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Background: The increasing prevalence of atrial fibrillation (AF) and chronic kidney diseases highlights the need for a deeper comprehension of the molecular mechanisms linking them. Mutations in PKD1, the gene encoding Polycystin-1 (PKD1 or PC1), account for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. This disease often includes cardiac complications such as AF. In cardiomyocytes, PC1 deletion reduces hypertrophic response to pressure overload but promotes baseline ventricular dysfunction, while deletion in fibroblasts ameliorates post-myocardial infarction fibrosis. Despite its known cardiac impact, the role of PC1 in atrial cardiomyocytes and arrhythmias is less understood. Here, we sought to investigate the role of PC1 in AF., Methods: We used intracardiac programmed stimulation and optical mapping to evaluate AF inducibility in two mouse models, Pkd1 R3277C, which recapitulates human ADPKD progression, and cardiomyocyte-specific Pkd1 deletion, and their respective controls. Isolated adult mouse atrial cardiomyocytes, human iPSC-derived atrial cardiomyocytes (hiPSC-aCM), and HL-1 cells served as in vitro cellular models. Molecular mechanisms were evaluated using optical mapping and molecular and biochemical approaches., Results: Loss-of-function PC1 mutations significantly increased AF susceptibility in vivo and facilitated local reentry in ex vivo left atrial appendages. Comprehensive in vitro experiments supported a direct effect of PC1 in atrial cardiomyocytes. PC1-deficient monolayers exhibited increased arrhythmic events, escalating into reentrant spiral waves post-tachypacing. Transcriptomics analysis revealed PC1-dependent regulation of DNA repair, with PC1 deficiency leading to increased DNA damage under stress. PARP1 inhibitors or nicotinamide riboside, which counteract DNA damage-related metabolic consequences, reduced in vitro arrhythmias PC1-deficient monolayers. Overexpression of the C-terminus of PC1 had the opposite effects in DNA repair genes, suggesting its regulatory effects in atrial cardiomyocytes through retinoblastoma/E2F. Analyses of human atrial tissue from non-ADPKD patients showed reduced levels of mature PC1, suggesting a broader relevance of impaired PC1 in AF., Conclusions: Impaired PC1 increases in vivo AF inducibility under programmed electrical stimulation and promotes in vitro arrhythmias in hiPSC-aCM and HL-1 cells. Our findings indicate that PC1 protects against DNA damage to reduce AF susceptibility.

Accurate assessment of evapotranspiration (ETa) and crop coefficient (Kc) is crucial for optimizing irrigation practices in water-scarce regions. While satellite-based surface energy balance models offer a promising solution, their application to sparse canopies like apple orchards requires specific validation. This study investigated the spatial and temporal dynamics of ETa and Kc in a drip-irrigated 'Pink Lady' apple orchard under Mediterranean conditions over three growing seasons (2012/13, 2013/14, 2014/15). The METRIC model, incorporating calibrated sub-models for leaf area index (LAI), surface roughness (Z om ), and soil heat flux (G), was employed to estimate ETa and Kc. These estimates were validated against field-scale Eddy Covariance data. Results indicated that METRIC overpredicted Kc and ETa with errors less than 10 %. These findings highlight the potential of the calibrated METRIC model as a valuable decision-making tool for irrigation management in apple orchards., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

In recent years, the sustainable development of agricultural water resources has received much attention. The mismatch between agricultural water distribution patterns, land resources, and socioeconomics threatens food production, especially in vast water-scarce plains. Therefore, monitoring agricultural water spatial equilibrium (AWRSE) is necessary. Based on equilibrium theory and information entropy, in this study, the AWRSE evaluation model is constructed from three aspects: agricultural water resources, land resources, and socioeconomics. In addition, the relationship between social factors with cropping pattern as the primary explanatory variable and AWRSE was examined in conjunction with the extended STIRPAT model and applied to the water-receiving area of the Middle Route of South-to-North Water Diversion Project (MR-SNWDP). The results show that compared with the pre-diversion period, the AWRSE of 75% of the water-receiving cities has been significantly improved by the MR-SNWTP water supply. The MK test z value of the overall regional AWRSE has changed from - 0.328 to - 2.65, and the AWRSE development has shifted from not significantly better to significantly better. The cropping pattern shows a positive response to this development, and this effect can be mitigated in the late stage of water transfer; when the proportion of food crop cultivation increases by 1%, the sub-regional AWRSE value will increase by 0.347%. The evaluation model demonstrates a broad range of inclusiveness and application potential; it provides novel insights for examining agroecological, social, and economic stability., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The integrated health management system (IHMS), which unites all health care-related institutions under a health-centered organizational framework, is of great significance to China in promoting the hierarchical treatment system and improving the new health care reform. China's IHMS policy consists of multiple policies at different levels and at different times; however, there is a lack of comprehensive interpretation and analysis of these policies, which is not conducive to the further development of the IHMS in China., Objective: This study aims to comprehensively analyze and understand the characteristics, development, and evolution of China's IHMS policy to inform the design and improvement of the system., Methods: We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to collect 152 policy documents. With the perspective of policy tools and policy orientation as the core, a comprehensive 6D framework including policy level, policy nature, release time, policy tools, stakeholders, and policy orientation was established by combining the content of policy texts. These dimensions were then analyzed using content analysis., Results: First, we found that, regarding the coordination of policy tools and stakeholders, China's IHMS policy was more inclined to use environment-based policy tools (1089/1929, 56.45%), which suggests a need for further balance in the internal structure of policy tools. Attention to different actors varied, and the participation of physicians and residents needs further improvement (65/2019, 3.22% and 11/2019, 0.54%, respectively). Second, in terms of level differences, Shanghai's IHMS policy used fewer demand-based policy tools (43/483, 8.9%), whereas the national IHMS policy and those of other provinces and cities used fewer supply-based tools (61/357, 17.1% and 248/357, 69.5%, respectively). The national IHMS strategy placed more emphasis on the construction of smart health care (including digital health; 10/275, 3.6%), whereas Shanghai was a leader in the development of healthy community and healthy China (9/158, 5.7% and 4/158, 2.5%, respectively). Third, in terms of time evolution, the various policy tools showed an increasing and then decreasing trend from 2014 to 2021, with relatively more use of environment-based policy tools and less use of demand-based policy tools in the last 3 years. The growth of China's IHMS policy can be divided into 3 stages: the disease-centered period (2014-2017), the e-health technology development period (2017-2019), and the health-centered period (2018-2021)., Conclusions: Policy makers should make several adjustments, such as coordinating policy tools and the uneven relationships among stakeholders; grasping key policy priorities in the context of local characteristics; and focusing on horizontal, multidimensional integration of health resources starting from the community. This study expands the objects of policy research and improves the framework for policy analysis. The findings provide some possible lessons for future policy formulation and optimization., (©Yang Yu, Sufen Wang, Lijue You. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 24.01.2024.)

Non-small cell lung cancer (NSCLC) is a malignant tumor that threatens human life and health. The development of a new NSCLC risk assessment model based on electronic medical records has great potential for reducing the risk of cancer recurrence. In this process, machine learning is a powerful method for automatically extracting risk factors and indicating impact weights for NSCLC deaths. However, when the number of samples reaches a certain value, it is difficult for machine learning to improve the prediction accuracy, and it is also challenging to use the characteristic data of subsequent patients effectively. Therefore, this study aimed to build a postoperative survival risk assessment model for patients with NSCLC that updates the model parameters and improves model accuracy based on new patient data. The model perspective was a combination of particle filtering and parameter estimation. To demonstrate the feasibility and further evaluate the performance of our approach, we performed an empirical analysis experiment. The study showed that our method achieved an overall accuracy of 92% and a recall of 71% for deceased patients. Compared with traditional machine learning models, the accuracy of the model estimated by particle filter parameters has been improved by 2%, and the recall rate for dead patients has been improved by 11%. Additionally, this study outcome shows that this method can better utilize subsequent patients' characteristic data, be more relevant to different patients, and help achieve precision medicine., (© 2023. The Author(s).)

