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Use of real-world data (RWD) is gaining wide attention. To bridge the gap between diverse healthcare stakeholders and to leverage the impact of Chinese real-world evidence (RWE) globally, a multi-stakeholder External Advisory Committee (EAC) and EAC meetings were initiated, aiming to elucidate the current and evolving RWD landscape in China, articulate the values of RWE in ensuring Chinese patients' equitable access to affordable medicines and solutions, and identify strategic opportunities and partnerships for expansion of RWE generation in China. Chinese and international experts who are clinicians and academic researchers were selected as EAC members based on their professional background and familiarity with RWD/RWE. Three EAC meetings were held quarterly in 2023. Various topics were presented and discussed for insights and suggestions. Nine experts from China, one from South Korea, and two from Europe were selected as EAC members and attended these meetings. Experts' presentations were summarized by theme, including the RWD landscape and RWE enablement in China, as well as global development of a patient-centric ecosystem. Experts' insights and suggestions on maximizing the RWD/RWE value to accelerate healthcare transformation in China were collected. We concluded that though data access, sharing, and quality are still challenging, RWD is developing to support evidence generation in the medicinal product lifecycle, inform clinical practice, and empower patient management in China. RWD/RWE creates value, accelerates healthcare transformation, and improves patient outcomes. Fostering a patient-centric ecosystem across healthcare stakeholders and maintaining global partnerships and collaboration are essential for unlocking the power of RWD/RWE. [ABSTRACT FROM AUTHOR]

Controlled quantum teleportation (CQT), which is regarded as the prelude and backbone for a genuine quantum internet, reveals the cooperation, supervision, and control relationship among the sender, receiver, and controller in the quantum network within the simplest unit. Compared with low-dimensional counterparts, high-dimensional CQT can exhibit larger information transmission capacity and higher superiority of the controller's authority. In this article, we report a proof-of-principle experimental realization of three-dimensional (3D) CQT with a fidelity of 97.4% ± 0.2%. To reduce the complexity of the circuit, we simulate a standard 4-qutrit CQT protocol in a 9×9-dimensional two-photon system with high-quality operations. The corresponding control powers are 48.1% ± 0.2% for teleporting a qutrit and 52.8% ± 0.3% for teleporting a qubit in the experiment, which are both higher than the theoretical value of control power in 2-dimensional CQT protocol (33%). The results fully demonstrate the advantages of high-dimensional multi-partite entangled networks and provide new avenues for constructing complex quantum networks. [ABSTRACT FROM AUTHOR]

Self-testing allows one to characterise quantum systems under minimal assumptions. However, existing schemes rely on quantum nonlocality and cannot be applied to systems that are not entangled. Here, we introduce a robust method that achieves self-testing of individual systems by taking advantage of contextuality. The scheme is based on the simplest contextuality witness for the simplest contextual quantum system—the Klyachko-Can-Binicioğlu-Shumovsky inequality for the qutrit. We establish a lower bound on the fidelity of the state and the measurements as a function of the value of the witness under a pragmatic assumption on the measurements. We apply the method in an experiment on a single trapped 40Ca+ using randomly chosen measurements and perfect detection efficiency. Using the observed statistics, we obtain an experimental demonstration of self-testing of a single quantum system. [ABSTRACT FROM AUTHOR]

Droplet microfluidics is a rapidly advancing area of microfluidic technology, which offers numerous advantages for cell analysis, such as isolation and accumulation of signals, by confining cells within droplets. However, controlling cell numbers in droplets is challenging due to the uncertainty of random encapsulation which result in many empty droplets. Therefore, more precise control techniques are needed to achieve efficient encapsulation of cells within droplets. Here, an innovative microfluidic droplet manipulation platform had been developed, which employed positive pressure as a stable and controllable driving force for manipulating fluid within chips. The air cylinder, electro-pneumatics proportional valve, and the microfluidic chip were connected through a capillary, which enabled the formation of a fluid wall by creating a difference in hydrodynamic resistance between two fluid streams at the channel junction. Lowering the pressure of the driving oil phase eliminates hydrodynamic resistance and breaks the fluid wall. Regulating the duration of the fluid wall breakage controls the volume of the introduced fluid. Several important droplet microfluidic manipulations were demonstrated on this microfluidic platform, such as sorting of cells/droplets, sorting of droplets co-encapsulated cells and hydrogels, and active generation of droplets encapsulated with cells in a responsive manner. The simple, on-demand microfluidic platform was featured with high stability, good controllability, and compatibility with other droplet microfluidic technologies. [ABSTRACT FROM AUTHOR]

Background: To compare the perioperative outcomes from McKeown minimally invasive esophagectomy (MIE) when performed in three-dimensional versus two-dimensional visualization system, and investigate the learning curve of a single surgeon who implemented three-dimensional McKeown MIE. Methods: A total of 335 consecutive cases (three-dimensional or two-dimensional) were identified. Perioperative clinical parameters were compared and cumulative sum learning curve was plotted. Propensity score matching was used to reduce selection bias from confounding factors. Results: Patients in three-dimensional group were associated with more chronic obstructive pulmonary disease (23.9% vs 3.0%, p < 0.01). After propensity score matching (108 matched patients in each groups), this finding was no longer statistically significant. Comparing to two-dimensional group, significant improvement in total retrieved lymph nodes (28 vs 33, p = 0.003) was observed in three-dimensional group. In addition, more lymph nodes around the right recurrent laryngeal nerve were harvested in three-dimensional group than that in two-dimensional group (p = 0.045). However, there were no significantly differences were found between the two groups in terms of other intraoperative parameters (e.g., operative time) and postoperative relevant outcomes (e.g., lung infection). Furthermore, the change point in the cumulative sum learning curves for intraoperative blood loss and thoracic procedure time was 33 procedures, respectively. Conclusion: Three-dimensional visualization system appears to be superior in performing lymphadenectomy during McKeown MIE to that of a two-dimensional technique. For surgeons proficient in performing two-dimensional McKeown MIE, the learning curve for a three-dimensional procedure appears to begin near proficiency after more than 33 cases. [ABSTRACT FROM AUTHOR]

Using the concept of non-degenerate Bell inequality, we show that quantum entanglement, the critical resource for various quantum information processing tasks, can be quantified for any unknown quantum state in a semi-device-independent manner, where the quantification is based on the experimentally obtained probability distributions and prior knowledge of the quantum dimension only. Specifically, as an application of our approach to multi-level systems, we experimentally quantify the entanglement of formation and the entanglement of distillation for qutrit-qutrit quantum systems. In addition, to demonstrate our approach for multi-partite systems, we further quantify the geometric measure of entanglement of three-qubit quantum systems. Our results supply a general way to reliably quantify entanglement in multi-level and multi-partite systems, thus paving the way to characterize many-body quantum systems by quantifying the involved entanglement. [ABSTRACT FROM AUTHOR]

