PI3K/HSCB axis facilitates FOG1 nuclear translocation to promote erythropoiesis and megakaryopoiesis.

Erythropoiesis and megakaryopoiesis are stringently regulated by signaling pathways. However, the precise molecular mechanisms through which signaling pathways regulate key transcription factors controlling erythropoiesis and megakaryopoiesis remain partially understood. Herein, we identified heat shock cognate B (HSCB), which is well known for its iron-sulfur cluster delivery function, as an indispensable protein for friend of GATA 1 (FOG1) nuclear translocation during erythropoiesis of K562 human erythroleukemia cells and cord-blood-derived human CD34+CD90+hematopoietic stem cells (HSCs), as well as during megakaryopoiesis of the CD34+CD90+HSCs. Mechanistically, HSCB could be phosphorylated by phosphoinositol-3-kinase (PI3K) to bind with and mediate the proteasomal degradation of transforming acidic coiled-coil containing protein 3 (TACC3), which otherwise detained FOG1 in the cytoplasm, thereby facilitating FOG1 nuclear translocation. Given that PI3K is activated during both erythropoiesis and megakaryopoiesis, and that FOG1 is a key transcription factor for these processes, our findings elucidate an important, previously unrecognized iron-sulfur cluster delivery independent function of HSCB in erythropoiesis and megakaryopoiesis.

Investigating the Influence of Fluctuating Humidity and Temperature on Creep Deformation in High-Performance Concrete Beams: A Comparative Study between Natural and Laboratorial Environmental Tests.

To investigate the influence of temperature and humidity variations on creep in high-performance concrete beams, beam tests were conducted in both natural and laboratory settings. The findings indicate that the variations in creep primarily stem from temperature changes, whereas humidity changes have little influence on fluctuations in both basic creep and total creep. The influence of humidity on creep is more strongly reflected in the magnitude of creep. Functions describing the influence of temperature and humidity on the creep behavior of high-performance concrete (HPC) subjected to fluctuating conditions are proposed. The findings were employed to examine creep deformation in engineering applications across four places. This study complements the correction method for the creep of members under fluctuating temperature and humidity. This research application can provide a basis for the calculation of the long-term deformation of HPC structures in natural environments.

Boldine promotes stemness of human urine-derived stem cells by activating the Wnt/ß-catenin signaling pathway.

Human urine-derived stem cells (hUSCs) process self-renewal and multilineage differentiation ability. Due to their non-invasive and easily available clinical source, hUSCs represent a promising alternative source of mesenchymal stem cells (MSCs) for application potential in cytotherapy. However, technical limitations, such as stemness property maintenance, have hindered hUSCs' clinical application. Certain some small molecules have been recognized with advantage in maintaining the stemness of stem cells. In this study, we identified stemness-regulated key targets of hUSCs based on the StemCellNet database, CMAP database and literature mining. Furthermore, we identified a small molecule compound, boldine, which may have the potential to promote the stemness of hUSCs. It promotes cell proliferation, multilineage differentiation and maintains stemness of hUSCs by cell viability assay, single-cell clone formation, osteogenic differentiation and stemness marker expression (OCT-4 and C-MYC). We identified that boldine may be a potential GSK-3ß inhibitor by molecular docking and confirmed that it can upregulate the level of ß-catenin and promote translocation of ß-catenin into nucleus of hUSCs using Western blotting and immunofluorescence analysis. Our study indicates boldine activates the Wnt/ß-catenin signaling pathway in hUSCs and provides an effective strategy for MSCs research and application of small molecules in maintaining the stemness of hUSCs.

Exploration on the first-line treatment of ERBB2-altered advanced non-small cell lung cancer: A multicenter retrospective study.