Background: This study aims to examine how big data resources affect the recall of prior medical knowledge by healthcare professionals, and how this differs in environments with and without remote consultation platforms., Method: This study investigated two distinct categories of medical institutions, namely 132 medical institutions with platforms, and 176 medical institutions without the platforms. Big data resources are categorized into two levels-medical institutional level and public level-and three types, namely data, technology, and services. The data are analyzed using SmartPLS2., Results: (1) In both scenarios, shared big data resources at the public level have a significant direct impact on the recall of prior medical knowledge. However, there is a significant difference in the direct impact of big data resources at the institutional level in both scenarios. (2) In institutions with platforms, for the three big data resources (the medical big data assets and big data deployment technical capacity at the medical institutional level, and policies of medical big data at the public level) without direct impacts, there exist three indirect pathways. (3) In institutions without platforms, for the two big data resources (the service capability and big data technical capacity at the medical institutional level) without direct impacts, there exist three indirect pathways., Conclusions: The different interactions between big data, technology, and services, as well as between different levels of big data resources, affect the way clinical doctors recall relevant medical knowledge. These interaction patterns vary between institutions with and without platforms. This study provides a reference for governments and institutions to design big data environments for improving clinical capabilities., (© 2023. The Author(s).)

Atmospheric longwave downward radiation (L d ) is one of the significant components of net radiation (R n ), and it drives several essential ecosystem processes. L d can be estimated with simple empirical methods using atmospheric emissivity (ε a ) submodels. In this study, eight global models for ε a were evaluated, and the best-performing model was calibrated on a global scale using a parametric instability analysis approach. The climatic data were obtained from a dynamically consistent scale resolution of basic atmospheric quantities and computed parameters known as NCEP/NCAR reanalysis (NNR) data. The performance model was evaluated with monthly average values from the NNR data. The Brutsaert equation demonstrated the best performance, and then it was calibrated. The seasonal global trend of the Brutsaert equation calibrated coefficient ranged between 1.2 and 1.4, and the K-means analysis identified five homogeneous zones (clusters) with similar behavior. Finally, the calibrated Brutsaert equation improved the R n estimation, with an error reduction, at the worldwide scale, of 64%. Meanwhile, the error reduction for each cluster ranged from 18 to 77%. Hence, Brutsaert's equation coefficient should not be considered a constant value for use in ε a estimation, nor in time or location., (© 2023. Springer Nature Limited.)

The particulate backscattering coefficient (b bp ) plays an important role in the growth of coral reefs by influencing the light field conditions. Small-scale optically shallow waters are commonly found in coastal fringing reefs, making it challenging to monitor the spatial and temporal patterns accurately using Aqua satellites with a low spatial resolution. In this study, six existing optimization-based algorithms for deriving b bp at 400 nm (b bp (400)) were evaluated with three simulated Landsat-8 (spatial resolution = 30 m) data sets and in situ data from the Luhuitou Peninsula, Sanya. The comparison results indicated that the HOPE (hyperspectral optimization process exemplar) (Fix-H-error or Fix-H-error-free) algorithm which sets an input value of the water depth alone outperformed other algorithms. However, the estimated b bp (400) from all the algorithms tended to be either overestimated and underestimated due to the improper the spectral shape value of the backscattering coefficient. The HOPE (Fix-H-error) algorithm estimated-b bp (400) from in situ reflectance also had a good correlation with the in situ total suspended particle concentrations data derived-b bp (400), with a correlation coefficient of 0.83. Therefore, the HOPE (Fix-H-error) algorithm was selected to estimate the b bp (400) from satellite-based Landsat-8 data of the Luhuitou Peninsula, Sanya. Time-series (2014-2021) results from these Landsat-8 images reveal the seasonal variation of b bp (400). The b bp (400) was low from May to September every year. From October to December or January, b bp (400) had an increasing trend, and then it decreased until May. Spatial analysis indicated that b bp (400) decreased with increasing water depth. The spatial and temporal patterns of b bp (400) were consistent with in situ observations reported in the literature. This study preliminarily showed the efficiency of an optimization-based algorithm in deriving b bp (400) in small-scale optically shallow water region using Landsat-8 data.

In previous studies, adipocytes were found to play an important role in regulating whole-body nutrition and energy balance, and are also important in energy metabolism, hormone secretion, and immune regulation. Different adipocytes have different contributions to the body, with white adipocytes primarily storing energy and brown adipocytes producing heat. Recently discovered beige adipocytes, which have characteristics in between white and brown adipocytes, also have the potential to produce heat. Adipocytes interact with other cells in the microenvironment to promote blood vessel growth and immune and neural network interactions. Adipose tissue plays an important role in obesity, metabolic syndrome, and type 2 diabetes. Dysfunction in adipose tissue endocrine and immune regulation can cause and promote the occurrence and development of related diseases. Adipose tissue can also secrete multiple cytokines, which can interact with organs; however, previous studies have not comprehensively summarized the interaction between adipose tissue and other organs. This article reviews the effect of multi-organ crosstalk on the physiology and pathology of adipose tissue, including interactions between the central nervous system, heart, liver, skeletal muscle, and intestines, as well as the mechanisms of adipose tissue in the development of various diseases and its role in disease treatment. It emphasizes the importance of a deeper understanding of these mechanisms for the prevention and treatment of related diseases. Determining these mechanisms has enormous potential for identifying new targets for treating diabetes, metabolic disorders, and cardiovascular diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Liu, Chen, He, Ma, Liu and Sun.)

Background: Stellate ganglion blockade (SGB) can control ventricular arrhythmias (VAs), but outcomes are unclear. Percutaneous stellate ganglion (SG) recording and stimulation in humans has not been reported., Objective: The purpose of this study was to assess the outcomes of SGB and the feasibility of SG stimulation and recording in humans with VAs., Methods: Two patient cohorts were included-group 1: patients undergoing SGB for drug-refractory VAs. SGB was performed by injection of liposomal bupivacaine. Incidence of VAs at 24 and 72 hours and clinical outcomes were collected; group 2: patients undergoing SG stimulation and recording during VA ablation; a 2-F octapolar catheter was placed at the SG at the C7 level. Recording (30 kHz sampling, 0.5-2 kHz filter) and stimulation (up to 80 mA output, 50 Hz, 2 ms pulse width for 20-30 seconds) was performed., Results: Group 1 included 25 patients [age 59.2 ± 12.8 years; 19 (76%) men] who underwent SGB for VAs. Nineteen patients (76.0%) were free of VA up to 72 hours postprocedure. However, 15 (60.0%) had VAs recurrence for a mean of 5.47 ± 4.52 days. Group 2 included 11 patients (mean age 63 ± 12.7 years; 82.7% men). SG stimulation caused consistent increases in systolic blood pressure. We recorded unequivocal signals with temporal association with arrhythmias in 4 of 11 patients., Conclusion: SGB provides short-term VA control, but has no benefit in the absence of definitive VA therapies. SG recording and stimulation is feasible and may have value to elicit VA and understand neural mechanisms of VA in the electrophysiology laboratory., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Cervical cancer is a female-specific cancer with relatively high morbidity and mortality. As known to all, immune cell infiltrations in the cancer microenvironment are closely related to the cancer diagnosis and prognosis. Here we revealed that the CD8+ T cell infiltration was significantly upregulated in cervical cancer versus normal cervix uteri samples. Through univariate and multivariate cox analyses, we discovered that the CD8+ T cell infiltration was the only independent beneficial factor for the prognosis of cervical cancer. To explore the genes associated with the CD8+ T cell infiltration in cervical cancer, we performed the WGCNA analysis on the differentially expressed genes (DEGs) of cervical cancer versus normal cervix uteri tissues. As a result, 231 DEGs were found to be associated with CD8+ T cell infiltration in cervical cancer. Subsequently, with the Cytoscape analysis, we identified 105 hub genes out of the 231 DEGs. To further explore the genes that might be responsible for the prognosis of cervical cancer, we performed a univariate cox analysis followed by a LASSO assay on the 105 hub genes and located four genes (IGSF6, TLR10, FCRL3, and IFI30) finally. The four genes could be applied to the prediction of the prognosis of cervical cancer, and relatively higher expression of these four genes predicted a better prognosis. These findings contributed to our understanding of the prognostic values of CD8+ T cell infiltration and its associated genes in cervical cancer and thus might benefit future immune-related therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Wang, Li, Wang, Zhao, Liu and Zhu.)

