and CH4 reduction in soil under rotation with different soil moisture contents is not well understood. To understand CH4 and N2O flux from soil with biochar amendment under water-unsaturated and water-saturated conditions, a field experiment was conducted in a tobacco-rice rotation field in subtropical China to investigate N2O and CH4 emissions following soil amendment with tobacco straw biochar at rates of 0, 10, 40 and 80 t·ha-1 (B0, B10, B40 and B80, respectively). N2O and CH4 emissions were monitored by a closed-chamber method in the water-unsaturated tobacco (UT) and water-saturated rice (SR) seasons during the 2015 planting season. The soil pH increased from 5.4 in the control to 6.1 in the soil amended with biochar at 80 t·ha-1 in the UT season. During both the UT and SR seasons, with biochar amendment at 40 and 80 t·ha-1, the soil bulk density (BD) decreased, while the soil organic matter (SOM) and available potassium (Av. K) contents increased. N2O flux was significantly greater in UT than in SR in the controls but decreased with the application of biochar during both the UT and SR seasons. The cumulative CH4 emission decreased with the rate of biochar application and the methanotroph pmoA gene copy number in soils and increased with the methanogenic archaea 16Sr DNA gene copy number in soils during the rice-cropping season. These results indicated that biochar amendment could decrease methanogenic archaea and increase of methanotroph pmoA gene, which are the mechanistic origin for CH4 reduction.

Reciprocal activation between PLK1 and Stat3 contributes to survival and proliferation of esophageal cancer cells.

BACKGROUND & AIMS: Aberrant activation of the signal transducer and activator of transcription (Stat)3 and overexpression of polo-like kinase (PLK)1 each have been associated with cancer pathogenesis. The mechanisms and significance of dysregulation of Stat3 and PLK1 in carcinogenesis and cancer progression are unclear. We investigated the relationship between Stat3 and PLK1 and the effects of their dysregulation in esophageal squamous cell carcinoma (ESCC) cells. METHODS: We used immunoblot, quantitative reverse-transcription polymerase chain reaction, immunochemistry, chromatin immunoprecipitation, mobility shift, and reporter assays to investigate the relationship between Stat3 and PLK1. We used colony formation, fluorescence-activated cell sorting, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and xenograft tumor assays to determine the effects of increased activation of Stat3 and PLK1 in proliferation and survival of ESCC cells. RESULTS: Stat3 directly activated transcription of PLK1 in esophageal cancer cells and mouse embryonic fibroblast cell NIH3T3. PLK1 then potentiated the expression of Stat3; ß-catenin was involved in PLK1-dependent transcriptional activation of Stat3. This mutual regulation between Stat3 and PLK1 was required for proliferation of esophageal cancer cells and resistance to apoptosis in culture and as tumor xenografts in mice. Furthermore, phosphorylation of Stat3 and overexpression of PLK1 were correlated in a subset of ESCC. CONCLUSIONS: Stat3 and PLK1 control each other's transcription in a positive feedback loop that contributes to the development of ESCC. Increased activity of Stat3 and overexpression of PLK1 promote survival and proliferation of ESCC cells in culture and in mice.

Changes in cropland topsoil organic carbon with different fertilizations under long-term agro-ecosystem experiments across mainland China.

