Impact path of digital economy on carbon emission efficiency: Mediating effect based on technological innovation.

The digital economy (DIE), a new economic form with digitalization at its core, has become an important driving force for promoting regional economy development. In the context of the COVID-19 pandemic, exploring the impact path of the DIE on carbon emission efficiency (CEE) is conducive to giving full play to the "carbon-reduction-and-efficiency-enhancement" role of the DIE, and to promoting the realization the "dual carbon" goal of carbon peak and carbon neutrality. In this paper, the Yellow River Basin (YRB) and the Yangtze River Economic Belt (YREB) are taken as study areas, the panel Tobit model is used to explore the impact of the DIE on CEE, and the intermediary-effect model and threshold-effect model are constructed to test the intermediary and threshold effects of technological innovation, respectively. The results show that the DIE has a U-shaped nonlinear impact on CEE in both the YRB and the YREB and that the impact has regional heterogeneity. Technological innovation can play a mediating effect between the DIE and CEE, whereas the mediating effect in the YRB is stronger than that in the YREB. Technological innovation has a threshold effect on the DIE to improve CEE, while the threshold value in the YREB is higher than that in the YRB. Furthermore, this paper proposes some suggestions to guide regional low-carbon and sustainable development.

The Enrichment of Docosahexaenoic Acid from Microalgal Oil by Urea Complexation via Rotary-evaporation Crystallization.

Urea complexation is a widely used method for enriching polyunsaturated fatty acids, and cooling is the traditional approach for urea crystallization. This study aimed to investigate the potential of rotary-evaporation under vacuum as an alternative method for urea crystallization in urea complexation to enrich docosahexaenoic acid (DHA). DHA-containing microalgal oil was converted to ethyl esters (EE) as the raw material. In comparison to cooling, rotary-evaporation crystallization, as a post-treatment method for urea complexation, led to higher DHA contents in the non-urea included fractions. The ratios of urea to EE converted from DHA-containing microalgal oil was found to be the primary factors influencing urea complexation when using rotary-evaporation crystallization. Through an orthogonal test, optimal process conditions were determined, including a urea/EE ratio of 2, an ethanol/urea ratio of 7, and a rotary-evaporation temperature of 75℃. Under these conditions, a concentrate containing more than 90% DHA could be obtained.

Association of nurse managers' paternalistic leadership and nurses' perceived workplace bullying: The mediating effect of organizational climate.

AIMS: To explore the association between nurse managers' paternalistic leadership and nurses' perceived workplace bullying (WPB), as well as to examine the mediating role of organizational climate in this association. BACKGROUND: There is a lack of empirical evidence regarding the relationship between nurse managers' paternalistic leadership, organizational climate and nurses' perceived WPB. Clarifying this relationship is crucial to understand how paternalistic leadership influences WPB and for nursing managers to seek organizational-level solutions to prevent it. METHODS: A cross-sectional survey was performed from 4 January to 10 February 2022, in six tertiary hospitals in mainland China. Demographic information, Paternalistic Leadership Scale, Organizational Climate Scale and Negative Acts Questionnaire-Revised were used in the survey. Descriptive statistics, Spearman correlation analyses and a structural equation model were used for data analysis. RESULTS: A total of 5093 valid questionnaires were collected. Moral leadership and authoritarian leadership have both direct and indirect effects on WPB through the mediating effect of organizational climate. The former is negatively related to WPB and the latter is positively related to WPB. Benevolent leadership was only negatively associated with WPB via the mediating effect of organizational climate. CONCLUSION: The three components of paternalistic leadership have different effects on WPB through the mediating effect of organizational climate. Nurse managers are recommended to strengthen moral leadership, balance benevolent leadership, reduce authoritarian leadership and strive to create a positive organizational climate in their efforts to mitigate WPB among nurses. IMPACT: This study enhanced our comprehension of the relationship between different leadership styles and WPB. Greater emphasis should be placed on moral leadership in the promotion of nursing managers and nursing leadership training programs. Additionally, nursing managers should focus on establishing a positive organizational climate that helps to reduce WPB. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. This study did not involve patients, service users, caregivers or members of the public.

Vascular smooth muscle cell-specific miRNA-214 deficiency alleviates simulated microgravity-induced vascular remodeling.