Background: Activating prior medical knowledge in diagnosis and treatment is an important basis for clinicians to improve their care ability. However, it has not been systematically explained whether and how various big data resources affect the activation of prior knowledge in the big data environment faced by clinicians., Objective: The aim of this study is to contribute to a better understanding on how the activation of prior knowledge of clinicians is affected by a wide range of shared and private big data resources, to reveal the impact of big data resources on clinical competence and professional development of clinicians., Method: Through the comprehensive analysis of extant research results, big data resources are classified as big data itself, big data technology and big data services at the public and institutional levels. A survey was conducted on clinicians and IT personnel in Chinese hospitals. A total of 616 surveys are completed, involving 308 medical institutions. Each medical institution includes a clinician and an IT personnel. SmartPLS version 2.0 software package was used to test the direct impact of big data resources on the activation of prior knowledge. We further analyze their indirect impact of those big data resources without direct impact., Results: (1) Big data quality environment at the institutional level and the big data sharing environment at the public level directly affect activation of prior medical knowledge; (2) Big data service environment at the institutional level directly affects activation of prior medical knowledge; (3) Big data deployment environment at the institutional level and big data service environment at the public level have no direct impact on activation of prior knowledge of clinicians, but they have an indirect impact through big data quality environment and service environment at the institutional level and the big data sharing environment at the public level., Conclusions: Big data technology, big data itself and big data service at the public level and institutional level interact and influence each other to activate prior medical knowledge. This study highlights the implications of big data resources on improvement of clinicians' diagnosis and treatment ability., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Background: Downregulation of HLA class I molecules is a major tumor escape mechanism from immune attack. However, its prognostic impact for patients with hepatocellular carcinoma is still unclear. This study aimed to investigate whether HLA class I has prognostic significance in patients with hepatocellular carcinoma., Methods: A cohort of 132 patients with hepatocellular carcinoma was enrolled. HLA class I expression was detected by immunohistochemistry. Levels of HLA class I expression were dichotomized as low and high according to staining intensity or staining percentage of positive tumor cells, respectively. Association of HLA class I expression with clinical characteristics and survival was analyzed., Results: None of the clinical characteristics, including gender, age, virus infection, cirrhosis, AFP, vascular invasion, tumor size and number, was significantly associated with staining percentage of HLA class I or staining intensity (p > 0.05). Low staining percentage of HLA class I was significantly associated with a worse survival (p = 0.011), which was further confirmed by Cox regression hazards model in multivariate analysis (HR 0.416, 95% CI 0.204 - 0.849, p = 0.016). Staining intensity of HLA class I was not significantly associated with survival (p > 0.05)., Conclusions: Expression of HLA class I might be a significant prognostic factor in hepatocellular carcinoma, and downregulation of HLA class I was significantly associated with a worse survival in terms of expression percentage of HLA class I.

Background: The application of big data resources and the development of medical collaborative networks (MCNs) boost each other. However, MCNs are often assumed to be exogenous. How big data resources affect the emergence, development, and evolution of endogenous MCNs has not been well explained., Objective: This study aimed to explore and understand the influence of the mechanism of a wide range of shared and private big data resources on the transaction efficiency of medical services to reveal the impact of big data resources on the emergence and development of endogenous MCNs., Methods: This study was conducted by administering a survey questionnaire to information technology staff and medical staff from 132 medical institutions in China. Data from information technology staff and medical staff were integrated. Structural equation modeling was used to test the direct impact of big data resources on transaction efficiency of medical services. For those big data resources that had no direct impact, we analyzed their indirect impact., Results: Sharing of diagnosis and treatment data (β=.222; P=.03) and sharing of medical research data (β=.289; P=.04) at the network level (as big data itself) positively directly affected the transaction efficiency of medical services. Network protection of the external link systems (β=.271; P=.008) at the level of medical institutions (as big data technology) positively directly affected the transaction efficiency of medical services. Encryption security of web-based data (as big data technology) at the level of medical institutions, medical service capacity available for external use, real-time data of diagnosis and treatment services (as big data itself) at the level of medical institutions, and policies and regulations at the network level indirectly affected the transaction efficiency through network protection of the external link systems at the level of medical institutions., Conclusions: This study found that big data technology, big data itself, and policy at the network and organizational levels interact with, and influence, each other to form the transaction efficiency of medical services. On the basis of the theory of neoclassical economics, the study highlighted the implications of big data resources for the emergence and development of endogenous MCNs., (©Junyi Yuan, Sufen Wang, Changqing Pan. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.04.2022.)

Atrial fibrillation induced stroke accounts for up to 15% of all strokes. These strokes are caused approximately 90% of the time by clot formation in the left atrial appendage (LAA). To prevent these clots, the most common approach is to administer blood thinners. However, contraindications prevent some people from being able to have blood thinners. Devices have been developed to seal the LAA to prevent clot formation in these patients. Current devices, such as the LARIAT® tie off the LAA theoretically preventing blood from entering the LAA. These have had limited clinical success mainly due to failure to completely close the LAA leaving holes and orifices for thrombi to form. To overcome this lack of complete closure, many surgeons use off-label approaches, classically filling the LAA filamentous coils, to cover these holes. Although this usually helps largely cover the holes, placement is challenging, the coils can migrate, the holes are not fully closed as there is space within and around the coils that don't fully mold to the LAA geometry. Furthermore, the coils can develop device related thrombi defeating their purpose. Therefore, these are not fully sufficient to complement the closure techniques in closing the LAA. To address limitation of the closure devices and coil sealing of remaining holes, we developed a thermally responsive hydrogel (Thermogel) that solidifies once injected into the LAA to uniformly and fully close off the LAA thus preventing clot formation and device related thrombi. This Thermogel consists of three portions: 1) a structural component composed of thiolated Pluronic F127 for gel to solid transition following injection, 2) Heparin for anticoagulation, and 3) Dopamine for adhesion to the surrounding endothelium in the turbulent flow encountered in cardiovascular applications. Here we have demonstrated that Thermogel, in conjunction with the LARIAT®, is capable of filling the defects in small and large animals through catheter injection. Thermogel was biocompatible and led to atrophy of the LAA at 5 weeks in a large animal model. Given the advantages of this Thermogel for sealing this defect and ability to be delivered through an endovascular approach, Thermogel presents a viable adjuvant to current occlusion-based treatments for sealing cardiovascular defects., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ennio Tasciotti, Francesca Taraballi, Miguel Valderrabano has patent Thermosensitive Hydrogel Sealing of the Left Atrial Appendage to Prevent Thromboembolism in Atrial Fibrillation pending to Ennio Tasciotti, Francesca Taraballi, Miguel Valderrabano.