BACKGROUND: Although the treatment of ERBB2-altered non-small cell lung cancer (NSCLC) has been studied for many years, there are no comprehensive studies to evaluate the benefits of various therapies as first-line treatment. Through the development of immunotherapy, more and more different combination treatments were applicated in clinical practice, therefore, we conducted a multicenter retrospective study to evaluate the efficacy of different treatments. METHODS: We enrolled patients with ERBB2-altered NSCLC who had undergone at least one-line systemic anticancer treatment to evaluate the efficacy of first-line chemotherapy alone (Chemo), anti-ERBB2 tyrosine kinase inhibitor (TKI), chemotherapy plus immunotherapy (Chemo + Immuno), chemotherapy plus anti-angiogenesis therapy (Chemo + Antiangio) and chemotherapy combined with immunotherapy and anti-angiogenesis therapy (Chemo + Immuno + Antiangio). The clinical outcomes included objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), one-year and three-year survival rate. RESULTS: We enroll 36 patients harboring ERBB2 mutation and 29 with ERBB2 amplification. The overall ORR was 30.8%, DCR was 69.2% and mPFS was 5.7 months. Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (7.8 vs 3.6 months, HR: 0.24, 95 %CI: 0.09-0.64, P = 0.002; 5.9 vs 3.6 months, HR: 0.36, 95 %CI: 0.15-0.88, P = 0.019; respectively), while there was no significant difference in mPFS between Chemo + Immuno or Chemo + Antiangio and Chemo (both P > 0.05), the mPFS of the first two was longer. For ERBB2-mutant patients, the mPFS was 5.9 months, and Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (12.9 vs 2.9 months, HR: 0.15, 95 %CI: 0.03-0.68, P = 0.005; 7.1 vs 2.9 months, HR: 0.50, 95 %CI: 0.29-0.88, P = 0.009, respectively). In the same therapies, patients with ERBB2 mutation or ERBB2 amplification showed no statistical significance in PFS (both P > 0.05). CONCLUSIONS: In the first-line treatment of ERBB2-altered NSCLC, chemotherapy combined with immunotherapy or anti-angiogenesis therapy may have greater survival benefits than ERBB2-target therapy, but the efficacy may not be better than that of chemotherapy.

Clinical characteristics and targeted therapy of different gene fusions in non-small cell lung cancer: a narrative review.

Background and Objective: Lung cancer is the most fatal malignant tumor in the world. Since the discovery of driver genes, targeted therapy has been demonstrated to be superior to traditional chemotherapy and has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The remarkable success of tyrosine kinase inhibitors (TKIs) in patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions has shifted the treatment from platinum-based combination chemotherapy to targeted therapy. Although the incidence rate of gene fusion is low in NSCLC, it is of great significance in advanced refractory patients. However, the clinical characteristics and the latest treatment progress of patients with gene fusions in lung cancer have not been thoroughly explored. The objective of this narrative review was to summarize the latest research progress of targeted therapy for gene fusion variants in NSCLC to improve understanding for clinicians. Methods: We conducted a search of PubMed database and American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), and World Conference on Lung Cancer (WCLC) abstracts meeting proceedings from 1 January 2005 to 31 August 2022 with the following keywords "non-small cell lung cancer", "fusion", "rearrangement", "targeted therapy" and "tyrosine kinase inhibitor". Key Content and Findings: We comprehensively listed the targeted therapy of various gene fusions in NSCLC. Fusions of ALK, ROS proto-oncogene 1 (ROS1), and rearranged during transfection proto-oncogene (RET) are relatively more common than others (NTRK fusions, NRG1 fusions, FGFR fusions, etc.). Among ALK-rearranged NSCLC patients treated with crizotinib, alectinib, brigatinib, or ensartinib, the Asian population exhibited a slightly better effect than the non-Asian population in first-line therapy. It was revealed that ceritinib may have a slightly better effect in the non-Asian ALK-rearranged population as first-line therapy. The effect of crizotinib might be similar in Asians and non-Asians with ROS1-fusion-positive NSCLC in first-line therapy. The non-Asian population were shown to be more likely to be treated with selpercatinib and pralsetinib for RET-rearranged NSCLC than the Asian population. Conclusions: The present report summarizes the current state of fusion gene research and the associated therapeutic methods to improve understanding for clinicians, but how to better overcome drug resistance remains a problem that needs to be explored.

Inhibition of phosphoinositide­3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model.

Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25- T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.

Detection Method for Tomato Leaf Mildew Based on Hyperspectral Fusion Terahertz Technology.