The human cardiovascular system has evolved to accommodate the gravity of Earth. Microgravity during spaceflight has been shown to induce vascular remodeling, leading to a decline in vascular function. The underlying mechanisms are not yet fully understood. Our previous study demonstrated that miR-214 plays a critical role in angiotensin II-induced vascular remodeling by reducing the levels of Smad7 and increasing the phosphorylation of Smad3. However, its role in vascular remodeling evoked by microgravity is not yet known. This study aimed to determine the contribution of miR-214 to the regulation of microgravity-induced vascular remodeling. The results of our study revealed that miR-214 expression was increased in the forebody arteries of both mice and monkeys after simulated microgravity treatment. In vitro, rotation-simulated microgravity-induced VSMC migration, hypertrophy, fibrosis, and inflammation were repressed by miR-214 knockout (KO) in VSMCs. Additionally, miR-214 KO increased the level of Smad7 and decreased the phosphorylation of Smad3, leading to a decrease in downstream gene expression. Furthermore, miR-214 cKO protected against simulated microgravity induced the decline in aorta function and the increase in stiffness. Histological analysis showed that miR-214 cKO inhibited the increases in vascular medial thickness that occurred after simulated microgravity treatment. Altogether, these results demonstrate that miR-214 has potential as a therapeutic target for the treatment of vascular remodeling caused by simulated microgravity.

Heterogeneous influence of neighborhood features on community satisfaction: a comparative study in Beijing's urban and suburban communities.

Introduction: Community satisfaction contributes to urban planning, community development, and policy formulation. Yet, we lack comprehensive knowledge about how different neighborhood features impact satisfaction, especially across diverse community types. Methods: Relied on a sample of 4,009 respondents in Beijing, this study examines the influence of neighborhood features on community satisfaction through neighborly interactions, focusing on the heterogeneity between urban and suburban communities, using structural equation models. Results: The results reveal that community service and community management exert significant influences on community satisfaction, primarily mediated by the role of neighborly interactions. Then, transportation convenience positively influences community satisfaction in urban areas, while no housing property has a negative effect in suburban communities. Discussion: These results highlight varied neighborhood effects on community satisfaction, informing tailored urban planning and policies that address unique traits and requirements of different communities.

Predictive value of von Willebrand factor for venous thrombosis in patients with chronic heart failure complicated with atrial fibrillation after anticoagulant therapy.

BACKGROUND: We investigated the value of von Willebrand factor (vWF) in predicting venous thrombosis in patients with chronic heart failure complicated with atrial fibrillation after anticoagulation therapy. METHODS: Totally, 126 patients with chronic heart failure complicated with atrial fibrillation who were treated with anticoagulant therapy and 60 healthy individuals were enrolled. One year after anticoagulant therapy, venous thrombosis occurred in 19 patients. Clinical data of patients were collected. The plasma vWF activity was detected and compared. The logistic regression analysis was used to analyze the influencing factors of vWF. ROC curve was used to evaluate the predictive value of plasma vWF. RESULTS: Plasma vWF activity was significantly higher in patients with heart failure and atrial fibrillation than control subjects (P < 0.01). The vWF activity in patients with venous thrombosis was significantly higher than that in patients without venous thrombosis (P < 0.01). ROC curve analysis showed that the cut-off value of vWF activity for venous thrombosis within one year after anticoagulant therapy was 267.5%, and the AUC was 0.742 (95% CI: 0.764-0.921, P < 0.05). The sensitivity was 80.0%, and the specificity was 63.6%. Factors of diabetes, myocardial ischemia, old myocardial infarction, and lower extremity atherosclerosis, but not sex, age, coronary heart disease, hypertension, and cardiac function, had significant effect on vWF activity (P < 0.05). Logistic regression analysis showed that vWF activity was significantly related with atherosclerosis of lower limbs and old myocardial infarction, but not significantly related with diabetes and myocardial ischemia. The risk of venous thrombosis in patients with vWF activity greater than 267.5% was 10.667 times higher than that in patients with vWF activity less than 267.5% (P < 0.05). CONCLUSION: The vWF activity greater than 267.5% has clinical predictive value for the risk of lower extremity venous thrombosis in patients with chronic heart failure complicated with atrial fibrillation within 1 year of anticoagulant therapy.