Cervical cancer is a serious threat to women's health and lives worldwide. The recovery and survival of cervical cancer can be improved by customizing therapy strategies based on individual-specific gene expression patterns. EFNA1 was reported to be dysregulated in many cancers and associated with their overall survivals, but its prognostic value in cervical cancer is still unclear. In this study, we performed analyses on the single-cell and bulk RNA sequencing data to study the role of EFNA1 in cervical cancer. EFNA1 was found to be significantly upregulated in cervical cancer tissue, especially the cancer cell subgroup within tumors, which was verified by immunohistochemistry. Through Cox regressions, we found that high EFNA1 expression is an independent risk factor for cervical cancer. Nomogram analysis indicated that EFNA1 could be a predicting factor for the survival probabilities of cervical cancer. Gene ontology and pathway analyses showed that EFNA1 was involved in many tumorigenesis pathways, protein, and virus productions. These findings suggested that EFNA1 could be a prognostic biomarker and potential therapeutic target for cervical cancer., (© 2022. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: The non-invasive identification of novel renal fibrosis biomarkers needs to be further studied., Methods: We collected urine samples from 77 biopsy-proven CKD patients and 15 healthy controls. The expression of urinary TREM-1 and TREM-2 was measured and the correlation with renal function parameter and pathological indicators was performed. The receiver operating characteristic (ROC) curve for the diagnosis of renal fibrosis was calculated. The protein expression of TREM-1 and TREM-2 in kidney tissues was measured., Results: The TREM-1/TREM-2 ratio was decreased in CKD patients and correlated with serum creatinine, estimated glomerular filtration rate and cystatin c. Further, the TREM-1/TREM-2 ratio was significantly decreased in moderate-severe fibrosis patients compared with none-mild renal fibrosis. TREM-1/TREM-2 ratio was correlated with the score of tubulointerstitial fibrosis (TIF) and the score of glomerular sclerosis. The ROC curve showed that the urinary TREM-1/TREM-2 ratio can diagnosemoderate-severe renal fibrosis at a cut-off value of 1.338 with a sensitivity of 86.4% and specificity of 81.8%. In human moderate-severe fibrosis kidney tissue, the protein expression of TREM-1 was lower and the TREM-2 was higher than none-mild fibrosis kidney tissue., Conclusion: Urinary TREM-1/TREM-2 ratio was a potential biomarker for the diagnosis of renal fibrosis in CKD patients.

Background: Venous ethanol ablation (VEA) is effective for treatment of left ventricular (LV) summit (LVS) arrhythmias. The LVS venous anatomy is poorly understood and has inconsistent nomenclature., Objective: The purpose of this study was to delineate the LVS venous anatomy by selective venography and 3-dimensional (3D) mapping during VEA and by venous-phase coronary computed tomographic angiography (vCTA)., Methods: We analyzed (1) LVS venograms and 3D maps of 53 patients undergoing VEA; and (2) 3D reconstructions of 52 vCTAs, tracing LVS veins., Results: Angiography identified the following LVS veins: (1) LV annular branch of the great cardiac vein (GCV) (19/53); (2) septal (rightward) branches of the anterior ventricular vein (AIV) (53/53); and (3) diagonal branches of the AIV (51/53). Collateral connections between LVS veins and outflow, conus, and retroaortic veins were common. VEA was delivered to target arrhythmias in 38 of 53 septal, 6 of 53 annular, and 2 of 53 diagonal veins. vCTA identified LVS veins (range 1-5) in a similar distribution. GCV-AIV transition could either form an angle close to the left main artery bifurcation (n = 16; 88° ± 13°) or cut diagonally (n = 36; 133°±12°) (P ≤.001). Twenty-one patients had LV annular vein. In 28 patients only septal LVS veins were visualized in vCTA, in 2 patients only diagonal veins and in 22 patients both septal and diagonal veins were seen. In 39 patients the LVS veins reached the outflow tracts and their vicinity., Conclusion: We provide a systematic atlas and nomenclature of LVS veins related to arrhythmogenic substrates. vCTA can be useful for noninvasive evaluation of LVS veins before ethanol ablation., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Variability of soil properties within large-scale fields not only exists in the horizontal domain, but also in the vertical direction, causing spatial variability in yield. Three yield zones were delineated based on measured yield in 2017 and 2018 within a large field in northwest China. The Soil Water Heat Carbon Nitrogen Simulator (WHCNS) model was calibrated and used to simulate yield, nitrogen uptake (N u ), water use efficiency (WUE), fertilizer N (nitrogen) use efficiency (FNUE), deep percolation (DP), nitrate leaching (NL) and residual nitrate (RN) at each sampling point in different yield zones. Based on the simulations, there were significant differences in N u , WUE, FNUE, DP, NL and RN in 0-100 cm and 100-160 cm soil layers among the three yield zones. DP, NL and RN in the layers were strongly determined by the interaction of zone and year (p < 0.05), thus yielding consistent patterns mainly determined by soil properties and meteorological factors. The modelled ranges of DP, NL, and RN (0-160 cm) were 25-119 mm, 15-94 kg ha -1 , and 178-476 kg·ha -1 respectively, across the field. Soil texture in the maize main root zone (0-100 cm) has a great influence on yield and N u , and in the 100-160 cm layer upon DP and NL. RN was abundant after harvest and should be taken into account to determine the nitrogen fertilization demand for the following crop. The study showed that the process of delineating zones can be based on historical yield, making it feasibly easier than mapping soil properties. In view of the fact that there were large losses of water and nitrogen with uniform irrigation and fertilization management, the effects of vertically variable soil properties should be considered in future precision agriculture research, to achieve higher economic benefits and utilization efficiency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Globally, agriculture is by far the largest water consuming sector and in areas where water is scarce, the spatial optimization of crop water consumption used to improve irrigation benefits becomes critical for regional water management. The spatial heterogeneity of environmental parameters brings great challenge to spatial optimization. Therefore, cellular automaton (CA), crop suitability (CS), spatial distributed crop water consumption model and optimization model were integrated and applied on the middle reaches of Heihe River basin, northwest of China. The cellular automata based Water Consumption Optimization (CA-WCSO) model is not only a spatial dynamic optimization model for crop water consumption, but also a decision support tool that reflects the interaction between water consumption at field level and management regulations at regional level. Six optimization paths: i) forward progressive (FP), ii) forward interlacing (F-IL), iii) forward interpolation (F-IP), iv) reverse progressive (R-P), v) reverse interlacing (R-IL) and vi) reverse interpolation (R-IP) of crop water consumption for the baseline year and the planning year were applied on the study site. Results for baseline year (2015) demonstrate that the six optimization paths can slightly reduce the water consumption (>1.4%) but significantly improve the irrigation benefits of the region by 20.56%. Using CA-WCSO model, decision makers can modify model's constraints and select appropriate optimization path to get the optimized crop planting patterns and make future regional water allocation plans., Competing Interests: Declaration of competing interest All authors declare no competing financial interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: NS5806 activates the transient outward potassium current I to , and has been claimed to reproduce Brugada Syndrome (BrS) in ventricular wedge preparations. I to modulates excitation-contraction coupling, which is critical in alternans dynamics. We explored NS5806-arrhythmogenic effects in the intact whole heart and its impact on alternans. Methods: Langendorff-perfused rabbit hearts ( n = 20) underwent optical AP and Ca mapping during pacing at decremental cycle lengths (CL). Spontaneous arrhythmias and pacing-induced alternans was characterized at baseline (BL), after perfusing with NS5806, before and after adding verapamil (VP), and SEA0400 (SEA, n = 5 each), to modulate Ca-current and Na-Ca exchange, the main AP-Ca coupling mechanisms. Results: NS5806 induced BrS-like ECG features in 6 out of 20 hearts. NS5806 prolonged steady-state (3 Hz) action potential duration (APD) by 16.8%, Ca decay constant by 34%, and decreased conduction velocity (CV) by 52.6%. After NS5806 infusion, spontaneous ventricular ectopy (VE) and AP/Ca alternans occurred. Pacing-induced alternans during NS5806 infusion occurred at longer CL and were AP/Ca discordant from its onset. Spatially discordant alternans after NS5806 infusion had non-propagation-driven nodal line distribution. No spontaneous phase-2 reentry occurred. Under NS5806 + VP, alternans became AP/Ca concordant and only induced in two out of five; NS5806 + SEA did not affect alternans but suppressed spontaneous ectopy. Conclusions: NS5806 disrupts AP-Ca coupling and leads to Ca-driven, AP/Ca-discordant alternans and VE. Despite BrS-like ECG features, no spontaneous sustained arrhythmias or phase-2 reentry occurred. NS5806 does not fully reproduce BrS in the intact rabbit heart., (Copyright © 2019 Wang, Rodríguez-Mañero, Ibarra-Cortez, Kreidieh, Valderrábano, Hemam, Tavares, Blanco and Valderrábano.)