Background: Tubulointerstitial inflammation (TII) is a critical pathological feature of kidney disease leading to renal fibrosis, and its treatment remains a major clinical challenge. We sought to explore the role of quercetin, a potential exosomes inhibitor, in exosomes release and TII. Methods: The effects of quercetin on exosomes release and TII were examined by two TII mouse models: the unilateral ureteral obstruction (UUO) models and the LPS-induced mouse models. In vitro, exosomes-mediated crosstalk between tubular epithelial cells (TECs) and macrophages was performed to investigate the mechanisms by which quercetin inhibited exosomes and TII. Results: In this study, we found that exosomes-mediated crosstalk between TECs and macrophages contributed to the development of TII. In vitro, exosomes released from LPS-stimulated TECs induced increased expression of inflammatory cytokines and fibrotic markers in Raw264·7 cells and vice versa. Interestingly, heat shock protein 70 (Hsp70) or Hsp90 proteins could control exosomes release from TECs and macrophages both in vivo and in vitro. Importantly, quercetin, a previously recognized heat shock protein inhibitor, could significantly reduce exosomes release in TII models by down-regulating Hsp70 or Hsp90. Quercetin abrogated exosomes-mediated intercellular communication, which attenuated TII and renal fibrosis accordingly. Conclusion: Quercetin could serve as a novel strategy for treatment of tubulointerstitial inflammation by inhibiting the exosomes-mediated crosstalk between tubules and macrophages. [ABSTRACT FROM AUTHOR]

Networks composed of independent sources of entangled particles that connect distant users are a rapidly developing quantum technology and an increasingly promising test-bed for fundamental physics. Here we address the certification of their post-classical properties through demonstrations of full network nonlocality. Full network nonlocality goes beyond standard nonlocality in networks by falsifying any model in which at least one source is classical, even if all the other sources are limited only by the no-signaling principle. We report on the observation of full network nonlocality in a star-shaped network featuring three independent sources of photonic qubits and joint three-qubit entanglement-swapping measurements. Our results demonstrate that experimental observation of full network nonlocality beyond the bilocal scenario is possible with current technology.Full network nonlocality, which certifies nonclassical behaviour in all sources of quantum networks, has so far only been demonstrated in the simplest scenarios. Here, the authors reach a complete experimental demonstration in a complex network involving three-qubit joint measurements. [ABSTRACT FROM AUTHOR]

An analytical solution for long waves propagating over a submerged atoll is established. The atolls involved in this study are annular coral reefs with large lagoons in the middle, and the expression of the cross section is a trinomial function of the radial distance, i.e., h=ar2s−brs+h0, where s is the positive rational number. This analytical solution extends the theory by Wang et al. (2018) as s is no longer limited to s=2/m, where m is the positive integer. In addition, by adjusting the terrain parameters properly, the analytic solution can be degenerated to describe the wave propagation over topography with a hump or pit. According to the relationship between wave rays and wave energy, the distribution characteristics and formation mechanism of energy over the topography are expounded. When the lagoon is non-existent, all wave rays converge at the x-axis, which results in an abrupt amplification of the wave amplitude around the convergence point. When a lagoon is mounted on the top of the atoll, the rays are scattered due to the refraction of the lagoon, and only some rays converge at the symmetrical axis and the ridges on both sides, which results in the amplification of wave amplitudes in these areas. [ABSTRACT FROM AUTHOR]

The frequent outbreak of global infectious diseases has prompted the development of rapid and effective diagnostic tools for the early screening of potential patients in point-of-care testing scenarios. With advances in mobile computing power and microfluidic technology, the smartphone-based mobile health platform has drawn significant attention from researchers developing point-of-care testing devices that integrate microfluidic optical detection with artificial intelligence analysis. In this article, we summarize recent progress in these mobile health platforms, including the aspects of microfluidic chips, imaging modalities, supporting components, and the development of software algorithms. We document the application of mobile health platforms in terms of the detection objects, including molecules, viruses, cells, and parasites. Finally, we discuss the prospects for future development of mobile health platforms. Smartphone-based mobile health platforms have drawn increasing attention from researchers developing point-of-care testing devices. Here the authors summarize recent progress and future directions of approaches combining microfluidics and artificial intelligence. [ABSTRACT FROM AUTHOR]

Background: The extent to which the presence of pleural adhesions affects the surgical and oncological outcomes of patients undergoing McKeown minimally invasive esophagectomy (MIE) for esophageal cancer (EC) has not previously been studied. Methods: Data of consecutive EC patients undergoing McKeown MIE by a single surgeon in the Department of Thoracic Surgery at Daping Hospital from November 2015 to December 2020 were collected. Patients were grouped according to the presence or absence of pleural adhesions when entering the chest cavity. Propensity score matching (PSM) was used to reduce selection bias from confounding factors. Kaplan–Meier was used to assess the survival differences. Results: A total of 617 consecutive EC patients underwent McKeown MIE were enrolled. There were 116 patients with pleural adhesions (Group A) and 501 patients without pleural adhesions (Group B). Patients in Group A were more likely to be older than those of patients in Group B: (66.26 vs. 63.27, P = 0.001). In addition, Group A had more patients with chronic obstructive pulmonary disease (COPD) (24.1% vs. 16.8%, P = 0.04). After propensity score matching (102 matched patients in Group A and 185 matched patients in Group B), these findings were no longer statistically significant. Postoperative pulmonary infection occurred in 57 patients in Group A and in 15 patients in Group B (53.9% vs. 13.0%, P < 0.001). In addition, the presence of pleural adhesions was significantly associated with the prolonged operation time (232 min vs. 210 min, P <.001), length of stay (12 days vs. 10 days, P = 0.001), and hydrothorax requiring drainage (12.7% vs. 5.4%, P = 0.04). However, the disease-specific survival and disease-free survival rates were comparable between the two groups (P = 0.40 and 0.13, respectively). Conclusions: The presence of pleural adhesions predicted an increased operation time, length of stay, postoperative pneumonia, and hydrothorax requiring drainage of EC patients undergoing McKeown MIE, but did not exert unfavourable effect on long-term survival. [ABSTRACT FROM AUTHOR]

Background: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury is a critical cellular event involved in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. This study aimed to investigate whether PMPs are deposited in podocytes and to assess their potential effects on podocyte injury in DN. Methods: The deposition of PMPs in podocytes was assessed by immunofluorescent staining and electron microscopy. The changes in renal pathology and ultra-microstructure were assessed by periodic acid-Schiff staining and electron microscopy, respectively. The expression of inflammatory cytokines and extracellular matrix proteins was measured by immuno-histochemical staining and western blot. Results: PMPs were widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with DN progression. Interestingly, aspirin treatment significantly inhibited the accumulation of PMPs in the glomeruli of diabetic rats, alleviated mesangial matrix expansion and fusion of foot processes, and decreased the protein expression of inflammatory cytokines and extracellular matrix secretion. An in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMP stimulation induced the phenotypic transition of podocytes through decreased podocin protein expression and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines. Conclusion: Our findings demonstrated for the first time that the deposition of PMPs in podocytes contributed to the development of DN. [ABSTRACT FROM AUTHOR]