Leaf mildew is a common disease of tomato leaves. Its detection is an important means to reduce yield loss from the disease and improve tomato quality. In this study, a new method was developed for the multi-source detection of tomato leaf mildew by THz hyperspectral imaging through combining internal and external leaf features. First, multi-source information obtained from tomato leaves of different disease grades was extracted by near-infrared hyperspectral imaging and THz time-domain spectroscopy, while the influence of low-frequency noise was removed by the Savitzky Golay (SG) smoothing algorithm. A genetic algorithm (GA) was used to optimize the selection of the characteristic near-infrared hyperspectral band. Principal component analysis (PCA) was employed to optimize the THz characteristic absorption spectra and power spectrum dimensions. Recognition models were developed for different grades of tomato leaf mildew infestation by incorporating near-infrared hyperspectral imaging, THz absorbance, and power spectra using the backpropagation neural network (BPNN), and the models had recognition rates of 95%, 96.67%, and 95%, respectively. Based on the near-infrared hyperspectral features, THz time-domain spectrum features, and classification model, the probability density of the posterior distribution of tomato leaf health parameter variables was recalculated by a Bayesian network model. Finally, a fusion diagnosis and health evaluation model of tomato leaf mildew with hyperspectral fusion THz was established, and the recognition rate of tomato leaf mildew samples reached 97.12%, which improved the recognition accuracy by 0.45% when compared with the single detection method, thereby achieving the accurate detection of facility diseases.

SDEGen: learning to evolve molecular conformations from thermodynamic noise for conformation generation.

Generation of representative conformations for small molecules is a fundamental task in cheminformatics and computer-aided drug discovery, but capturing the complex distribution of conformations that contains multiple low energy minima is still a great challenge. Deep generative modeling, aiming to learn complex data distributions, is a promising approach to tackle the conformation generation problem. Here, inspired by stochastic dynamics and recent advances in generative modeling, we developed SDEGen, a novel conformation generation model based on stochastic differential equations. Compared with existing conformation generation methods, it enjoys the following advantages: (1) high model capacity to capture multimodal conformation distribution, thereby searching for multiple low-energy conformations of a molecule quickly, (2) higher conformation generation efficiency, almost ten times faster than the state-of-the-art score-based model, ConfGF, and (3) a clear physical interpretation to learn how a molecule evolves in a stochastic dynamics system starting from noise and eventually relaxing to the conformation that falls in low energy minima. Extensive experiments demonstrate that SDEGen has surpassed existing methods in different tasks for conformation generation, interatomic distance distribution prediction, and thermodynamic property estimation, showing great potential for real-world applications.

Detection of tomato water stress based on terahertz spectroscopy.

China's tomato cultivation area is nearly 15 thousand km2, and its annual tomato output is about 55 million tons, accounting for 7% of its total vegetable production. Because of the high drought sensitivity of tomatoes, water stress inhibits their nutrient uptake, leading to a decrease in tomato quality and yield. Therefore, the rapid, accurate and non-destructive detection of water status is important for scientifically and effectively managing tomato water and fertilizer, improving the efficiency of water resource utilization, and safeguarding tomato yield and quality. Because of the extreme sensitivity of terahertz spectroscopy to water, we proposed a tomato leaf moisture detection method based on terahertz spectroscopy and made a preliminary exploration of the relationship between tomato water stress and terahertz spectral data. Tomato plants were grown at four levels of water stress. Fresh tomato leaves were sampled at fruit set, moisture content was calculated, and spectral data were collected through a terahertz time-domain spectroscope. The raw spectral data were smoothed using the Savitzky-Golay algorithm to reduce interference and noise. Then the data were divided by the Kennard-Stone algorithm and the sample set was partitioned based on the joint X-Y distance (SPXY) algorithm into a calibration set and a prediction set at a ratio of 3:1. SPXY was found to be the better approach for sample division. On this basis, the stability competitive adaptive re-weighted sampling algorithm was used to extract the feature frequency bands of moisture content, and a multiple linear regression model of leaf moisture content was established under the single dimensions of power, absorbance and transmittance. The absorbance model was the best, with a prediction set correlation coefficient of 0.9145 and a root mean square error of 0.1199. To further improve the modeling accuracy, we used a support vector machine (SVM) to establish a tomato moisture fusion prediction model based on the fusion of three-dimensional terahertz feature frequency bands. As water stress intensified, the power and absorbance spectral values both declined, and both were significantly and negatively correlated with leaf moisture content. The transmittance spectral value increased gradually with the intensification of water stress, showing a significant positive correlation. The SVM-based three-dimensional fusion prediction model showed a prediction set correlation coefficient of 0.9792 and a root mean square error of 0.0531, indicating that it outperformed the three single-dimensional models. Hence, terahertz spectroscopy can be applied to the detection of tomato leaf moisture content and provides a reference for tomato moisture detection.