Background: Renal fibrosis is a common outcome of all pathological types of chronic kidney disease (CKD). However, the noninvasive detection of renal fibrosis remains a challenge., Methods: We collected urine samples from 154 biopsy-proven IgA nephropathy (IgAN) patients and 61 healthy controls. The expression of mTOR was measured and the correlation with renal function parameter and pathological indicators. The receiver operating characteristic (ROC) curve for the diagnosis of IgAN and renal fibrosis was calculated., Results: The urinary mammalian target of rapamycin (mTOR) expression was decreased in IgAN patients. The expression of mTOR was correlated with serum creatinine, blood urea nitrogen, estimated glomerular filtration rate, 24 h proteinuria, and cystatin C. Further, the urinary mTOR expression was significantly decreased in severe renal fibrosis patients compared with mild or moderate renal fibrosis patients. Urinary mTOR expression was correlated with score of tubulointerstitial fibrosis (TIF) and score of glomerular sclerosis. The ROC curve showed that mTOR can diagnose IgAN at a cut-off value of 0.930 with the sensitivity of 90.2% and specificity of 73.8% and renal fibrosis at a cut-off value of 0.301 with the sensitivity of 71.7% and specificity of 64.8%., Conclusion: Urinary mTOR mRNA expression was a potential biomarker for diagnosis of IgAN and renal fibrosis in IgAN patients., Competing Interests: The authors declare that they have no conflicts of interest.

A time series of satellite data on Chlorophyll-a concentration (Chl-a) that used ocean color was studied to determine mechanisms of phytoplankton variation in recent decade in the Yellow Sea, China during 2003-2015. The variability patterns on seasonal and inter-annual oscillation periods were confirmed using the Empirical Orthogonal Function (EOF), and Morlet wavelet transform analyses, respectively. The first EOF mode for Chl-a was dominated by obvious spring and fall blooms in a spatial pattern that was related to the strong mixing of the water masses from the Yellow Sea Cold Warm Mass (YSCWM) and the Yellow Sea Warm Current (YSWC) in winter. The second EOF mode for Chl-a showed an opposite spatial pattern between the northern and southern regions. The temporal coefficient showed differences in the timing of blooms. On an inter-annual scale, Chl-a indicated variation at periods of 2-4 years during 2003-2015. Chl-a showed a significantly negative correlation with the sea surface temperature (r = -0.21, p<0.01), with time lags of 4 months (Chl-a ahead). Chl-a was coupled with El Niño Southern Oscillation (ENSO) events, with a positive correlation (r = 0.46, p<0.01) at a lag of 3-5 months (ENSO ahead). The present study demonstrated that the variation in phytoplankton biomass was controlled primarily by water mass seasonally, and it was influenced by ENSO events on an inter-annual scale., Competing Interests: The authors have declared that no competing interests exist.

Background The autonomic nervous system response to apnea and its mechanistic connection to atrial fibrillation (AF) are unclear. We hypothesize that sensory neurons within the ganglionated plexi (GP) play a role. We aimed to delineate the autonomic response to apnea and to test the effects of ablation of cardiac sensory neurons with resiniferatoxin (RTX), a neurotoxic TRPV1 (transient receptor potential vanilloid 1) agonist. Methods Sixteen dogs were anesthetized and ventilated. Apnea was induced by stopping ventilation until oxygen saturations decreased to 80%. Nerve recordings from bilateral vagal nerves, left stellate ganglion, and anterior right GP were obtained before and during apnea, before and after RTX injection in the anterior right GP (protocol 1, n=7). Atrial effective refractory period and AF inducibility on single extrastimulation were assessed before and during apnea, and before and after intrapericardial RTX administration (protocol 2, n=9). GPs underwent immunohistochemical staining for TRPV1. Results Apnea increased anterior right GP activity, followed by clustered crescendo vagal bursts synchronized with heart rate and blood pressure oscillations. On further oxygen desaturation, a tonic increase in stellate ganglion activity and blood pressure ensued. Apnea-induced effective refractory period shortening from 110.20±31.3 ms to 90.6±29.1 ms ( P<0.001), and AF induction in 9/9 dogs versus 0/9 at baseline. After RTX administration, increases in GP and stellate ganglion activity and blood pressure during apnea were abolished, effective refractory period increased to 126.7±26.9 ms ( P=0.0001), and AF was not induced. Vagal bursts remained unchanged. GP cells showed cytoplasmic microvacuolization and apoptosis. Conclusions Apnea increases GP activity, followed by vagal bursts and tonic stellate ganglion firing. RTX decreases sympathetic and GP nerve activity, abolishes apnea's electrophysiological response, and AF inducibility. Sensory neurons play a role in apnea-induced AF.

Background: The aim of the study is to investigate whether programmed death ligand l (PD-L1) on tumor cells has prognostic significance in patients with hepatocellular carcinoma., Methods: A cohort of 143 patients with hepatocellular carcinoma was enrolled. PD-L1 expression was detected by immunohistochemistry. The association of PD-L1 expression with clinical characteristics and survival was analyzed., Results: PD-L1 positive rate in our study was 13.3% (19/143). None of clinical characteristics, including gender, age, virus infection, AFP, vascular invasion, tumor size, and number, was significantly associated with PD-L1 expression (p > 0.05). PD-L1 expression was significantly associated with cirrhosis (p = 0.016). PD-L1 expression was not significantly associated with survival (Log-rank p = 0.076; HR: 0.363 p = 0.091)., Conclusions: PD-L1 expression failed to have a markedly significant prognostic association with survival in patients with hepatocellular carcinoma.

Objective: Sympathetic predominance and ventricular repolarization abnormalities represent epilepsy-associated cardiac alterations and may underlie seizure-induced ventricular arrhythmias. Myocardial ion channel and electrical remodeling have been described early in epilepsy development and may contribute to ventricular repolarization abnormalities and excitability. Using the pilocarpine-induced acquired epilepsy model we sought to examine whether altered myocardial ion channel levels and electrophysiological changes also occur in animals with long-standing epilepsy., Methods: We examined myocardial adrenergic receptor and ion channel protein levels of epileptic and age-matched sham rats (9-20 months old) using western blotting. Cardiac electrical properties were examined using optical mapping ex vivo and electrophysiology in vivo. We investigated the propensity for ventricular tachycardia (VT) and the effects of β-adrenergic blockade on ventricular electrical properties and excitability in vivo., Results: In animals with long-standing epilepsy, we observed decreased myocardial voltage-gated K + channels Kv 4.2 and Kv 4.3 , which are known to underlie early ventricular repolarization in rodents. Decreased β1 and increased α1 A adrenergic receptor protein levels occurred in the myocardium of chronically epileptic animals consistent with elevated sympathetic tone. These animals exhibited many cardiac electrophysiological abnormalities, represented by longer QRS and corrected QT (QTc) intervals in vivo, slower conduction velocity ex vivo, and stimulation-induced VT. Administration of a β-adrenergic antagonist late in epilepsy was beneficial, as the therapy shortened the QTc interval and decreased stimulation-induced VT., Significance: Our findings demonstrate that myocardial ion channel remodeling and sympathetic predominance, risk factors for increased ventricular excitability and arrhythmias, persist in chronic epilepsy. The beneficial effects of β-adrenergic antagonist treatment late in the course of epilepsy suggest that attenuating elevated sympathetic tone may represent a therapeutic target for ameliorating epilepsy-associated cardiac morbidity.