Limosilactobacillus reuteri consumption significantly reduces the total cholesterol concentration without affecting other cardiovascular disease risk factors in adults: A systematic review and meta-analysis.

As one of the most significant probiotics, Limosilactobacillus reuteri (L. reuteri) has been exploited as a nutritional supplement. We hypothesized that L. reuteri consumption might improve the significant risk factors of cardiovascular disease, including blood pressure, blood lipid, and blood glucose. However, previous clinical studies have shown controversial results. This study aims to explore the effect of L. reuteri consumption on these risk factors. PubMed, Embase, Scopus, the Cochrane Library, and Web of Science were searched for eligible randomized controlled trials published before May 2022. A total of 6 studies with 4 different L. reuteri strains and including 512 participants were included. The results showed that L. reuteri consumption significantly reduced total cholesterol (TC) by -0.26 mmol/L compared with the control group. In contrast, it did not affect systolic blood pressure, diastolic blood pressure, fasting blood glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), or triglycerides. Subgroup analysis showed a significant reduction in TC when participants were <55 years old, had a body mass index between 25 and 30, or had hypercholesterolemia. In addition, TC decreased significantly when L. reuteri supplementation was >5 × 109 colony-forming unit or the length of the intervention was <12 weeks. Strain subgroup analysis showed that L. reuteri NCIMB 30242 significantly reduced TC and LDL-C. In conclusion, L. reuteri consumption has a significant TC-lowering effect, which can effectively reduce the risks of cardiovascular disease associated with hypercholesterolemia. However, the results do not support the effectiveness of L. reuteri consumption on other metabolic outcomes. Further examination of larger sample sizes is needed to confirm these findings.

Aptamer modified Zr-based porphyrinic nanoscale metal-organic frameworks for active-targeted chemo-photodynamic therapy of tumors.

Active-targeted nanoplatforms could specifically target tumors compared to normal cells, making them a promising therapeutic agent. The aptamer is a kind of short DNA or RNA sequence that can specifically bind to target molecules, and could be widely used as the active targeting agents of nanoplatforms to achieve active-targeted therapy of tumors. Herein, an aptamer modified nanoplatform DOX@PCN@Apt-M was designed for active-targeted chemo-photodynamic therapy of tumors. Zr-based porphyrinic nanoscale metal organic framework PCN-224 was synthesized through a one-pot reaction, which could produce cytotoxic 1O2 for efficient treatment of tumor cells. To improve the therapeutic effect of the tumor, the anticancer drug doxorubicin (DOX) was loaded into PCN-224 to form DOX@PCN-224 for tumor combination therapy. Active-targeted combination therapy achieved by modifying the MUC1 aptamer (Apt-M) onto DOX@PCN-224 surface can not only further reduce the dosage of therapeutic agents, but also reduce their toxic and side effects on normal tissues. In vitro, experimental results indicated that DOX@PCN@Apt-M exhibited enhanced combined therapeutic effect and active targeting efficiency under 808 nm laser irradiation for MCF-7 tumor cells. Based on PCN-224 nanocarriers and aptamer MUC1, this work provides a novel strategy for precisely targeting MCF-7 tumor cells.

Mechanical stimulation controls osteoclast function through the regulation of Ca2+-activated Cl- channel Anoctamin 1.

Mechanical force loading is essential for maintaining bone homeostasis, and unloading exposure can lead to bone loss. Osteoclasts are the only bone resorbing cells and play a crucial role in bone remodeling. The molecular mechanisms underlying mechanical stimulation-induced changes in osteoclast function remain to be fully elucidated. Our previous research found Ca2+-activated Cl- channel Anoctamin 1 (Ano1) was an essential regulator for osteoclast function. Here, we report that Ano1 mediates osteoclast responses to mechanical stimulation. In vitro, osteoclast activities are obviously affected by mechanical stress, which is accompanied by the changes of Ano1 levels, intracellular Cl- concentration and Ca2+ downstream signaling. Ano1 knockout or calcium binding mutants blunts the response of osteoclast to mechanical stimulation. In vivo, Ano1 knockout in osteoclast blunts loading induced osteoclast inhibition and unloading induced bone loss and. These results demonstrate that Ano1 plays an important role in mechanical stimulation induced osteoclast activity changes.

The Interactive Relationship between Street Centrality and Land Use Intensity-A Case Study of Jinan, China.