Facing the future of transit ridership: shifting attitudes towards public transit and auto ownership among transit riders during COVID-19.

Public transit agencies face a transformed landscape of rider demand and political support as the COVID-19 pandemic recedes. We explore people's motivations for returning to or avoiding public transit a year into the pandemic. We draw on a March 2021 follow-up survey of over 1,900 people who rode transit regularly prior to the COVID-19 pandemic in Toronto and Vancouver, Canada, and who took part in a prior survey on the topic in May 2020. We investigate how transit demand changes associated with the pandemic relate to changes in automobile ownership and its desirability. We find that pre-COVID frequent transit users between the ages of 18-29, a part of the so-called "Gen Z," and recent immigrants are more attracted to driving due to the pandemic, with the latter group more likely to have actually purchased a vehicle. Getting COVID-19 or living with someone who did is also a strong and positive predictor of buying a car and anticipating less transit use after the pandemic. Our results suggest that COVID-19  may have increased the attractiveness of auto ownership among transit riders likely to eventually purchase cars anyway (immigrants, twentysomethings), at least in the North American context. We also conclude that getting COVID-19 or living with someone who did is a positive predictor of having bought a car. Future research should consider how having COVID-19 transformed some travelers' views, values, and behaviour. Supplementary Information: The online version contains supplementary material available at 10.1007/s11116-022-10344-2.

Application of Machine Learning Algorithms to Predict Acute Kidney Injury in Elderly Orthopedic Postoperative Patients.

Objective: There has been a worldwide increment in acute kidney injury (AKI) incidence among elderly orthopedic operative patients. The AKI prediction model provides patients' early detection a possibility at risk of AKI; most of the AKI prediction models derive, however, from the cardiothoracic operation. The purpose of this study is to predict the risk of AKI in elderly patients after orthopedic surgery based on machine learning algorithm models. Methods: We organized a retrospective study being comprised of 1000 patients with postoperative AKI undergoing orthopedic surgery from September 2016, to June, 2021. They were divided into training (80%;n=799) and test (20%;n=201) sets.We utilized nine machine learning (ML) algorithms and used intraoperative information and preoperative clinical features to acquire models to predict AKI. The performance of the model was evaluated according to the area under the receiver operating characteristic (AUC), sensitivity, specificity and accuracy. Select the optimal model and establish the nomogram to make the prediction model visualization. The concordance statistic (C-statistic) and calibration curve were used to discriminate and calibrate the nomogram respectively. Results: In predicting AKI, nine ML algorithms posted AUC of 0.656-1.000 in the training cohort, with the randomforest standing out and AUC of 0.674-0.821 in the test cohort, with the logistic regression model standing out. Thus, we applied the logistic regression model to establish nomogram. The nomogram was comprised of ten variables: age, body mass index, American Society of Anesthesiologists, hypoproteinemia, hypertension, diabetes, anemia, duration of low mean arterial pressure, mean arterial pressure, transfusion.The calibration curves showed good agreement between prediction and observation in both the training and test sets. Conclusion: By including intraoperative and preoperative risk factors, ML algorithm can predict AKI and logistic regression model performing the best. Our prediction model and nomogram that are based on this ML algorithm can help lead decision-making for strategies to inhibit AKI over the perioperative duration.

Copper nanoclusters-based fluorescent sensor array to identify metal ions and dissolved organic matter.

