Search

Large-eddy simulations of flow over a "horizontally" uniform model forest are used to investigate the effects of gentle topography on the turbulent kinetic energy (TKE) budget within the canopy roughness sublayer. Despite significant differences between simulations using idealized sinusoidal topography and real topography of the Amazon forest, results indicate that the effects of topography are located predominantly in the upper canopy and above, and are mostly caused by mean advection of TKE. The "horizontally" averaged TKE budget from idealized and real gentle topographies are almost identical to that for flat terrain, including a clear inertial layer above the roughness sublayer in which shear production is balanced by local dissipation. At topography crests, where observational towers are usually located, mean vertical advection of TKE can be as important as horizontal advection. We propose the use on an approximate TKE balance equation to estimate mean advection from single tower measurements, and introduce a new advection index that can be used as a proxy to quantify the importance of the topography on the TKE budget. [ABSTRACT FROM AUTHOR]

Taking the revitalization strategy in conservation and renewal of Shangxiahang historical and cultural district as an example, the paper analyzes the main problems at the present stage and the main contradictions with urban development, and puts forward the revitalization practice for conservation and renewal of Shangxiahang historical district by using related revitalization theory and planning principles. Furthermore, the contemporary practicality of Shangxiahang district is increased on the basis of protection, giving play to its contemporary charm. [ABSTRACT FROM AUTHOR]

Mid-wavelength infrared HgCdTe avalanche photodiodes (APDs) are becoming increasingly significant in research and practical applications for the high linear gain, low excess noise and high quantum efficiency. However, the performance of HgCdTe APDs is largely limited by the voltage dependence of dark current. It has been well known that the tunneling current is the main component of the dark current of the p-i-n diode. However, the current contribution of different physical mechanism still needs to be indicated in different reverse voltages. In this paper, we mainly study the mechanism of the relationship between dark current and reverse voltage of mid-wavelength infrared Hg 1 - x Cd x Te (x = 0.3) mesa p-i-n avalanche diode. Several physical models are used for the dark current numerical simulation. The results show that for detection of Hg 1 - x Cd x Te mesa p-i-n detector under low temperature, dark current is mainly caused by tunneling current. With the reverse voltage increasing, the main component of dark current turns from trap-assisted tunneling current to direct band-to-band tunneling. The transition voltage is positively related to the energy level difference between trap energy level and conduction band. The results may provide a guideline to improve the performance of the mid-wavelength infrared APD detector by ranking the importance of different structural parameters. [ABSTRACT FROM AUTHOR]

The significance of air flow within dense canopies situated on hilly terrain is not in dispute given its relevance to a plethora of applications in meteorology, wind energy, air pollution, atmospheric chemistry and ecology. While the mathematical description of such flows is complex, progress has proceeded through an interplay between experiments, mathematical modelling, and more recently large‐eddy simulations (LESs). In this contribution, LES is used to investigate the topography‐induced changes in the flow field and how these changes propagate to scalar transport within the canopy. The LES runs are conducted for a neutral atmospheric boundary layer above a tall dense forested canopy situated on a train of two‐dimensional sinusoidal hills. The foliage distribution is specified using leaf area density measurements collected in an Amazon rain forest. A series of LES runs with increasing hill amplitude are conducted to disturb the flow from its flat‐terrain state. The LES runs successfully reproduce the recirculation region and the flow separation on the lee‐side of the hill within the canopy region in agreement with prior laboratory and LES studies. Simulation results show that air parcels released inside the canopy have two preferential pathways to escape the canopy region: a "local" pathway similar to that encountered in flat terrain and an "advective" pathway near the flow‐separation region. Further analysis shows that the preferential escape location over the flow‐separation region leads to a "chimney"‐like effect that becomes amplified for air parcel releases near the forest floor. The work here demonstrates that shear‐layer turbulence is the main mechanism exporting air parcels out the canopy for both pathways. However, compared to flat terrain, the mean updraught at the flow separation induced by topography significantly shortens the in‐canopy residence time for air parcels released in the lower canopy, thus enhancing the export fraction of reactive gases. [ABSTRACT FROM AUTHOR]