Ganoderic acids (GAs) are well recognized as important pharmacological components of the medicinal species belonging to the basidiomycete genus Ganoderma. However, transcription factors directly regulating the expression of GA biosynthesis genes remain poorly understood. Here, the genome of Ganoderma lingzhi is de novo sequenced. Using DNA affinity purification sequencing, we identify putative targets of the transcription factor sterol regulatory element-binding protein (SREBP), including the genes of triterpenoid synthesis and lipid metabolism. Interactions between SREBP and the targets are verified by electrophoretic mobility gel shift assay. RNA-seq shows that SREBP targets, mevalonate kinase and 3-hydroxy-3-methylglutaryl coenzyme A synthetase in mevalonate pathway, sterol isomerase and lanosterol 14-demethylase in ergosterol biosynthesis, are significantly upregulated in the SREBP overexpression (OE::SREBP) strain. In addition, 3 targets involved in glycerophospholipid/glycerolipid metabolism are upregulated. Then, the contents of mevalonic acid, lanosterol, ergosterol and 13 different GAs as well as a variety of lipids are significantly increased in this strain. Furthermore, the effects of SREBP overexpression on triterpenoid and lipid metabolisms are recovered when OE::SREBP strain are treated with exogenous fatostatin, a specific inhibitor of SREBP. Taken together, our genome-wide study clarify the role of SREBP in triterpenoid and lipid metabolisms of G. lingzhi. An integration of genomic, DAP-seq, RNA-seq, metabolomic and genetic approaches identifies SREBP as a key transcription factor regulating triterpenoid and lipid metabolisms in the medicinal fungus Ganoderma lingzhi. [ABSTRACT FROM AUTHOR]

Peritubular capillaries (PTCs) are closely related to renal tubules in structure and function, and both are pivotal regulators in the development and progression of acute kidney injury (AKI). However, the mechanisms that underlie the interaction between PTCs and tubules during AKI remain unclear. Here we explored a new mode of tubulovascular crosstalk mediated by small extracellular vesicles (sEV) after AKI. In response to renal ischemia/reperfusion (I/R) injury, endothelial proliferation of PTCs and tubular expression of vascular endothelial growth factor-A (VEGF-A) were increased, accompanied by a remarkable redistribution of cytoplasmic VEGF-A to the basolateral side of tubular cells. Meanwhile, the secretion mode of VEGF-A was converted in the injured tubular cells, which showed a much greater tendency to secrete VEGF-A via sEV other than the free form. Interestingly, tubular cell-derived VEGF-A-enriched sEV (sEV-VEGF-A) turned out to promote endothelial proliferation which was regulated by VEGF receptors 1 and 2. Furthermore, inhibition of renal sEV secretion by Rab27a knockdown resulted in a significant decrease in the proliferation of peritubular endothelial cells in vivo. Importantly, taking advantage of the newly recognized endogenous repair response of PTCs, exogenous supplementation of VEGF-A + sEV efficiently recused PTC rarefaction, improved renal perfusion, and halted the AKI to CKD transition. Taken together, our study uncovered a novel intrinsic repair response after AKI through renal tubule-PTC crosstalk via sEV-VEGF-A, which could be exploited as a promising therapeutic angiogenesis strategy in diseases with ischemia. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is prevalent and remarkably increases the risk of cardiovascular (CV) events and mortality in hemodialysis (HD) patients. However, whether diaphragm dysfunction predicts clinical outcomes in HD patients is unknown. This was a prospective cohort study of 103 HD patients. After assessment of diaphragm function by ultrasonography and collection of other baseline data, a 36-month follow-up was then initiated. Participants were divided into diaphragm dysfunction (DD+) group and normal diaphragm function (DD−) group, according to cutoff value of thickening ratio (i.e. the change ratio of diaphragm thickness) at force respiration. The primary endpoint was the first nonfatal CV event or all-cause mortality. A secondary endpoint was less serious CV events (LSCEs, a composite of heart failure readmission, cardiac arrhythmia or myocardial ischemia needed pharmacological intervention in hospital). 98 patients were eligible to analysis and 57 (58.16%) were men. 28 of 44 patients(63.64%) in DD+ group and 23 of 54 patients (42.59%) in DD− group had at least one nonfatal CV event or death (p = 0.038). Compared to DD− group, DD+ group had significantly higher incidence of LSCEs (21 vs.14, p = 0.025) and shorter survival time (22.02 ± 12.98 months vs. 26.74 ± 12.59 months, p = 0.046). Kaplan–Meier analysis revealed significantly higher risks of primary endpoint (p = 0.039), and LSCEs (p = 0.040) in DD+ group. Multivariate hazard analysis showed that DD+ group had significantly higher risk of primary endpoint [hazard ratio (HR) 1.59; 95% confident interval (CI) 1.54–1.63], and LSCEs (HR 1.47; 95%CI 1.40–1.55). Ultrasound-assessed diaphragm dysfunction predicts clinical outcomes in HD patients. Trial registration: This study was registered with Chinese Clinical Trials Registry (www.chictr.org.cn) as ChiCTR1800016500 on Jun 05, 2018. [ABSTRACT FROM AUTHOR]

To compare the trophic ecologies of mother–offspring pairs of the jumbo squid (Dosidicus gigas), we examined carbon and nitrogen stable isotopes in the eye lens core and lens cortex from 18 D. gigas specimens collected from the equatorial waters of the eastern-central Pacific. Both δ13C and δ15N values in lens cores were smaller than in lens cortexes. Significant difference in δ13C between lens cores and lens cortexes suggested that maternal squid used different habitats as compared with their offspring. Higher variation of δ15N in offspring than maternal squid indicated that maternal squid have a more general feeding strategy than their offspring. The degree of fitting of the probability density distribution curves of δ13C and δ15N and the isotopic niches of mothers and their offspring indicate that these squid have a flexible feeding strategy and that mothers and daughters are spawning in different locations. [ABSTRACT FROM AUTHOR]