In recent years, the prevention and control of water pollution has received extensive attention. There is a need to develop simple and effective strategies for the rapid detection of metal ions and dissolved organic matter (DOM) in order to improve water quality. To this end, the first copper nanoclusters (CuNCs)-based fluorescent sensor array was done to identify 12 metal ions (Pb2+, Fe3+, Cu2+, Cd2+, Cr3+, Co2+, Ni2+, Zn2+, Ag+, Fe2+, Hg2+, and Al3+) and DOM (humic substances, lipids, fatty acids, amino acids, and lignans). The results revealed that CuNCs that were synthesized with polyethyleneimine (PEI), histidine (His), and glutathione (GSH) exhibited different binding abilities to metal ions and DOM. These unique fluorescence responses were analyzed using principal component analysis (PCA) and linear discriminant analysis (LDA) to identify metal ions and DOM in the buffer. The aforementioned 12 metal ions were classified at a limit concentration of 1.5 µM. Moreover, quantification of metal ions was achieved even at a low concentration of 0.83 µM (Zn2+). This array also worked well in the recognition of metal ions in tap water as well as distinguishing riverine and seawater samples of different regions, which was of great significance in environmental monitoring.

Eliminating barriers to nighttime activity participation: the case of on-demand transit in Belleville, Canada.

Demand-responsive technologies are rapidly changing the transportation landscape. The City of Belleville, Ontario has recently replaced its evening and nighttime fixed route bus service with an on-demand transit (ODT) service. Preliminary reports have found a 300% increase in nighttime bus ridership since the implementation of this service, yet to fully understand the social return on the investment in on-demand services, we must also quantify whether and for whom these new services have enabled time savings and increased levels of activity participation. Furthermore, it remains unclear whether riders are satisfied with the service, and whether satisfaction levels have an impact on activity participation. As such, this study explores the determinants of activity participation of ODT users using a custom ridership survey instrument. We collect information on travel experience, satisfaction, and perceived changes in activity participation due to ODT. We then performed a factor analysis and estimated structural equation models to identify the relationships between aspects of the ODT service and activity participation. Our results show that reliability and service quality are the most important aspects of the ODT services in terms of positively influencing activity participation, and that shorter wait times, are most likely to lead to an increase in activity participation. Our findings further suggest that Belleville can eliminate barriers to nighttime activity participation by providing reliable and affordable ODT service, and that ODT can be an effective solution to provide transit services for transport-poor in low demand areas or during low demand periods of the day. Supplementary Information: The online version contains supplementary material available at 10.1007/s11116-021-10215-2.

New Drimane Sesquiterpenes and Polyketides from Marine-Derived Fungus Penicillium sp. TW58-16 and Their Anti-Inflammatory and α-Glucosidase Inhibitory Effects.

Marine fungi-derived natural products represent an excellent reservoir for the discovery of novel lead compounds with biological activities. Here, we report the identification of two new drimane sesquiterpenes (1 and 2) and six new polyketides (3-8), together with 10 known compounds (9-18), from a marine-derived fungus Penicillium sp. TW58-16. The planar structures of these compounds were elucidated by extensive 1D and 2D NMR, which was supported by HR-ESI-MS data. The absolute configurations of these compounds were determined by experimental and calculated electronic circular dichroism (ECD), and their optical rotations compared with those reported. Evaluation of the anti-inflammatory activity of compounds 1-18 revealed that compound 5 significantly inhibited the release of nitric oxide (NO) induced by lipopolysaccharide (LPS) in RAW264.7 cells, correlating with the inhibition of expression of inducible nitric oxide synthase (iNOS). In addition, we revealed that compounds 1, 3-6, 14, 16, and 18 showed strong α-glucosidase inhibitory effects with inhibition rates of 35.4%, 73.2%, 55.6%, 74.4%, 32.0%, 36.9%, 88.0%, and 91.1%, respectively, which were comparable with or even better than that of the positive control, acarbose. Together, our results illustrate the potential of discovering new marine-based therapeutic agents against inflammation and diabetes mellitus.

Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin-induced diabetes.