Background/Aims: Recently, microRNAs (miRNAs) have been demonstrated to act as regulators of activation of hepatic stellate cells (HSCs). It is well known that the main profibrogenic inducer transforming growth factor-β1 (TGF-β1) contributes to HSC activation, which is a key event in liver fibrosis. Increasing studies show that miR-9-5p is down-regulated in liver fibrosis and restoration of miR-9-5p limits HSC activation. However, the role of miR-9-5p in TGF-β1-induced HSC activation is still not clear. Methods: miR-9-5p expression was quantified using real-time PCR in chronic hepatitis B (CHB) patients and TGF-β1-treated LX-2 cells. In CHB patients, histological activity index (HAI) and fibrosis stages were assessed using the Ishak scoring system. Effects of miR-9-5p on liver fibrosis in vivo and in vitro were analyzed. Luciferase activity assays were performed to examine the binding of miR-9-5p to the 3'-untranslated region of type I TGF-β receptor (TGFBR1) as well as TGFBR2. Results: Compared with healthy controls, miR-9-5p was reduced in CHB patients. There was a lower miR-9-5p expression in CHB patients with higher fibrosis scores or HAI scores. miR-9-5p was down-regulated by TGF-β1 in a dose-dependent manner. TGF-β1-induced HSC activation including cell proliferation, a-SMA and collagen expression was blocked down by miR-9-5p. Notably, miR-9-5p ameliorates carbon tetrachloride-induced liver fibrosis. As determined by luciferase activity assays, TGFBR1 and TGFBR2 were targets of miR-9-5p. Further studies demonstrated that miR-9-5p inhibited TGF-β1/Smads pathway via TGFBR1 and TGFBR2. Interestingly, promoter methylation was responsible for miR-9-5p down-regulation in liver fibrosis. The relationship between miR-9-5p expression and methylation was confirmed in CHB patients and TGF-β1-treated cells. Conclusion: Our results demonstrate that miR-9-5p could inhibit TGF-β1-induced HSC activation through TGFBR1 and TGFBR2. Loss of miR-9-5p is associated with its methylation status in liver fibrosis. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition ( EMT) of tubular epithelial cells ( TECs) is crucial for the induction and progression of kidney fibrosis. However, the underlying molecular mechanisms that trigger the EMT programme have not been identified. In the present study, we demonstrate that transforming growth factor ( TGF)-β1 and activated hedgehog signaling mediate the EMT programme following kidney injury. Tissue samples from fibrotic kidneys show enhanced TGF-β1 levels, as well as upregulated hedgehog signaling activity, during the EMT process; these levels decrease when fibrosis is reversed. Injury promotes TGF-β1 expression and activates hedgehog signaling, thus inducing tubular EMT of TECs and extracellular matrix ( ECM) accumulation in vitro. The EMT response and fibrotic appearance are also induced by enhanced TGF-β1 levels or activated hedgehog signaling. Downregulation of TGF-β1 inhibits aristolochic acid ( AA)- and TGF-β1-induced EMT and ECM synthesis and correlates with decreased hedgehog signaling. Similarly, inhibiting the hedgehog pathway abolishes AA- and hedgehog-mediated EMT, resulting in reduced TGF-β1 levels. These findings highlight a key role for cross-talk between TGF-β1 and hedgehog signaling in promoting injury-induced EMT and ECM deposition in TECs. [ABSTRACT FROM AUTHOR]

Large-eddy simulation (LES) has proven to be a valuable tool for high-fidelity modeling of environmental and geophysical turbulent flows. An important application of LES is to study the transport of effluents (e.g. oils from a subsea blowout) in the ocean mixed layer (OML). Oil plumes being transported in the OML experience the action of shear-generated turbulence, Langmuir circulations, Ekman transport and submesoscale quasi-geostrophic eddies. To resolve such turbulent processes, grid sizes of a few meters are desirable while horizontal domain sizes of LES are typically restricted from hundreds of meters to a few kilometers, for LES to remain practically affordable. Yet transported oil plumes evolve to large scales extending to tens or even hundreds of kilometers. In this study, the Extended Nonperiodic Domain LES for Scalar transport (ENDLESS) is proposed as a multi-scale approach to tackle this challenge while being computationally affordable. The basic idea is to simulate the shear turbulence and Langmuir circulations on a small horizontal domain with periodic boundary conditions while the resulting transport velocity field is replicated periodically following adaptively the large-scale plume as it evolves spatially towards much larger scales. This approach also permits the superposition of larger-scale quasi two-dimensional flow motions on the oil advection, allowing for coupling with regional circulation models. A validation case and two sample applications to oil plume evolution in the OML are presented in order to demonstrate key features and computational speedup associated with the ENDLESS method. [ABSTRACT FROM AUTHOR]