Glyconanoparticles (G-NPs), biofunctional nanomaterials that can fully combine the unique properties of nanoparticles (NPs) with the bioactivities of carbohydrates, have become an appealing nanoplatform in analytical chemistry and biomedical research. However, there is currently a lack of an efficient and universal method for facile immobilization of reducing carbohydrates on NPs while maintaining their structure integrity, greatly limiting the preparation and application of G-NPs. Herein, a new and universal strategy for preparing carbohydrate-functionalized gold nanoclusters (Au NCs) was developed by using S-(3-(methoxyamino)propyl) thioacetate (MPTA) as a new bifunctional linker. MPTA with an N-methoxyamine group (-NHOMe) and a thioacetyl group (-SAc) was synthesized by a two-step strategy and then grafted onto Au NCs by an efficient click reaction. Subsequently, reducing carbohydrates could be readily immobilized onto MPTA-functionalized Au NCs (MPTA-Au NCs) by a reducing end ring-closure reaction under mild conditions. The obtained G-NPs showed average size of 1.9 ± 0.42 nm and strong fluorescence at 610 nm. Carbohydrates grafted on G-NPs still retained their structure integrity and specific recognition ability toward their receptor proteins. Notably, the affinity between G-NPs and proteins was increased by 1300 times compared with free carbohydrates with an association constant of (1.47 ± 0.356) × 106 M−1. The prepared fluorescent G-NPs were also successfully applied to lectin sensing and targeted breast cancer cell imaging with good performance. These results indicated that the intact immobilization of reducing carbohydrates (whether naturally or chemically accessed) on NPs could be easily achieved using MPTA, providing a simple, efficient, and universal strategy for G-NP preparation. [ABSTRACT FROM AUTHOR]

Large-scale interceptors constitute the main structure of offshore self-driven floating marine litter collection devices, and the structural stability of such interceptors under the action of waves directly influences the overall safety of the device. When the ratio of the diameter of a horizontal cylinder in such interceptors to the incident wavelength is larger than 0.25, the wave force can be calculated by using the diffraction theory, by considering the problem as that of the interaction between the waves and a partially immersed large-scale horizontal cylinder. In this study, an analytical approach to calculate the wave force on a partially immersed large-scale horizontal cylinder was formulated by using the stepwise approximation method. Physical model tests were conducted to investigate the effects of different factors (wave height, period, and immersion depth) on the wave force on a large-scale horizontal cylinder under conditions involving short-period waves. The results show that both horizontal and vertical wave forces on the cylinder increase as the wave height (immersion depth) increases in most cases. The vertical wave force decreases with the decrease of the period. For the horizontal wave force, it increases with the decrease of the period when the wavelength is larger than the diameter of the cylinder and decreases with the decrease of the period when the wavelength is smaller than the diameter of the cylinder. [ABSTRACT FROM AUTHOR]

Background: Aberrant activation of Wnt/β-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/β-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity. Methods: The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/β-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of β-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo. Results: Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with β-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase β-Trcp1 for β-catenin binding, thereby decreasing β-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner β-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with β-catenin expression levels. Conclusions: Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/β-catenin signaling via SHARPIN-mediated stabilization of β-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive β-catenin signaling in a subset of human gastric cancers. [ABSTRACT FROM AUTHOR]

Background: No studies have examined endogenous insulin secretion in pediatric patients with type 1 diabetes in China using the gold-standard mixed-meal tolerance test. Because the latter is labor-intensive, we examined simpler surrogate markers of endogenous insulin secretion in Chinese youth, as previously reported for a European population. Methods: Participants were 57 children and adolescents with type 1 diabetes aged 4.4–16.8 years (56% females). We performed 120-minute mixed-meal tolerance tests with serum C-peptide (CP) measurements every 30 minutes. Severe insulin deficiency (SID) was defined as CP peak < 0.2 nmol/L. Urine CP and creatinine levels were measured at 0 and 120 minutes. Results: Twenty-five (44%) patients had SID. Fasting CP levels missed one case (96% sensitivity) with no false positives (100% specificity). While the 120-minute urine CP/creatinine had 100% sensitivity, it yielded markedly lower specificity (63%). Every 1-year increase in diabetes duration and 1-year decrease in age at diagnosis were associated with 37% (P < 0.001) and 20% (P = 0.005) reductions in serum CP area-under-the-curve, respectively. Thus, 86% of children aged < 5 years had SID compared to none among patients aged ≥ 11 years. Conclusions: Simple fasting CP measurements could be used to detect most SID cases in Chinese youth with type 1 diabetes. Fasting CP is a far more reliable measure of endogenous insulin secretion than the more commonly used insulin dose. Therefore, it could more precisely determine insulin secretory capacity to target those who could benefit, if treatments to preserve residual insulin secretion are developed. [ABSTRACT FROM AUTHOR]

To identify altered inter-hemispheric communication between patients with primary insomnia (PIs) and good sleepers (GSs), and their relationships with sleep and emotion-related parameters. Forty-eight PIs and 48 status-matched GSs were asked to complete a number of sleep and emotion-related questionnaires. Voxel-mirrored homotopic connectivity(VMHC) and seed-based functional connectivity were used to characterize the inter-hemispheric coordination. Seven PIs were examined twice to evaluate the test-retest reliability. Support vector machine and ROC curve were applied to discriminate the two groups. Pearson correlation and mediating causality analysis were used to describe the relationships between insomnia-related brain networks and sleep/emotion-related parameters. High test-retest stability (intraclass correlation coefficient ≥ 0.8) of the VMHC maps was observed. Intra-, and inter-hemispheric coordination dysfunctions of the default mode network, visual pathways and executive control network were found. These differences received good discriminatory power to distinguish the two groups (AUC, 0.887; sensitivity, 81.3%; specificity, 87.5%). Intra-, and inter-hemispheric communication within the default mode network and visual pathways correlated with and partially mediated the insomnia-related parameters, while the executive control network correlated with post-insomnia negative emotions. Altered inter-hemispheric coordination within the default mode network and visual pathway may be identified as core predisposing or perpetuating factors in the etiology of PIs, while the executive control network may underlie the post-insomnia negative emotional symptoms. These findings may suggest that the inter-hemispheric communication might be potential neuroimaging markers to discribe underlie neurobiological mechanism of PIs and expand our understanding of the etiology of PIs. [ABSTRACT FROM AUTHOR]

The study of mooring forces is an important issue in marine engineering and offshore structures. Although being widely applied in mooring system, numerical simulations suffer from difficulties in their multivariate and nonlinear modeling. Data-driven model is employed in this paper to predict the mooring forces in different lines, which is a new attempt to study the mooring forces. The height and period of regular wave, length of berth, ship load, draft and rolling period are considered as potential influencing factors. Input variables are determined using mutual information (MI) and principal component analysis (PCA), and imported to an artificial neural network (NN) model for prediction. With study case of 200 and 300 thousand tons ships experimental data obtained in Dalian University of Technology, MI is found to be more appropriate to provide effective input variables than PCA. Although the three factors regarding ship characteristics are highly correlated, it is recommended to input all of them to the NN model. The accuracy of predicting aft spring line force attains as high as 91.2%. The present paper demonstrates the feasibility of MI-NN model in mapping the mooring forces and their influencing factors. [ABSTRACT FROM AUTHOR]