It is of great significance to study the interactive relationship between urban transportation and land use for promoting the healthy and sustainable development of cities. Taking Jinan, China, as an example, this study explored the interactive relationship between street centrality (SC) and land use intensity (LUI) in the main urban area of Jinan by using the spatial three-stage least squares method. The results showed that the closeness centrality showed an obvious "core-edge" pattern, which gradually decreased from the central urban area to the edge area. Both the betweenness centrality and the straightness centrality showed a multi-center structure. The commercial land intensity (CLUI) showed the characteristics of multi-core spatial distribution, while the residential land intensity (RLUI) and public service land intensity (PLUI) showed the characteristics of spatial distribution with the coexistence of large and small cores. There was an interactive relationship between SC and LUI. The closeness centrality and straightness centrality had positive effects on LUI, and LUI had a positive effect on closeness centrality and straightness centrality. The betweenness centrality had a negative impact on LUI, and LUI also had a negative impact on betweenness centrality. Moreover, good location factors and good traffic conditions were conducive to improving the closeness and straightness centrality of the regional traffic network. Good location factors, good traffic conditions and high population density were conducive to improving regional LUI.

Postmenopausal osteoporosis: a bioinformatics-integrated experimental study the pathogenesis.

Postmenopausal osteoporosis (PMOP) is a chronic bone metabolic disease, which often causes fractures and various complications, it causes a great social and economic burden, and it is urgent to use modern research techniques to elucidate the pathogenesis of PMOP. At the same time, because of the complex physiological and pathological interaction mechanism between osteoporosis and sarcopenia, the correlation research has become a hot topic. Ovary removal is a commonly used experimental method to study the endocrine system of female animals, and it is also the best animal model to study PMOP. In this study, the preparation of the ovariectomized rat was confirmed through the detection of vaginal smear, the level of bone formation markers, and the analysis of bone tissue morphology. Transcriptome sequencing was used to analyze the molecular mechanism of PMOP in ovariectomized rats, qRT-PCR was used to verify the key targets. Results of Micro-CT and scanning electron microscopy (SEM) showed that the trabecular structure was disorganized and the symptoms of osteoporosis appeared, this indicating that the ovariectomized rats model was successfully prepared. Transcriptional sequencing results of femur tissue showed that 452 differentially expressed genes (DEGs) were screened. Bioinformatics analysis results showed that the osteoporosis caused by ovariectomized rats was mainly related to muscle contraction, calcium signaling pathway, etc. Results of qRT-PCR were consistent with transcriptome analysis. These results reveal the pathogenesis of PMOP in ovariectomized rats and also offer a possibility for elucidating the relevance of action between PMOP and sarcopenia.

Non-Invasive Skin Imaging Assessment of Human Stress During Head-Down Bed Rest Using a Portable Handheld Two-Photon Microscope.

Spaceflight presents a series of physiological and pathological challenges to astronauts resulting from ionizing radiation, microgravity, isolation, and other spaceflight hazards. These risks cause a series of aging-related diseases associated with increased oxidative stress and mitochondria dysfunction. The skin contains many autofluorescent substances, such as nicotinamide adenine dinucleotide phosphate (NAD(P)H), keratin, melanin, elastin, and collagen, which reflect physiological and pathological changes in vivo. In this study, we used a portable handheld two-photon microscope to conduct high-resolution in vivo skin imaging on volunteers during 15 days of head-down bed rest. The two-photon microscope, equipped with a flexible handheld scanning head, was used to measure two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) images of the left forearm, left front chest, and forehead of volunteers. Changes in TPEF, SHG, and the extended SHG-to-AF(TPEF) aging index of the dermis (SAAID) were measured. It was found that TPEF intensity increased during bed rest and was restored to normal levels after recovery. Meanwhile, SHG increased slightly during bed rest, and the skin aging index increased. Moreover, we found the skin TPEF signals of the left forearm were significantly negatively associated with the oxidative stress marker malondialdehyde (MDA) and DNA damage marker 8-hydroxy-2'-desoxyguanosine (8-OHdG) values of subjects during head-down bed rest. Meanwhile, the SHG signals were also significantly negatively correlated with MDA and 8-OHDG. A significant negative correlation between the extended SAAID of the left chest and serum antioxidant superoxide dismutase (SOD) levels was also found. These results demonstrate that skin autofluorescence signals can reflect changes in human oxidant status. This study provides evidence for in-orbit monitoring of changes in human stress using a portable handheld two-photon microscope for skin imaging.