Pharmacological therapies for cardiovascular diseases are limited by short-term pharmacokinetics and extra-cardiac adverse effects. Improving delivery selectivity specifically to the heart, wherein therapeutic drug levels can be maintained over time, is highly desirable. Nanoparticle (NP)-based pericardial drug delivery could provide a strategy to concentrate therapeutics within a unique, cardiac-restricted compartment to allow sustained drug penetration into the myocardium. Our objective was to explore the kinetics of myocardial penetration and retention after pericardial NP drug delivery. Fluorescently-tagged poly(lactic-co-glycolic acid) (PLGA) NPs were loaded with BODIPY, a fluorophore, and percutaneously administered into the pericardium via subxiphoid puncture in rabbits. At distinct timepoints hearts were examined for presence of NPs and BODIPY. PLGA NPs were found non-uniformly distributed on the epicardium following pericardial administration, displaying a half-life of ~2.5days in the heart. While NPs were mostly confined to epicardial layers, BODIPY was capable of penetrating into the myocardium, resulting in a transmural gradient. The distinct architecture and physiology of the different regions of the heart influenced BODIPY distribution, with fluorophore penetrating more readily into atria than ventricles. BODIPY proved to have a long-term presence within the heart, with a half-life of ~7days. Our findings demonstrate the potential of utilizing the pericardial space as a sustained drug-eluting reservoir through the application of nanoparticle-based drug delivery, opening several exciting avenues for selective and prolonged cardiac therapeutics., (Copyright © 2017 Elsevier B.V. All rights reserved.)

N-myc downstream-regulated gene 3 (NDRG3), which belongs to the NDRG family, is believed to play important roles in human cancer. In this present study, one-step quantitative reverse transcription-polymerase chain reaction (qPCR) and western blotting tests with 10 fresh-frozen laryngeal squamous cell carcinoma (LSCC) samples and immunohistochemistry (IHC) analysis in 109 LSCC cases were performed to investigate the relationship between NDRG3 expression and the clinicopathological characteristics of LSCC. Results demonstrated that NDRG3 mRNA and protein expression levels were statistically higher in LSCC tissues than that in non-cancerous tissues (all p<0.05). IHC data showed that the NDRG3 protein expression was remarkably correlated with lymph node metastasis (p=0.043). Univariate and multivariate survival analysis implied that high NDRG3 expression (p=0.004), lymph node metastasis (p=0.044) and TNM stage (p=0.020) were independently associated with the unfavourable overall survival of patients with LSCC. The above findings suggested that NDRG3 may be identified as a novel biomarker predicting the prognosis of LSCC., (Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Three patients' medical history, clinical manifestation, imaging characteristic, therapy and prognosis of calvaria metastasis from follicular thyroid carcinoma (FTC) in our hospital were retrospectively analyzed by reviewing medical literature. In case one, the tumor in frontal bone and fossa orbital was total resected, no further treatment was performed, the patient gave up on therapy and died of extensive metastasis at 22 months after the initial operation. In case two, the tumor in parietal and occipital bone was total resected, the subtotal resection of bilateral thyroid gland and isthmus was performed and combined with therapy of Levothyroxine and (131)I radio-iodine therapy, no evidence of tumor recurrence at 30 months after the primary operation. In case three, the tumor in occipital bone was gross total resected, total resection of bilateral thyroid gland and clearance of lymph node was performed after two months, adjunctive therapy with Levothyroxine, (131)I radio-iodine and skull radiotherapy, no evidence of tumor recurrence at 21 months after the primary operation. Correct diagnosis of calvaria metastasis from FTC preoperative is difficult because it's rarity, patients can survive for years after synthetic therapy including total resection of metastatic tumor, radical operation of thyroid carcinoma, adjunctive therapy of Levothyroxine, (131)I radio-iodine and skull radiotherapy.

Modelling crop evapotranspiration (ET) response to different planting scenarios in an irrigation district plays a significant role in optimizing crop planting patterns, resolving agricultural water scarcity and facilitating the sustainable use of water resources. In this study, the SWAT model was improved by transforming the evapotranspiration module. Then, the improved model was applied in Qingyuan Irrigation District of northwest China as a case study. Land use, soil, meteorology, irrigation scheduling and crop coefficient were considered as input data, and the irrigation district was divided into subdivisions based on the DEM and local canal systems. On the basis of model calibration and verification, the improved model showed better simulation efficiency than did the original model. Therefore, the improved model was used to simulate the crop evapotranspiration response under different planting scenarios in the irrigation district. Results indicated that crop evapotranspiration decreased by 2.94% and 6.01% under the scenarios of reducing the planting proportion of spring wheat (scenario 1) and summer maize (scenario 2) by keeping the total cultivated area unchanged. However, the total net output values presented an opposite trend under different scenarios. The values decreased by 3.28% under scenario 1, while it increased by 7.79% under scenario 2, compared with the current situation. This study presents a novel method to estimate crop evapotranspiration response under different planting scenarios using the SWAT model, and makes recommendations for strategic agricultural water management planning for the rational utilization of water resources and development of local economy by studying the impact of planting scenario changes on crop evapotranspiration and output values in the irrigation district of northwest China.

Background: The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca(2+) leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca(2+) release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms., Methods and Results: CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca(2+) release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca(2+)/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca(2+) release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca(2+)-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice., Conclusions: RyR2-mediated SR Ca(2+) leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca(2+) release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.