The hydroelastic responses of a submerged horizontal solid/porous plate attached at the front of a very large rectangular floating structure (VLFS) under wave action has been investigated in the context of linear water wave theory. Darcy's law is adopted to represent energy dissipation in pores. It is assumed that the porous plates are made of material with very fine pores so that the normal velocity across the perforated porous is linearly associated with the pressure drop. In the analytic method, the eigenfunction expansion-matching method (EEMM) for multiple domains is applied to solve the hydrodynamic problem and the elastic equation of motion is solved by the modal expansion method. The performance of the proposed submerged horizontal solid/porous plate can be significantly enhanced by selecting optimal design parameters, such as plate length, horizontal position, submerged depth and porosity. It is concluded that good damping effect can be achieved through installation of solid and porous plate. Porous plate has better damping effect at low frequencies, while solid plate has better damping effect at high frequencies. The optimal ratio of plate length to water depth is 0.25–0.375, and the optimal ratio of submerged depth to water depth is 0.09–0.181. [ABSTRACT FROM AUTHOR]

The certification of entanglement dimensionality is of great importance in characterizing quantum systems. Recently, it was pointed out that quantum correlation of high-dimensional states can be simulated with a sequence of lower-dimensional states. Such a problem may render existing characterization protocols unreliable—the observed entanglement may not be a truly high-dimensional one. Here, we introduce the notion of irreducible entanglement to capture its dimensionality that is indecomposable in terms of a sequence of lower-dimensional entangled systems. We prove this new feature can be detected in a measurement-device-independent manner with an entanglement witness protocol. To demonstrate the practicability of this technique, we experimentally apply it on a 3-dimensional bipartite state, and the result certifies the existence of irreducible (at least) 3-dimensional entanglement. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a promising strategy for tumor treatment. Still, its therapeutic efficacy is compromised by the unsatisfactory cytotoxicity to specific subcellular organelles and insidious tumor microenvironment properties like hypoxia and high glutathione levels. Here, we fabricated a novel nanoenzyme that derived from metal-organic framework (MOF) with intrinsic catalase-like activities to decompose H2O2 to O2 and simultaneous glutathione consumption for enhancing PDT efficacy. The obtained Mn3O4 nanoparticle shows a larger pore size and surface area compared to native MOF particles, which can be used to load high dose photosensitizer. When decorated with AS1411 aptamer and polyethylene glycol (PEG), the obtained Mn3O4-PEG@C&A particle exhibits excellent stability and cell nucleus targeting ability. Remarkably, Mn3O4-PEG@C&A particle inhibited the tumor growth in the mouse model with high efficacy without any biotoxicity. This is the first report that applied MOF-derived nanoparticle to nucleus-targeted PDT. It may provide a new approach for designing functional nanoenzyme to subcellular organelles-targeted tumor modulation. [ABSTRACT FROM AUTHOR]

Underpotential deposition offers a predominant way to tailor the electronic structure of the catalytic surface at the atomic level, which is key to engineering materials with a high activity for (electro)catalysis. However, it remains challenging to precisely control and directly probe the underpotential deposition of a (sub)monolayer of atoms on nanoparticle surfaces. In this work, we in situ observe silver electrodeposited on gold nanocrystals surface from sub-monolayer to one monolayer by designing a highly sensitive electrochemical dark field scattering setup. The spectral variation is used to reconstruct the optical "cyclic voltammogram" of every single nanocrystal for understanding the underpotential deposition process on nanocrystals, which cannot be achieved by any other methods but are essential for creating novel nanomaterials. Underpotential deposition (UPD) is important to modify the surface properties of nanocrystals. Here, the authors show the application of in situ electrochemical dark field spectroscopy in identifying the UPD processes of silver on different facets of gold nanocrystals at the single nanoparticle level. [ABSTRACT FROM AUTHOR]

The three-dimensional hierarchical morphology of surfaces greatly affects the wettability, absorption and microfabrication properties of their hybrid materials, however few scalable methods exist that controls simultaneously complex geometric shape and spatial scattered location and their physical properties tuned. Consequently, this report describes a synthetic strategy that enables the position of well-ordered biomorph nano-microstructures on hydrophobic surfaces to be precisely controlled. The hierarchical architecture can be accurately positioned on polydimethylsiloxane (PDMS) surfaces in an unprecedented level by leveraging a solid/liquid/gas triphase dynamic reaction diffusion system strategy. The effect of salt concentrations, pH, CO2 levels, temperature and substrate patterning on this self-assembly process has been investigated, enabling protocols to be devised that enables the hydrophobic properties of the hierarchically assembled multiscale microstructures to be tuned as required. This combined top-down/bottom-up approach can be used to produce composites with outstanding hydrophobicity properties, affording superhydrophobic materials that are capable of retaining water droplets on their surfaces, even when the material is inverted by 180°, with a wide range of potential applications in oil/water separation technology and for selective cell recognition in biological systems. [ABSTRACT FROM AUTHOR]

Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Nevertheless, little is known regarding diaphragm dysfunction in HD patients. We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion during quiet and deep breathing. HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity (0.386 ± 0.144 cm vs. 0.439 ± 0.134 cm, p < 0.01) and thickening fraction (TF) (0.838 ± 0.618 vs. 1.127 ± 0.757; p < 0.01) compared to controls. The velocity and excursion of the diaphragm were significantly lower in the HD patients during deep breathing (3.686 ± 1.567 cm/s vs. 4.410 ± 1.720 cm/s, p < 0.01; 5.290 ± 2.048 cm vs. 7.232 ± 2.365 cm; p < 0.05). Changes in diaphragm displacement from quiet breathing to deep breathing (△m) were lower in HD patients than in controls (2.608 ± 1.630 vs. 4.628 ± 2.110 cm; p < 0.01). After multivariate adjustment, diaphragmatic excursion during deep breathing was associated with haemoglobin level (regression coefficient = 0.022; p < 0.01). We also found that the incidence of dyspnoea and hiccup and the fatigue scores, all of which were related to diaphragmatic dysfunction, were significantly higher in HD patients than in controls (all p < 0.01). Improving diaphragm function through targeted therapies may positively impact clinical outcomes in HD patients. [ABSTRACT FROM AUTHOR]