Construction of multifunctional mesoporous silicon nano-drug delivery system and study of dual sensitization of chemo-photodynamic therapy in vitro and in vivo.

This study was conducted to construct a multifunctional nanodrug delivery system (NDDS) to deplete glutathione (GSH) in tumor cells and amplify oxidative stress, enhancing the synergistic effect of chemotherapy and photodynamic therapy (PDT). l-Buthionine-sulfoximine (BSO) and chlorin e6 (Ce6) were loaded into mesoporous silicon nanoparticles (MSN), and then MSN were modified with oxidized hyaluronic acid (OHA) as a pore-blocking agent. Cisplatin (Pt(II)) was further loaded by a coordination reaction with carboxyl groups in OHA to yield a multifunctional NDDS (denoted as MSN@OHA-Ce6/BSO/Pt). The physicochemical properties and antitumor activity of the prepared nanoparticles were characterized in detail. In vitro and in vivo experiments demonstrated that OHA was shed from MSN@OHA-Ce6/BSO/Pt under acidic conditions in tumors, resulting in the release of free BSO, Ce6, and Pt(II). The released BSO could reduce intracellular GSH expression by 48.8 %, effectively enhancing the PDT effect of Ce6 and the chemotherapy effect of Pt(II). Finally, the tumor inhibitory rate (vs saline) reached 73.8 % ± 2.5 % for MSN@OHA-Ce6/BSO/Pt in A549/DDP tumor-bearing nude mice. Therefore, the multifunctional NDDS significantly enhanced the synergistic effect of PDT and chemotherapy.

Osteoblast Derived Exosomes Alleviate Radiation- Induced Hematopoietic Injury.

As hematopoietic stem cells can differentiate into all hematopoietic lineages, mitigating the damage to hematopoietic stem cells is important for recovery from overdose radiation injury. Cells in bone marrow microenvironment are essential for hematopoietic stem cells maintenance and protection, and many of the paracrine mediators have been discovered in shaping hematopoietic function. Several recent reports support exosomes as effective regulators of hematopoietic stem cells, but the role of osteoblast derived exosomes in hematopoietic stem cells protection is less understood. Here, we investigated that osteoblast derived exosomes could alleviate radiation damage to hematopoietic stem cells. We show that intravenous injection of osteoblast derived exosomes promoted WBC, lymphocyte, monocyte and hematopoietic stem cells recovery after irradiation significantly. By sequencing osteoblast derived exosomes derived miRNAs and verified in vitro, we identified miR-21 is involved in hematopoietic stem cells protection via targeting PDCD4. Collectively, our data demonstrate that osteoblast derived exosomes derived miR-21 is a resultful regulator to radio-protection of hematopoietic stem cells and provide a new strategy for reducing radiation induced hematopoietic injury.

[Blood Group Distribution Characteristics of COVID-19 Patients in Xinjiang].

OBJECTIVE: To analyze and summarize ABO and Rh(D) blood group distribution and related indicators of COVID-19 patients, and understand the relationship between blood group and disease course of COVID-19 patients in Xinjiang. METHODS: A total of 831 patients with confirmed or asymptomatic COVID-19 infection treated in People's Hospital of Xinjiang Uygur Autonomous Region from July 2020 to August 2020 were enrolled as study group, and 2 778 healthy people in a third Grade A hospital in the region during the same period were selected as control group. ABO and Rh(D) blood group antigens were identified, and relevant medical data were collected for statistical analysis. RESULTS: The proportion of O-type population and Rh(D) positive population in the study group was 24.79% and 96.27%, which were lower than those in the normal control group (29.73% and 97.73%) (P<0.05). The proportion of AB type and Rh(D) negative population was 14.20% and 3.73%, which was higher than that in control group (10.62% and 2.27%) (P<0.05). The proportion of female patients in Type O group was lower than that in control group. The proportion of female patients in AB group was higher than that in control group (P<0.01), while the proportion of type O patients in the age group less than or equal to 45 years old and greater than 60 years old was lower. Different blood groups of Uygur population showed their own characteristics in different sex, but there was no statistical significance due to the limited sample (P>0.05). Moreover, the course of disease and clinical diagnosis of COVID-19 patients were different among different blood groups (P<0.05). CONCLUSION: This study found that the blood type distribution of COVID-19 patients in Xinjiang has its own characteristics, and the blood type is related to the course and clinical diagnosis of COVID-19. In the future, the data can be widely included in people from different ethnic groups and different regions to improve relevant studies.