BACKGROUND: Type 1 diabetes (T1D) is a multiple factor autoimmune disease characterized by T cell-mediated immune destruction of islet ß cells. Autologous hematopoietic stem cell transplantation (AHSCT) has been a novel strategy for patients with new-onset T1D, but not for those with a later diagnosis. Disturbance of regulatory T cells (Tregs) likely contributes to poor response after transplantation in later-stage T1D. Inhibition of phosphoinositide 3-kinases (PI3K)/Akt signaling maintains Tregs' homeostasis. METHODS: We built a later-stage streptozotocin (STZ)-induced T1D mouse model. Syngeneic bone marrow transplantation (syn-BMT) was performed 20 days after the onset of diabetes in combination with BKM120 (a PI3K inhibitor). Meanwhile, another group of STZ-diabetic mice were transplanted with bone marrow cells cocultured with BKM120 in vitro for 24 h. Fasting glucose and glucose tolerance were recorded during the entire experimental observation after syn-BMT. Samples were collected 126 days after syn-BMT. Hematoxylin and eosin (H&E) staining was used to detect the effect of PI3K inhibitor combined with syn-BMT on morphology of the T1D pancreas. CD4+CD25- T cells and CD4+CD25+ T cells were sorted by magnetic cell sorting (MACS), then fluorescence activated cell sorting (FACS) and quantitative real-time PCR (qPCR) were used to detect the effect of PI3K inhibitor on modulating immune disorder and restoring the function of Treg cells. RESULTS: Our investigation showed syn-BMT in combination with BKM120 effectively maintained normoglycemia in later-stage T1D. The disease remission effects may be induced by the rebalance of Th17/Tregs dysregulation and restoration of Tregs' immunosuppressive function by BKM120 after syn-BMT. CONCLUSIONS: These results may reveal important connections for PI3K/Akt inhibition and Tregs' homeostasis in T1D after transplantation. AHSCT combining immunoregulatory strategies such as PI3K inhibition may be a promising therapeutic approach in later-stage T1D.

Overexpressed miR-335-5p reduces atherosclerotic vulnerable plaque formation in acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) may induce cardiovascular death. The correlation of mast cells related microRNAs (miRs) with risk of ACS has been investigated. We explored regulatory mechanism of miR-335-5p on macrophage innate immune response, atherosclerotic vulnerable plaque formation, and revascularization in ACS in relation to Notch signaling. METHODS: ACS-related gene microarray was collected from Gene Expression Omnibus database. After different agomir or antagomir, or inhibitor of Notch signaling treatment, IL-6, IL-1ß, TNF-α, MCP-1, ICAM-1, and VCAM-1 levels were tested in ACS mice. Additionally, Notch signaling-related genes and matrix metalloproteinases (MMPs) were measured after miR-335-5p interference. Finally, mouse atherosclerosis, lipid accumulation, and the collagen/vessel area ratio of plaque were determined. RESULTS: miR-335-5p targeted JAG1 and mediated Notch signaling in ACS. miR-335-5p up-regulation and Notch signaling inhibition reduced expression of JAG1, Notch pathway-related genes, IL-6, IL-1ß, TNF-α, MCP-1, ICAM-1, VCAM-1, and MMPs, but promote TIMP1 and TIMP2 expression. Additionally, vulnerable plaques were decreased and collagen fiber contents were observed to increase after miR-335-5p overexpression and Notch signaling inhibition. CONCLUSIONS: Overexpression of miR-335-5p inhibited innate immune response of macrophage, reduced atherosclerotic vulnerable plaque formation, and promoted revascularization in ACS mice targeting JAG1 through Notch signaling.

Organic carbon in a seepage face of a subterranean estuary: Turnover and microbial interrelations.