Laboratory experiments are performed to investigate the hydrodynamics around a submerged breakwater due to regular incident waves. With an in-house code, a constrained interpolation profile (CIP)-based model is employed to simulate this process. The model is built on a Cartesian grid system with the Navier-Stokes equations using a CIP method for the flow solver and an immersed boundary method (IBM) is used for the treatment of the solid body boundary. A more accurate interface capturing scheme, the tangent of hyperbola for interface capturing/slope weighting (THINC/SW) scheme, is used to track the free surface. The numerical results are compared with experimental data. Reasonably good agreement is achieved in terms of the wave profiles at six measuring stations, the flow velocities at three different space locations and the pressures of eight points on the surface of the submerged breakwater. Moreover, the water mass transfer over the breakwater is discussed using a two-phase VOF model and the wave spectrum is also presented for analysis. It is indicated that the present model can accurately predict the hydrodynamic characteristics of the wave over a submerged bar. Furthermore, the experimental data in the present work can provide reliable basic data, including the wave transformations, the velocities and the dynamic pressures, for the validation of other CFD models. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the effects of aspirin on podocyte injury and its underlying mechanisms in diabetic nephropathy (DN).Methods: Eight-week-old male Sprague-Dawley rats were divided into three groups: non-diabetic rats (Control), streptozotocin-induced diabetic rats (DM), and diabetic rats treated with aspirin (DM + Aspirin) for 12 weeks. Intracellular lipid accumulation was evaluated by Oil Red O staining and quantitative free cholesterol assays. Podocyte injury and the levels of COX-2, inflammatory cytokines, and low-density lipoprotein receptor (LDLr) pathway-related proteins were evaluated by electron microscopy, immunohistochemical staining, and Western blotting, respectively.Results: Lipid levels and urinary albumin-creatinine ratios were higher in the DM rats than in the Control rats. Periodic acid-Schiff staining showed glomerular hypertrophy and mild mesangial area widening in the DM rats. Electron microscopy showed that the podocyte foot processes were significantly flattened or absent in the DM rats. The protein expression levels of WT-1 and nephrin in the podocytes of DM rats were reduced. Interestingly, lipid accumulation in the kidneys of DM rats was significantly increased due to increased protein expression levels of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), SREBP-2, cyclooxygenase-2 (COX-2), and inflammatory cytokines. Confocal immunofluorescent staining showed that COX-2 and WT-1 were co-expressed. Furthermore, COX-2 protein expression levels were positively correlated with LDLr protein expression levels. However, when COX-2 expression was inhibited by aspirin, these changes in the DM rats were significantly attenuated.Conclusion: Aspirin attenuates podocyte injury in DN, which may be through COX-2-mediated dysregulation of LDLr pathway. [ABSTRACT FROM AUTHOR]

As a major active component extracted from traditional Chinese herb Tripterygium wilfordii Hook F, triptolide exhibits multiple pharmacological effects. Autophagy is an evolutionary conserved intracellular catabolic process involved in cytoplasmic materials degradation. Autophagic dysfunction contributes to the pathologies of many human diseases, which makes it a promising therapeutic target. Recent studies have shown that triptolide exerts neuroprotection, anti-tumor activities, organ toxicity, and podocyte protection by modulating autophagy. This article highlights the current information on triptolide-modulated autophagy, analyzes the possible pathways involved, and describes the crosstalk between autophagy and apoptosis modulated by triptolide, in hope of providing implications for the roles of autophagy in pharmacological effects of triptolide and expanding its novel usage as an autophagy modulator. [ABSTRACT FROM AUTHOR]

A rapid and sensitive N-glycan profiling strategy for MALDI-MS incorporating the use of deglycosylation with microwave assistance and the co-derivatization of glycosylamine labeling with tris(2,4,6-trimethoxyphenyl)phosphonium acetic acid N-hydroxysuccinimide ester (TMPP-Ac-OSu) and methylamidation has been developed in this work. Notably, highly efficient release and tagging of N-glycans from ribonuclease B was achieved in less than 90 min, providing up to 35-fold enhancement of MALDI-MS sensitivity with comparison to underivatized N-glycans. After further validation with other two standard glycoproteins (ovalbumin and bovine fetuin), the proposed strategy was applied to human serum for preliminary pathological analysis of N-glycans between healthy and lung cancer individuals. As a result, significant differences ( T test p value <0.01) of 6 glycan structures were determined from 54 detected N-glycan structures with only 50 nL of loading amount and further confirmed through PCA and ROC (AUC) analyses between two sample sets. Subsequently, the trend of each lung cancer stage and controls in expression of the selected glycans was implemented with T test and box-plots. Accordingly, these structures can be used as potential lung cancer glycan-based biomarkers and for further definition of cancer progression highlighting the ability of proposed method to rapidly and efficiently analyze N-glycome present in human serum. [ABSTRACT FROM AUTHOR]

Age determination of the jumbo squid ( Dosidicus gigas) has been successfully carried out over its geographic range based on the use of the rings present in the statoliths. In this study, we propose an additional method to identify ages of D. gigas off the Ecuadorian and Chilean Exclusive Economic Zones (EEZs) waters by using upper beak rostrum sagittal section (RSS) analysis. Our results show periodic growth increments and occasional checks located in the RSS surface. Growth increments meet at the internal rostral axis in the shape of chevron, and the marks in the hood are more discernable and clearer than in the crest. As has been suggested for octopi, checks are thought to represent temperature oscillation and reproductive events. Growth increments are laid down in the RSS daily, and numbers were similar to the numbers of increments used to determine age in statoliths. There was a significant regional difference in age but not in increment width when mantle length effects were considered, where squid off the warm Ecuadorian EEZ waters had a shorter lifespan and higher somatic growth in mantle length than those in the temperate Chilean EEZ waters. [ABSTRACT FROM AUTHOR]

This investigation demonstrates that programmed cell death (PCD) in a cyanobacterium, Microcystis aeruginosa, resulting from allelopathic stress induced by a submerged macrophyte, Myriophyllum spicatum, in a co-culture system. The hallmarks of PCD, caspase-3-like protease activity, DNA fragmentation, and destruction of cell ultrastructure, as well as intracellular PCD signaling radicals, reactive oxygen species (ROS), and nitric oxide (NO), were measured in M. aeruginosa cells co-cultured with M. spicatum for 7 days. The results showed a dose-response relationship between M. spicatum biomass and M. aeruginosa mortality. A caspase-3-like protease was activated and elevated from day 3. Thylakoid disintegration, cytoplasmic vacuolation, and fuzzy nuclear zone were observed by transmission electron microscopy, and distinct DNA fragmentation was detected in M. aeruginosa cells at a M. spicatum biomass of 6.0 g fresh weight (FW) L during the 7 days. Allelochemicals of total phenolic compounds (TPCs) were determined in co-culture water, and the concentration increased with increasing of M. spicatum biomass and co-culture time. Compared with the level of ROS production in the control group, a significant overproduction of ROS was detected in M. aeruginosa cells in the treatment group, and this was positively correlated with TPC concentration. Furthermore, the level of intracellular NO increased with the percent mortality of M. aeruginosa. The results indicated that a PCD pathway was induced in the cyanobacterium M. aeruginosa when co-cultured with the submerged macrophyte M. spicatum. [ABSTRACT FROM AUTHOR]