Vascular smooth muscle cell-specific miRNA-214 knockout inhibits angiotensin II-induced hypertension through upregulation of Smad7.

Vascular remodeling is a prominent trait during the development of hypertension, attributable to the phenotypic transition of vascular smooth muscle cells (VSMCs). Increasing studies demonstrate that microRNA plays an important role in this process. Here, we surprisingly found that smooth muscle cell-specific miR-214 knockout (miR-214 cKO) significantly alleviates angiotensin II (Ang II)-induced hypertension, which has the same effect as that of miR-214 global knockout mice in response to Ang II stimulation. Under the treatment of Ang II, miR-214 cKO mice exhibit substantially reduced systolic blood pressure. The vascular medial thickness and area in miR-214 cKO blood vessels were obviously reduced, the expression of collagen I and proinflammatory factors were also inhibited. VSMC-specific deletion of miR-214 blunts the response of blood vessels to the stimulation of endothelium-dependent and -independent vasorelaxation and phenylephrine and 5-HT induced vasocontraction. In vitro, Ang II-induced VSMC proliferation, migration, contraction, hypertrophy, and stiffness were all repressed with miR-214 KO in VSMC. To further explore the mechanism of miR-214 in the regulation of the VSMC function, it is very interesting to find that the TGF-ß signaling pathway is mostly enriched in miR-214 KO VSMC. Smad7, the potent negative regulator of the TGF-ß/Smad pathway, is identified to be the target of miR-214 in VSMC. By which, miR-214 KO sharply enhances Smad7 levels and decreases the phosphorylation of Smad3, and accordingly alleviates the downstream gene expression. Further, Ang II-induced hypertension and vascular dysfunction were reversed by antagomir-214. These results indicate that miR-214 in VSMC established a crosstalk between Ang II-induced AT1R signaling and TGF-ß induced TßRI /Smad signaling, by which it exerts a pivotal role in vascular remodeling and hypertension and imply that miR-214 has the potential as a therapeutic target for the treatment of hypertension.

Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination.

BACKGROUND: Without adequate treatment, pathological cardiac hypertrophy induced by sustained pressure overload eventually leads to heart failure. WWP1 (WW domain-containing E3 ubiquitin protein ligase 1) is an important regulator of aging-related pathologies, including cancer and cardiovascular diseases. However, the role of WWP1 in pressure overload-induced cardiac remodeling and heart failure is yet to be determined. METHODS: To examine the correlation of WWP1 with hypertrophy, we analyzed WWP1 expression in patients with heart failure and mice subjected to transverse aortic constriction (TAC) by Western blotting and immunohistochemical staining. TAC surgery was performed on WWP1 knockout mice to assess the role of WWP1 in cardiac hypertrophy, heart function was examined by echocardiography, and related cellular and molecular markers were examined. Mass spectrometry and coimmunoprecipitation assays were conducted to identify the proteins that interacted with WWP1. Pulse-chase assay, ubiquitination assay, reporter gene assay, and an in vivo mouse model via AAV9 (adeno-associated virus serotype 9) were used to explore the mechanisms by which WWP1 regulates cardiac remodeling. AAV9 carrying cardiac troponin T (cTnT) promoter-driven small hairpin RNA targeting WWP1 (AAV9-cTnT-shWWP1) was administered to investigate its rescue role in TAC-induced cardiac dysfunction. RESULTS: The WWP1 level was significantly increased in the hypertrophic hearts from patients with heart failure and mice subjected to TAC. The results of echocardiography and histology demonstrated that WWP1 knockout protected the heart from TAC-induced hypertrophy. There was a direct interaction between WWP1 and DVL2 (disheveled segment polarity protein 2). DVL2 was stabilized by WWP1-mediated K27-linked polyubiquitination. The role of WWP1 in pressure overload-induced cardiac hypertrophy was mediated by the DVL2/CaMKII/HDAC4/MEF2C signaling pathway. Therapeutic targeting WWP1 almost abolished TAC induced heart dysfunction, suggesting WWP1 as a potential target for treating cardiac hypertrophy and failure. CONCLUSIONS: We identified WWP1 as a key therapeutic target for pressure overload induced cardiac remodeling. We also found a novel mechanism regulated by WWP1. WWP1 promotes atypical K27-linked ubiquitin multichain assembly on DVL2 and exacerbates cardiac hypertrophy by the DVL2/CaMKII/HDAC4/MEF2C pathway.

Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells.

Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer. Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA. Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations. Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Alteration of calcium signalling in cardiomyocyte induced by simulated microgravity and hypergravity.

OBJECTIVES: Cardiac Ca2+ signalling plays an essential role in regulating excitation-contraction coupling and cardiac remodelling. However, the response of cardiomyocytes to simulated microgravity and hypergravity and the effects on Ca2+ signalling remain unknown. Here, we elucidate the mechanisms underlying the proliferation and remodelling of HL-1 cardiomyocytes subjected to rotation-simulated microgravity and 4G hypergravity. MATERIALS AND METHODS: The cardiomyocyte cell line HL-1 was used in this study. A clinostat and centrifuge were used to study the effects of microgravity and hypergravity, respectively, on cells. Calcium signalling was detected with laser scanning confocal microscopy. Protein and mRNA levels were detected by Western blotting and real-time PCR, respectively. Wheat germ agglutinin (WGA) staining was used to analyse cell size. RESULTS: Our data showed that spontaneous calcium oscillations and cytosolic calcium concentration are both increased in HL-1 cells after simulated microgravity and 4G hypergravity. Increased cytosolic calcium leads to activation of calmodulin-dependent protein kinase II/histone deacetylase 4 (CaMKII/HDAC4) signalling and upregulation of the foetal genes ANP and BNP, indicating cardiac remodelling. WGA staining indicated that cell size was decreased following rotation-simulated microgravity and increased following 4G hypergravity. Moreover, HL-1 cell proliferation was increased significantly under hypergravity but not rotation-simulated microgravity. CONCLUSIONS: Our study demonstrates for the first time that Ca2+ /CaMKII/HDAC4 signalling plays a pivotal role in myocardial remodelling under rotation-simulated microgravity and hypergravity.

Dual sensing reporter system of assembled gold nanoparticles toward the sequential colorimetric detection of adenosine and Cr(III).

A facile and sensitive sequential colorimetric detection strategy for adenosine and Cr3+ has been presented by using the aptamer and 11-mercaptoundecanoic acid assembled gold nanoparticles. The thiolated DNA and 11-mercaptoundecanoic acid was simultaneously assembled to the surface of gold nanoparticles in one step by gold-sulfur interaction. Adenosine aptamer was linked to functionalized gold nanaoparticles based on the strict complementary nature of the DNA base pairs. Conformational change of aptamer will be induced due to its specific binding with targets. As a result, this aptamer tethered aggregated nanoparticles underwent fast disassembly into dispersed nanoparticles upon binding of adenosine, and this distance change between particles induced a distinct solution color changing from blue to red. The dispersed particles were sensitive to Cr3+ due to the chelation effect between the carboxyl group of 11-mercaptoundecanoic acid and metal ions, and further occurred obvious aggregation accompanying with a color change from red to blue. Depended on this principle, a sensitive and selective sequential colorimetric sensor for detection of adenosine and Cr3+ was developed. The proposed colorimetric sensor exhibited wide linear ranges and low detection limits towards the detection of adenosine and Cr3+. Regarding adenosine, linear range was 1 × 10-7 ∼ 1 × 10-4 M with low detection limit of 1.8 × 10-8 M, and the naked eye detection limit was estimated as 20 µM. With regard to Cr3+, good linear relationship was ranged from 1 × 10-10 to 1 × 10-6 M with low detection limit of 1.7 × 10-11 M，and the naked eye detection limit was as low as 0.1 nM. Meanwhile, bifunctional recognition was successfully used for practical human urine samples with good recoveries from 89.0% to 112.6% for adenosine and 90.2%-113.4% for Cr3+. It also highlights the potential applications of other aptamers and ligands in cascade analysis of other analytes.