Subterranean estuaries, the mixing zone between terrestrial groundwater and coastal seawater, are important biogeochemical hotspots. In the present study, organic carbon cycling and related drivers, including the characterization of different organic carbon pools and sediment microbial community, were investigated in a subterranean estuary seepage face. Within the first 20 cm depth seepage face sediments, both production and removal of dissolved organic carbon (DOC) were observed, mainly driven by heterotrophic microbes. From spring to autumn, active DOC production occurred on the seepage face at the 15-20 cm depth, likely via aerobic degradation of sediment organic carbon (SOC) with subsequent release of dissolved fractions into the porewater. During winter, DOC production moved to a shallower depth of the seepage face due to increasing SOC content in the surface layer. DOC production rate depended on heterotrophic microbial biomass (e.g. Proteobacteria) and was enhanced by high microbial activity and porewater advection. DOC removal frequently occurred at the 0-5 cm depth layer except in winter. The seasonal shift in carbon source utilization (SOC to DOC) in this layer likely resulted from the decrease in SOC pool, especially the labile portion of SOC and the increased availability of DOC due to production in the deeper sediment (15-20 cm). Given the similarity in microbial community structure along the sediment profile, this shift suggests SOC as the preferential carbon source for benthic microbes as well as adaptive flexibility in microbial carbon source utilization. DOC removal was also significantly tied to microbial activity and advection rate. Because DOC production rates were higher compared to DOC consumption the seepage face acted as a net source of DOC to the coastal ecosystem.

Atorvastatin alleviates left ventricular remodeling in isoproterenol-induced chronic heart failure in rats by regulating the RhoA/Rho kinase signaling pathway.

BACKGROUND: Chronic heart failure (CHF) is characterized by left ventricular dysfunction and altered autonomic control of cardiac function. This study aimed to investigate the effects of atorvastatin on left ventricular remodeling (LVR) and cardiac function in rats with isoproterenol-induced CHF and the possible mechanism. METHODS: An isoproterenol-induced CHF model was established in rata, which were subsequently treated with atorvastatin. Echocardiography, hemodynamic, and left ventricular mass indexes were assessed. The mRNA expression of RhoA, Rho kinase, and endothelial nitric oxide synthase (eNOS) was determined by RT-qPCR. The protein expression of myosin-binding subunit (MBS), MBS-P, eNOS, phosphorylated-eNOS, RhoA, and Rho kinase was measured by Western blot analysis. The relative activity of NADPH oxidase, ROS, and NO was assessed by ELISA. RESULTS: Isoproterenol-induced CHF rats treated with atorvastatin exhibited decreased left ventricular end-systolic dimension, left ventricular end-diastolic dimension, left ventricular end-diastolic pressure, left ventricular mass index, maximum fall rate of change in left ventricular pressure, heart rate (p < 0.001), expression of RhoA, Rho kinase, MBS and MBS-P (p < 0.01), and relative activity of NADPH oxidase, ROS and NO (p < 0.05) and increased left ventricular short axis fractional shortening, left ventricular end-systolic pressure, maximum rise rate of change in left ventricular pressure (p < 0.001) and expression of eNOS, and phosphorylated-eNOS ser1177 (all p < 0.05) compared with those of rats with isoproterenol-induced CHF. CONCLUSION: We demonstrated that atorvastatin inhibits LVR and improves cardiac function in rats with isoproterenol-induced CHF through inhibition of the RhoA/Rho kinase signaling pathway.

Hydrophilic graphene oxide/bismuth selenide nanocomposites for CT imaging, photoacoustic imaging, and photothermal therapy.

A nanotheranostic agent has been fabricated by direct deposition of Bi2Se3 nanoparticles on graphene oxide (GO) in the presence of polyvinylpyrrolidone (PVP) using a one-pot solvothermal method. The resulting GO/Bi2Se3/PVP nanocomposites show low in vitro cytotoxicity, negligible hemolytic activity and little in vivo toxicity. GO/Bi2Se3/PVP nanocomposites could serve as an efficient bimodal contrast agent to simultaneously enhance X-ray computed tomography imaging and photoacoustic imaging in vivo. In addition, the nanocomposites exhibit significant photothermal cytotoxicity to cancer cells under 808 nm laser irradiation. After intratumoral or intravenous injection of the nanocomposites, irreversible photothermal ablation of tumors in the mouse model is successfully achieved by using 808 nm laser irradiation. All of the positive results highlight that the GO/Bi2Se3/PVP nanocomposites can be developed as a promising nanoplatform for efficient tumor theranostic applications.