SRT1720, a new discovered drug, was reported to activate silent information regulator 1 (SIRT1) and inhibit the chondrocyte apoptosis. However, the underlying mechanism remains elusive. In the present study, the chondrocytes were extracted from the cartilage tissues of New Zealand white rabbits, cultured in the presence of sodium nitroprusside (SNP) (2.5 mmol/L) and divided into five groups: 1, 5, 10, and 20 μmol/L SRT1720 groups and blank control group (0 μmol/L SRT1720). MTT assay was used to detect the chondrocyte viability and proliferation, and DAPI staining and flow cytometry to measure the chondrocyte apoptosis. The expression levels of SIRT1, p53, NF-κB/p65, Bax, and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) were detected by Western blotting and the expression levels of SIRT1, type II collagen, and aggrecan mRNA by RT-PCR. The results showed that in the SRT1720-treated groups, the nuclei of chondrocytes were morphologically intact and had uniform chromatin. In the blank control group, nuclear rupture into debris was observed in chondrocytes. With the SRT1720 concentration increasing, the chondrocyte viability increased, the apoptosis rate decreased, the protein expression levels of SIRT1 and PGC-1α and the mRNA expression levels of type II collagen and aggrecan increased ({ptP}<0.05), and the expression levels of p53, NF-κB and bax decreased ( P<0.05). It was suggested that SRT1720 inhibits chondrocyte apoptosis by activating the expression of SIRT1 via p53/bax and NF-κB/PGC-1α pathways. [ABSTRACT FROM AUTHOR]

Cephalopods exhibit a variety of movement patterns during their lifespan, from the passive drifting of eggs and paralarvae to the active long-distance migrations of adults between feeding and spawning grounds. However, it is difficult to observe directly the movements of cephalopods at these different stages of development. An alternative approach is the use of elemental signatures recorded in statoliths to gain valuable insight into cephalopod movement. Dosidicus gigas is an economically important squid that undertakes large-scale migrations over its lifespan to satisfy its habitat requirements at different life history stages. In this study we used D. gigas as an example to illustrate a new approach to reconstructing cephalopod migration patterns using the relationship between sea surface temperature and elemental signature analyses of statoliths. We found that statolith elemental signatures are a useful natural tag to ascertain D. gigas migration routes from juvenile to adult stages. This approach is not applicable to embryonic and paralarval stages during which movement is more likely passive and determined by ocean currents. The conclusions which can be drawn from this study improve our knowledge of the distribution and migration of juvenile and adult cephalopods. Supplementary trophic analyses using stable isotopes would further benefit the reconstruction of cephalopod migration pathways. [ABSTRACT FROM AUTHOR]

Aims: Diabetic nephropathy (DN) is a chronic inflammatory disease that is accompanied by different degrees of lipid disorders. The present study was conducted to determine whether inflammatory stress exacerbates lipid accumulation in podocytes and to investigate its underlying mechanisms in DN using in vitro and in vivo studies. Methods: We used IL-1β stimulation in podocytes in vitro and casein injections in db/db mice in vivo to induce inflammatory stress. The plasma levels of serum inflammatory cytokines were determined using an enzyme-linked immunosorbent assay. The renal pathology was evaluated using pathological staining and electron microscopy. Intracellular lipid accumulation was evaluated by Oil Red O staining and a cholesterol quantitative assay. The gene and protein expression levels of extracellular matrix proteins, biomarkers of podocyte injury, and molecules involved in the LDLr pathway were evaluated using immunofluorescence staining, real-time PCR, and western blot analysis. Results: Increased plasma levels of inflammatory cytokines in the casein-injected db/db mice indicated a successful induction of the inflamed DN model. The kidney morphological changes, podocyte injury, and epithelial mesenchymal transition (EMT) were more significant in casein-injected db/db mice. Moreover, inflammation increased the lipid droplet accumulation in the kidneys of db/db mice, which resulted from the increased protein expression levels of LDLr, sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), and SREBP-2 in the kidneys of db/db mice. The in vitro studies further demonstrated that inflammation increased the lipid accumulation in the podocytes and induced podocyte EMT, which were correlated with inflammation-mediated increases in the expression levels of LDLr, SCAP, and SREBP-2, and increased translocation of the SCAP/SREBP-2 complex from the endoplasmic reticulum to the Golgi in the podocytes. Conclusion: Inflammation induced lipid accumulation and the EMT of podocytes through the dysregulation of the LDLr pathway, which contributed to podocyte injury and accelerated the progression of DN. [ABSTRACT FROM AUTHOR]

Analysis of growth increments in beak rostrum sagittal sections (RSSs) has been increasingly used for estimating octopus age. In this study, we develop an effective method to process and read the RSS of four oceanic ommastrephid squid species ( Dosidicus gigas, Ommastrephes bartramii, Illex argentinus and Sthenoteuthis oualaniensis) and validate the daily deposition of the increments by comparing to corresponding statolith-determined ages. The proposed method of processing yielded readable rates ranging from 42.9 % in I. argentinus to 71.7 % in D. gigas for samples from I. argentinus to D. gigas. The high precision of the increment readings with low independent counting coefficient of variation indicates that the processing and counting methods used are reliable. This study suggests that the RSS of the upper beak is an appropriate tool for estimating the age of D. gigas, O. bartramii and perhaps S. oualaniensis, although erosion of the rostral region may result in an underestimation of squid ages. [ABSTRACT FROM AUTHOR]

Aim:NLRP3 inflammasome plays an important role in renal injury and may be a therapeutic target in the treatment of patients with progressive chronic kidney disease. In this study we investigated whether angiotensin II (Ang II)-induced NLRP3 inflammasome activation was linked to endoplasmic reticulum stress (ERS) in human renal proximal tubular cells in vitro.Methods:Human kidney proximal epithelial cells (HK-2) were pretreated with telmisartan or 4-PBA, and then treated with Ang II. The expression levels of mRNAs and proteins related to NLRP3 inflammasomes and ERS was examined by real-time PCR, Western blot and immunofluorescence.Results:Treatment with Ang II (10, 100, and 1000 nmol/L) increased the expression of the inflammasome markers NLRP3 and ASC, as well as caspase-1, IL-1β, and IL-18 in dose- and time-dependent manners with peak levels detected at 100 nmol/L and 12 h. Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1β, and IL-18 were significantly reduced by pretreatment with telmisartan (1 μmol/L). Immunofluorescence studies showed that Ang II increased the expression of NLRP3 and ASC, which was inhibited by telmisartan. Furthermore, Ang II treatment increased the expression of ERS markers GRP78 and p-eIF2α in dose- and time-dependent manners, which was significantly reduced by telmisartan. Moreover, Ang II-induced increases in the expression of NLRP3, ASC, caspase-1, IL-1β, and IL-18 were significantly inhibited by pretreatment with the ERS inhibitor 4-PBA (5 mmol/L).Conclusion:Ang II treatment induces NLRP3 inflammasome activation in HK-2 cells in vitro and ER stress is involved in this process, which may represent a new mechanism for the renal rennin-angiotensin system to induce tubulointerstitial inflammation. [ABSTRACT FROM AUTHOR]