Nutrient restriction (NR) prolongs longevity via enhanced mitochondrial function. We tested the hypothesis that NR enhances resistance to ischemia/reperfusion (IR) arrhythmias via preserved calcium (Ca) cycling and mitochondrial function. We examined the protective effects of NR on regional IR in cultured neonatal rat ventricular myocyte monolayers. Optical mapping of intracellular Ca and mitochondrial membrane potential Δψ(m) was performed using Rhod 2-AM and TMRE, respectively. Regional ischemia was mimicked by covering a portion of monolayer with a glass coverslip until loss of Ca propagation, and reperfusion was mimicked by removing the coverslip. NR was mimicked by culture in serum- and glucose-free medium for 24 h. Relative to controls, NR monolayers: (1) sustained Ca oscillations during longer periods of ischemia (19.2 ± 1.8 min vs 10.4 ± 1.4 min, p<0.001); (2) had attenuated increases in Ca transient duration (CaD) and time decay constant (Tau) during ischemia; (3) had preserved conduction velocity (CV) during early reperfusion, leading to protection against reperfusion arrhythmias; (4) had minimal "rebound" decreased CaD and Tau during reperfusion; and (5) had no depolarization of Δψ(m) during IR. NR attenuates IR arrhythmias via (1) stable calcium cycling and (2) prevention of Δψ(m) depolarization during IR. Enhanced mitochondrial resistance to IR arrhythmias may play a role in NR-induced longevity prolongation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Prognosis of patients with gastric cancer (GC) is generally poor due to the lack of non-invasive tools for GC detection. The purpose of present study was to identify a serum microRNA (miRNA) expression profile that can serve as a novel diagnostic biomarker for GC detection and to assess its clinical applications in monitoring disease progression., Methods: Serum samples were taken from 164 GC patients and 127 age- and gender-matched tumour-free controls. An initial screening of miRNA expression by Solexa sequencing was performed using serum samples pooled from 20 patients and 20 controls, respectively. Differential expression was validated using hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in individuals samples, the samples were arranged in two phases., Results: The Solexa sequencing results demonstrated that 19 serum miRNAs were markedly upregulated in the GC patients compared to the controls. The qRT-PCR analysis further identified a profile of five serum miRNAs (miR-1, miR-20a, miR-27a, miR-34 and miR-423-5p) as a biomarker for GC detection. The analysis results showed that the expression level of five serum miRNAs was correlated to tumour stage. The areas under the receiver operating characteristic (ROC) curve of this five-serum miRNA signature were 0.879 (95% confidence interval (CI) 0.822-0.936) and 0.831 (95% CI 0.767-0.898) for the two sets of serum samples, respectively, markedly higher than those of the biomarkers carcinoembryonic antigen (CEA) (0.503) and carbohydrate antigen 19-9 (CA19-9) (0.600)., Conclusions: We identified five-miRNA signature for GC diagnosis by genome-wide serum miRNA expression profiling. Expression levels of this serum miRNA-based biomarker also indicate tumour progression stages., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome. The aim of this study was to determine whether a gain-of-function mutation in RyR2 increases the propensity to cardiac arrhythmias and sudden death in young mice., Methods and Results: Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in RyR2 (R176Q/+). Young R176Q/+ mice exhibited a higher incidence of sudden death compared with wild-type littermates. Optical mapping of membrane potentials and intracellular calcium in 1- to 7-day-old R176Q/+ and wild-type mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3- to 10-day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias after provocation with epinephrine and caffeine. Intracardiac pacing studies in 12- to 18-day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with wild-type mice. Reverse transcription-polymerase chain reaction and Western blotting showed that expression levels of other calcium handling proteins were unaltered, suggesting that calcium leak through mutant RyR2 underlies arrhythmogenesis and sudden death in young R176Q/+ mice., Conclusions: Our findings demonstrate that a gain-of-function mutation in RyR2 confers an increased risk of cardiac arrhythmias and sudden death in young mice and that young R176Q/+ mice may be used as a model for elucidating the complex interplay between genetic and environmental risk factors associated with sudden infant death syndrome.

A trial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca2+ handling. Diastolic Ca2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice. Rapid atrial pacing resulted in increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2, while both pharmacologic and genetic inhibition of CaMKII prevented AF inducibility in Ryr2R176Q/+ mice. This result suggests that AF requires both an arrhythmogenic substrate (e.g., RyR2 mutation) and enhanced CaMKII activity. Increased CaMKII phosphorylation of RyR2 was observed in atrial biopsies from mice with atrial enlargement and spontaneous AF, goats with lone AF, and patients with chronic AF. Genetic inhibition of CaMKII phosphorylation of RyR2 in Ryr2S2814A knockin mice reduced AF inducibility in a vagotonic AF model. Together, these findings suggest that increased RyR2-dependent Ca2+ leakage due to enhanced CaMKII activity is an important downstream effect of CaMKII in individuals susceptible to AF induction.

In unexcitable, noncardiac cells, ultrashort (nanosecond) high-voltage (megavolt-per-meter) pulsed electrical fields (nsPEF) can mobilize intracellular Ca2+ and create transient nanopores in the plasmalemma. We studied Ca2+ responses to nsPEF in cardiac cells. Fluorescent Ca2+ or voltage signals were recorded from isolated adult rat ventricular myocytes deposited in an electrode microchamber and stimulated with conventional pulses (CPs; 0.5-2.4 kV/cm, 1 ms) or nsPEF (10-80 kV/cm, 4 ns). nsPEF induced Ca2+ transients in 68/104 cells. Repeating nsPEF increased the likelihood of Ca2+ transient induction (61.8% for <10 nsPEF vs. 80.6% for > or =10 nsPEF). Repetitive Ca2+ waves arising at the anodal side and Ca2+ destabilization occurred after repeated nsPEF (12/29) or during steady-state single nsPEF delivery at 2 Hz. Removing extracellular Ca2+ abolished responses to nsPEF. Verapamil did not affect nsPEF-induced Ca2+ transients, but decreased responses to CP. Tetrodotoxin and KB-R7943 increased the repetition threshold in response to nsPEF: 1-20 nsPEF caused local anodal Ca2+ waves without Ca2+ transients, and > or =20 nsPEF caused normal transients. Ryanodine-thapsigargin and caffeine protected against nsPEF-induced Ca2+ waves and showed less recovery of diastolic Ca2+ levels than CP. Voltage recordings demonstrated action potentials triggered by nsPEF, even in the presence of tetrodotoxin. nsPEF can mobilize intracellular Ca2+ in cardiac myocytes by inducing action potentials. Anodal Ca2+ waves and resistance to Na+ and Ca2+ channel blockade suggest nonselective ion channel transport via sarcolemmal nanopores as a triggering mechanism.

Objective: To investigate whether sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition attenuates myocardial injury during resuscitation from ventricular fibrillation through effects on energy metabolism, using an open-chest pig model in which coronary perfusion was controlled by extracorporeal circulation., Design: Randomized controlled animal study., Setting: University research laboratory., Subjects: Male domestic pigs., Interventions: Ventricular fibrillation was electrically induced and left untreated for 8 mins, after which extracorporeal circulation was started and its flow adjusted to maintain a coronary perfusion pressure of 10 mm Hg. After 10 mins of extracorporeal circulation, restoration of spontaneous circulation was attempted by epicardial defibrillation and gradual reduction in extracorporeal flow. Two groups of eight pigs each were randomized to receive the NHE-1 inhibitor zoniporide (3 mg.kg-1) or vehicle control immediately before starting extracorporeal circulation., Measurements and Main Results: Identical extracorporeal flows (approximately = 9% of baseline cardiac index) were required in zoniporide and control groups to attain the target coronary perfusion pressure, resulting in comparable left anterior descending coronary artery blood flow (9 +/- 1 and 10 +/- 1 mL.min-1) and resistance (0.10 +/- 0.01 and 0.10 +/- 0.01 dyne.sec.cm(-5)). Yet zoniporide prevented reductions in left ventricular volume and wall thickening while favoring higher myocardial creatine phosphate to creatine ratios (0.14 +/- 0.03 vs. 0.06 +/- 0.01, p < .05), lower myocardial adenosine (0.7 +/- 0.1 vs. 1.3 +/- 0.2, p < .05), and lower myocardial lactate (80 +/- 9 vs. 125 +/- 6 mmol.kg-1, p < .001). Postresuscitation, zoniporide-treated pigs had higher left ventricular ejection fraction (0.57 +/- 0.07 vs. 0.29 +/- 0.05, p < .05) and higher cardiac index (4.8 +/- 0.4 vs. 3.4 +/- 0.2 L.min-1.m-2, p < .05)., Conclusions: Zoniporide ameliorated myocardial injury during resuscitation from ventricular fibrillation through beneficial effects on energy metabolism without effects on coronary vascular resistance and coronary blood flow., ((C) 2007 Lippincott Williams & Wilkins, Inc.)