Topsoil soil organic carbon (SOC) data were collected from long-term Chinese agro-ecosystem experiments presented in 76 reports with measurements over 1977 and 2006. The data set comprised 481 observations (135 rice paddies and 346 dry croplands) of SOC under different fertilization schemes at 70 experimental sites (28 rice paddies and 42 dry croplands). The data set covered 16 dominant soil types found in croplands across 23 provinces of mainland China. The fertilization schemes were grouped into six categories: N (inorganic nitrogen fertilizer only), NP (compound inorganic nitrogen and phosphorus fertilizers), NPK (compound inorganic nitrogen, phosphorus and potassium fertilizers), O (organic fertilizers only), OF (combined inorganic/organic fertilization) and Others (other unbalanced fertilizations such as P only, K only, P plus K and N plus K). Relative change in SOC content was analyzed, and rice paddies and dry croplands soils were compared. There was an overall temporal increase in topsoil SOC content, and relative annual change (RAC, g kg(-1) yr(-1)) ranged -0.14-0.60 (0.13 on average) for dry cropland soils and -0.12-0.70 (0.19 on average) for rice paddies. SOC content increase was higher in rice paddies than in dry croplands. SOC increased across experimental sites, but was higher under organic fertilization and combined organic/inorganic fertilizations than chemical fertilizations. SOC increase was higher under balanced chemical fertilizations with compound N, P and K fertilizers than unbalanced fertilizations such as N only, N plus P, and N plus K. The effects of specific rational fertilizations on SOC increase persisted for 15 years in dry croplands and 20 years in rice paddies, although RAC values decreased generally as the experiment duration increased. Therefore, the extension of rational fertilization in China's croplands may offer a technical option to enhance C sequestration potential and to sustain long-term crop productivity.

Survivin stable knockdown by siRNA inhibits tumor cell growth and angiogenesis in breast and cervical cancers.

Increased resistance to apoptosis is a hallmark of many tumor cells. Survivin, a member of IAP family protein, is expressed in many human cancers and plays an important role in protecting cells from apoptosis. Here we show that vector-based small interfering RNAs (siRNA) stably knockdown survivin expression in several cancer cell lines, leading to increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin or TNF-alpha. The apoptotic susceptibility was dependent on divergent levels of survivin expression. The stable transfectants exhibited abnormal morphology, suppressed cell growth, enhanced spontaneous apoptosis and cell cycle hindrance. Furthermore, in nude mice xenografts of survivin-positive tumors, cells expressing survivin-targeted siRNAs exhibited decreased tumor formation and reduced angiogenesis. Results from these studies: (1) provide direct evidence that intracellular silencing of survivin by siRNA sensitizes human tumor cells to apoptosis; (2) define survivin as a promising molecular target for cancer therapy; and (3) suggest the potential applicability of survivin-targeted siRNA for treating human tumors, probably in combination with chemotherapy.

Stable knockdown of estrogen receptor alpha by vector-based RNA interference suppresses proliferation and enhances apoptosis in breast cancer cells.

Breast cancer, the most common malignancy in women, has a known association with the steroid hormone estrogen. Estrogen receptor alpha (ERalpha) plays an important role in the clinical care of breast cancer patients, both as a prognostic factor and as a therapeutic target. Here, we show that a small interfering RNA (siRNA) against ERalpha downregulates ERalpha expression in human MCF-7 and Bcap-37 breast cancer cells, causing a significant decrease in breast cancer cell proliferation. Tumor cells lacking ERalpha expression grew at a much slower rate than did control cells in vitro. Moreover, ERalpha knockdown in breast cancer cells resulted in decreased, even completely abrogated tumor growth in BALB/c nude mice, providing direct evidence for an essential role of ERalpha in breast cancer growth. Our results suggest siRNA-mediated gene silencing of ERalpha may impair tumorigenicity, and even suppress the tumor growth.

[Study on apoptosis of human cervical carcinoma HeLa cells with RNA interference targeting hTERT].

AIM: To study the induction of tumor cell apoptosis by RNA interference-mediated inhibition of the expression of telomerase in cancer cells. METHODS: HeLa cells were transfected with the successfully established siRNA(small interfering RNA) expression vectors targeting hTERT (human telomerase reverse transcriptase). By electronic microscopy, Western blot and FCM (flow cytometry), the apoptosis of HeLa cells was tested. RESULTS: The established siRNA expression vectors could induce apoptosis of HeLa cells. CONCLUSION: Transfection of siRNA expression vectors targeting hTERT can induce apoptosis of HeLa cells.