Digital single-cell assays hold high potentials for the analysis of cell apoptosis and the evaluation of chemotherapeutic reagents for cancer therapy. In this paper, a microfluidic hydrodynamic trapping system was developed for digital single-cell assays with the capability of monitoring cellular dynamics over time. The microfluidic chip was designed with arrays of bypass structures for trapping individual cells without the need for surface modification, external electric force, or robotic equipment. After optimization of the bypass structure by both numerical simulations and experiments, a single-cell trapping efficiency of ∼90 % was achieved. We demonstrated the method as a digital single-cell assay for the evaluation of five clinically established chemotherapeutic reagents. As a result, the half maximal inhibitory concentration (IC) values of these compounds could be conveniently determined. We further modeled the gradual decrease of active drugs over time which was often observed in vivo after an injection to investigate cell apoptosis against chemotherapeutic reagents. The developed method provided a valuable means for cell apoptotic analysis and evaluation of anticancer drugs. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Aim:FTY720, a new immunomodulatory drug with low cytotoxicity, is currently used to treat multiple sclerosis. In this study, we investigated the effects of FTY720 on inflammatory cell infiltration in albumin overload-induced nephropathy of rats.Methods:Male Wistar rats were subjected to right-side nephrectomy and divided into 3 groups. One week after the surgery, albumin overload (AO) group was treated with BSA (5 g·kg−1·d−1, ip) for 9 weeks; AO+FTY720 group was given BSA (5 g·kg−1·d−1, ip) plus FTY720 (0.5 g·kg−1·d−1, ip) for 9 weeks; and control group received daily ip injection of equivalent volume of saline. All rats were killed 9 weeks after nephrectomy.Results:AO rats exhibited gradually increased urinary protein excretion accompanied by elevated urinary N-acetyl-β-O-glucosaminidase activity, and both reached their peak values at week 7. Furthermore, AO significantly increased lymphocytes and monocytes in circulation and the inflammatory cells recruited to tubulointerstitium, and the expression of inflammatory cytokines MCP-1, TNF-α and IL-6, as well as sphingosine 1-phosphate (S1P) receptors S1pr1 and S1pr3, and S1P-synthesizing enzyme sphingosine kinase 1 (Sphk1) in the kidney. Concomitant administration of FTY720 significantly attenuated all the AO-induced pathological changes.Conclusion:FTY720 alleviates tubulointerstitium inflammation in an AO rat model of nephropathy via down-regulation of the Sphk1 pathway. [ABSTRACT FROM AUTHOR]

Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) has been a major approach for glycan analysis. However, the preferential cleavage of the sialic acid moiety by in- and post-source decay influences the determination of sialylated glycans by MALDI-MS. Many chemical derivatization methods were introduced to stabilize the sialylated glycan during MALDI-MS. Among current derivatization methods, methylamidation is a promising means for simultaneous analysis of natural sialylated glycans regardless of their sialic acid linkage types. Here, a novel derivatization method was developed, in which proteins were conjugated on the solid-phase support in order to stabilize the sialic acids by methylamidation and to reduce sample loss and contamination during the derivatization process. This derivatization strategy was used to investigate N-glycans from fetuin, a glycoprotein containing different types of complex N-glycans. The developed method was also applied to the N-glycan profiling of human serum from patients and healthy volunteers. Results were consistent with N-glycan profiling by HPLC-fluorescence detection. This new method provided a sensitive, simple, and robust approach for profiling glycan structures of complex samples. [ABSTRACT FROM AUTHOR]

Aim:Proteinuria is not only a common marker of renal disease, but also involved in renal tubulointerstitial inflammation and fibrosis. The aim of this study was to investigate the mechanisms underlying the protective effects of enalapril, an ACEI, against nephropathy in rats.Methods:Wistar rats underwent unilateral right nephrectomy, and then were treated with BSA (5 g·kg−1·d−1, ip), or BSA plus enalapril (0.5 g·kg−1·d−1, po) for 9 weeks. The renal lesions were evaluated using histology and immunohistochemistry. The expression of NLRP3, caspase-1, IL-1β and IL-18 was analyzed using immunohistochemistry, RT-PCR and Western blot.Results:BSA-overload resulted in severe proteinuria, which peaked at week 7, and interstitial inflammation with prominent infiltration of CD68+ cells (macrophages) and CD3+ cells (T lymphocytes), particularly of CD20+ cells (B lymphocytes). BSA-overload markedly increased the expression of NLRP3, caspase-1, IL-1β and IL-18 in the proximal tubular epithelial cells, and in inflammatory cells as well. Furthermore, the expression of IL-1β or IL-18 was significantly correlated with proteinuria (IL-1β: r=0.757; IL-18: r=0.834). These abnormalities in BSA-overload rats were significantly attenuated by concurrent administration of enalapril.Conclusion:Enalapril exerts protective effects against BSA-overload nephropathy in rats via suppressing NLRP3 inflammasome expression and tubulointerstitial inflammation. [ABSTRACT FROM AUTHOR]

With the maturation of microfluidic technologies, microchip electrophoresis has been widely employed for amino acid analysis owing to its advantages of low sample consumption, reduced analysis time, high throughput, and potential for integration and automation. In this article, we review the recent progress in amino acid analysis using microchip electrophoresis during the period from 2007 to 2012. Innovations in microchip materials, surface modification, sample introduction, microchip electrophoresis, and detection methods are documented, as well as nascent applications of amino acid analysis in single-cell analysis, microdialysis sampling, food analysis, and extraterrestrial exploration. Without doubt, more applications of microchip electrophoresis in amino acid analysis may be expected soon. [ABSTRACT FROM AUTHOR]

Kinases play a key role in cellular signaling, and the overactivation or overexpression of these kinases has been linked to a variety of cancers. Tyrosine kinase inhibitors treat the mechanism of these cancers by targeting the specific kinases that are overactive. Some patients, however, do not respond to these inhibitors or develop resistance to these inhibitors during treatment. Additionally, even within cancers of the same tissue type, different kinases may be overactive in different patients. For example, some lung cancers overexpress epidermal growth factor receptor (EGFR) and respond to EGFR inhibitors, whereas other lung cancers do not overexpress EGFR and receive no benefit from this treatment. Even among patients exhibiting EGFR overexpression, some do not respond to EGFR kinase inhibitors because other kinases, such as Met kinase, are also overactivated. Here we describe a quantitative and specific multiplexed microfluidic assay using a hydrogel immobilized substrate for measuring the kinase activity of Met and Abl kinase from cancer cells. We immobilized kinase-specific substrates on macroporous hydrogel micropillars in microchannels. These microchannels were incubated with 6 μl of a kinase reaction solution containing cancer cell lysate, and we measured kinase activity via fluorescence detection of a phosphotyrosine antibody. We showed that the assay can specifically measure the activity of both Met and Abl kinase within one microchannel and has the potential to measure the activity of as many as five kinases within one microchannel. The assay also detected Met kinase inhibition from lysates of cancer cells grown in the Met kinase inhibitor PHA665752. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]