Background: intracellular Na+ accumulation during ischemia and reperfusion leads to cytosolic Ca2+ overload through reverse-mode operation of the sarcolemmal Na+ -Ca2+ exchanger. Cytosolic Ca2+ accumulation promotes mitochondrial Ca2+ (Ca2+ m) overload, leading to mitochondrial injury. We investigated whether limiting sarcolemmal Na+ entry during resuscitation from ventricular fibrillation (VF) attenuates Ca2+ m overload and lessens myocardial dysfunction in a rat model of VF and closed-chest resuscitation., Methods: hearts were harvested from 10 groups of 6 rats each representing baseline, 15 min of untreated VF, 15 min of VF with chest compression given for the last 5 min (VF/CC), and 60 min postresuscitation (PR). VF/CC and PR included four groups each randomized to receive before starting chest compression the new NHE-1 inhibitor AVE4454B (1.0 mg/kg), the Na+ channel blocker lidocaine (5.0 mg/kg), their combination, or vehicle control. The left ventricle was processed for intracellular Na+ and Ca2+ m measurements., Results: limiting sarcolemmal Na+ entry attenuated cytosolic Na+ increase during VF/CC and the PR phase and prevented Ca2+ m overload yielding levels that corresponded to 77% and 71% of control hearts at VF/CC and PR, without differences among specific Na+ -limiting interventions. Limiting sarcolemmal Na+ entry attenuated reductions in left ventricular compliance during VF and prompted higher mean aortic pressure (110 +/- 7 vs. 95 +/- 11 mmHg, P < 0.001) and higher cardiac work index (159 +/- 34 vs. 126 +/- 29 g x m x min(-1) x kg(-1), P < 0.05) with lesser increases in circulating cardiac troponin I at 60 min PR., Conclusions: Na+ -limiting interventions prevented excess Ca2+ m accumulation induced by ischemia and reperfusion and ameliorated myocardial injury and dysfunction.

Human recombinant erythropoietin (rhEPO) can protect the myocardium during ischemia and reperfusion. We investigated whether rhEPO could ameliorate previously identified functional myocardial abnormalities that develop during resuscitation from cardiac arrest, using a rat model of ventricular fibrillation (VF) and closed-chest resuscitation. VF was electrically induced and maintained, untreated, for 10 minutes. Chest compression and ventilation were then started and electrical defibrillation was attempted 8 minutes later. Rats were randomized to receive rhEPO (5000 U/kg) in the right atrium at baseline, 15 minutes before induction of VF (rhEPOBL -15-min), or at 10 minutes of VF, immediately before the start of chest compression (rhEPOVF 10-min), or to receive 0.9% NaCl solution instead (control). rhEPO given at the time of resuscitation (rhEPOVF 10-min group) -- but not at baseline -- prompted more effective chest compression, yielding higher coronary perfusion pressures for a given compression depth (1.95 +/- 0.27 mm Hg/mm; P < 0.05 in comparison with rhEPOBL -15-min [1.63 +/- 0.23 mm Hg/mm] and control [1.62 +/- 0.26 mm Hg/mm], by Dunnett's multicomparison method). Post-resuscitation, rats in the rhEPOVF 10-min group displayed higher mean aortic pressure associated with numerically higher cardiac index, stroke work index, and systemic vascular resistance index. rhEPO may rapidly induce myocardial protection during resuscitation from cardiac arrest.

Ca(2+) overload and reactive oxygen species can injure mitochondria during ischemia and reperfusion. We hypothesized that mitochondrial injury occurs during cardiac resuscitation, causing release of cytochrome c to the cytosol and bloodstream while activating apoptotic pathways. Plasma cytochrome c was measured using reverse-phase HPLC and Western immunoblotting in rats subjected to 4 or 8 min of untreated ventricular fibrillation and 8 min of closed-chest resuscitation followed by 240 min of postresuscitation hemodynamic observation. A sham group served as control. Plasma cytochrome c rose progressively to levels 10-fold higher than in sham rats 240 min after resuscitation (P < 0.01), despite reversal of whole body ischemia (decreases in arterial lactate). Cytochrome c levels were inversely correlated with left ventricular stroke work (r = -0.40, P = 0.02). Western immunoblotting of left ventricular tissue demonstrated increased levels of 17-kDa cleaved caspase-3 fragments in the cytosol. Plasma cytochrome c was then serially measured in 12 resuscitated rats until the rat died or cytochrome c returned to baseline. In three survivors, cytochrome c rose slightly to

Objective: To compare the hemostatic effect of Flos Sophorae in crude, parched and carbonized forms and its extracts, including rutin, quercetin and tannin., Methods: All the testing samples were orally administered to the experimental animals for 5 days, then the bleeding time (BT), coagulation time (CT), platelet count and capillary permeability (CP) in the treated mice were tested, and the prothrombin time (PT), fibrinogen (FBG) content and platelet aggregation rate (PAR) in the treated rats were determined., Results: All the samples could lower the CP, BT and CT in mice and also decrease the plasma PT in rats. All three forms of Flos Sophorae could increase FBG in rats, while the three extracts of it could inhibit the PAR in rats obviously. In addition, rutin had the effect of raising the platelet count., Conclusion: All the three forms and three extracts of Flos Sophorae have hemostatic effect, the effect of parched and carbonized form is higher than that of crude drug. The mechanism of the hemostatic effect of the six kinds of sample might be various.

A new kind of amphiphilic derivative of carboxymethylchitosan, a group of (2-hydroxyl-3-butoxyl)propylcarboxymethylchitosans (HBP-CMCHS), has been synthesized, and the surface and aggregate properties have been studied by means of surface tension, surface pressure and fluorescence measurements. HBP-CMCHS can adsorb on the surface to decrease the surface tension of the solution. The adsorption film was quite stable, which can make the relative compressed pressure increase dramatically with the decrease of the surface area. In solution, hydrophobic aggregations were identified by the decrease in the ratio of the fluorescence emission intensity of the first and third pyrene vibronic peaks ( I(1)/ I(3)). Results showed that the aggregation began to form at a concentration similar to that of the polymer transfer to the air-water interface. Aggregate formation of the polymers is a gradually compact process with hydrophobic associations. Increase of DS and addition of NaCl to the HBP-CMCHS solution can make the surface tension decrease, make the aggregation occur at lower concentration, and make the aggregation more hydrophobic.

Mitoxantrone (MXT), an anti-tumor antibiotic, shows irreversible electrochemical behavior at a waxed graphite electrode in a 0.05 M Tris-HCl buffer (pH 7.4) solution. The interaction between MXT and calf thymus DNA (ctDNA) in solution has been studied using cyclic voltammetry. An electrochemical equation suitable for examining the binding of irreversibly electroactive molecules to DNA is established. Determination of diffusion coefficients of both free and binding MXT (D(f), D(b)), the binding constant (K) and binding site size (s base pairs per molecule, bp) of MXT with DNA was performed on the basis of the equation. A nonlinear fit analysis of the experimental data yielded: D(f)=3.76 x 10(-5) cm(2)s(-1), D(b)=2.73 x 10(-7) cm(2)s(-1), K=8.7 x 10(9) cm(3)mol(-1), s=2.8 bp. The results demonstrate that MXT binds tightly to ctDNA and covers three base pairs. The anthraquinone of MXT, which is a planar heterocyclic ring, intercalates between the DNA's base pairs. The two aminoethylamino side-chains of the drug fit to the major groove reinforce the combination of MXT and DNA. The results show that MXT is a DNA intercalator with a high binding constant compared to those of other anthraquinones.

A rapid method for investigation of the interaction of DNA and electroactive ligands based on an electrochemical equation for irreversible processes is presented. The binding constant (K) and the size of binding site (s) are simultaneously obtained from the dependence of the current on the amount of added DNA in voltammetry. A non-intercalative binder (Hoechst 33258) and two DNA-intercalators (mitoxantrone (MXT) and actinomycin D (AMD)) were examined in experiments. It was found that the binding constant of Hoechst 33258, mitoxantrone and actinomycin D, were 2.1 x 10(8), 8.9 x 10(9) and 9.1 x 10(9) cm(3) mol(-1); and the size of their binding sites were 4, 3 and 8, respectively. The study provides a convenient and sensitive approach for estimating affinity parameters and outlining the interaction between DNA and electroactive targeting compounds.