The new type of 3D printing consumables is an essential development premise for the diversity of 3D printed products. So, the composites made of metal alloy and flexible polymer were studied to replace the inorganic particle reinforced composites for electromagnetic protective shell products. The comprehensive evaluation of this 3D printed composite is based on rheological test, microscopic observation, element distribution, mechanical analysis, and electromagnetic detection. We found that 2 mm-thick 3D printed sample with a filling rate of 30% reduced the electric field radiation from 281 to 41 V/m. When the filling rate turned to less than 20%, the tensile strength and elongation at break of 3D printed samples were improved. At the same time, the improvement of tensile mechanics and absorbing performance by the unique texture structure of 3D printed samples was also compared and analyzed. In this regard, this paper provides ideas and case products for promoting the diversification and structural design of 3D printed materials. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: While timely assessment of long‐term survival for patients with colorectal cancer (CRC) is essential for evaluation on early detection and screening programs of colorectal cancer, those data are extremely scarce in China. We aimed to timely and accurately assess long‐term survival for CRC patients in eastern China. Methods: Patients diagnosed with CRC during 2004–2018 and followed up until December 31, 2018 from four cancer registries with high‐quality data from Taizhou, eastern China were included. Period analysis was used to calculate 5‐year relative survival (RS) for overall and the stratification by sex, age at diagnosis and region. The projected 5‐year RS of CRC patients during 2019–2023 was also assessed using a model‐based period analysis. Results: Overall 5‐year RS for patients with CRC during 2014–2018 reached 78.8%, being 74.9% for men and 86.1% for women. 5‐year RS declined along with aging, decreasing from 84.1% for age < 45 years to 48.9% for age > 74 years, while 5‐year RS for urban area was higher compared to rural area (83.9% vs. 75.8%). Projected overall 5‐year RS of CRC patients could reach 85.9% during the upcoming period 2019–2023. Conclusions: We provided, for first time in China using period analysis, most up‐to‐date 5‐year RS for patients with CRC from Taizhou, eastern China and also found 5‐year RS for CRC patients have improved greatly during 2004–2018. [ABSTRACT FROM AUTHOR]

Abstract: A far-field model of Moiré Interferometer (MI) using the mode decomposition method is proposed using the analytical formulation of the scalar diffraction theory. The wave propagation within the defined MI far-field domain is solved analytically for a single frequency surface relieved grating structure, following the Rayleigh−Sommerfeld formulation under the paraxial approximation. It is shown that the electrical field solution of the single frequency grating structure follows the linear relationship in the spatial frequency domain. Furthermore, we show that the far-field electrical field and the intensity interferogram can be calculated using the mode deposition method. A series of MI interferograms is obtained from the Finite Element Analysis (FEA) deformation field using chirp-z transform and inverse chirp-z transform. By performing strain extraction using Continuous Wavelet Transform (CWT), the simulated interferograms are validated and matched against the FEA deformation field. It is concluded that the proposed far-field modeling of MI is accurate and computationally efficient. The proposed method can help design high resolution and high sensitivity MI and interpret complex MI interferogram patterns. [Copyright &y& Elsevier]

Abstract: In this study, we propose a new method to validate the basic assumptions used in Moiré Interferometry (MI) measurement using exact electromagnetic (EM) theory; and simulate the EM fields in a few microns region above the surface of the diffraction grating. Proving that spatial frequency of EM field matches the spatial frequency of strain field is critical to ensure accuracy of MI measurement at nanoscale resolution. The EM simulations for a deformed diffraction grating structure were performed by introducing a single defect that acts as a variation on the periodic diffraction grating. The spatial frequency of simulated EM field was quantified using Continuous Wavelet Transform (CWT) algorithm. The results were compared with the strain field to show the correlations between the two. The study shows that there is a strong correlation (correlation factor R=0.869) of spatial frequency response between EM field and strain field at the nanoscale. The study shows that using the traditional MI assumptions for nanoscale strain measurement introduces an error in the order of 2.7%. We demonstrate that MI measurement can be used for nanoscale strain measurement within acceptable measurement errors using the proposed method. The proposed method can help to evaluate the MI instrument design to enhance the measurement performance. [Copyright &y& Elsevier]

Abstract: In this study, the influence of substitution of Nd with Pr on the magnetic of sintered permanent magnets was investigated. The samples were prepared by traditional powder metallurgical technique. The nominal composition of the alloys is (Nd1−x Pr x )29Dy1.3R3.1Febal (R=Al0.3Cu0.2 Co1.5 B1Zr0.1, wt%) with x varying from 0 to 1 in steps of 0.2. Experimental results show that the overall magnetic properties, especially the intrinsic coercivity and thermal stability of the magnets, could be improved by substituting Nd with Pr in the magnets. When the Pr replaces all Nd in the magnets, excellent performance magnets with Br=13.65KGs, Hcj=22.13KOe, (BH)max =46.1MGsOe are obtained with a low Dy content (1.3wt%). [Copyright &y& Elsevier]

Objective. Our aim was to investigate the protective effects of a Lipoxin A4 analogue (LXA4) in the early phase of acute pancreatitis in rats. Materials and methods. Severe acute pancreatitis (SAP) was induced by injection of 5% sodium taurocholate into the pancreatic duct. Rats with SAP were treated with LXA4 (0.1 mg/kg), 10 min after the 5% sodium taurocholate injection, after which LXA4 was administrated every 8 hours, three times (LXA4 group). The sham group was only given the vehicle after operation. Plasma amylase activity, serum levels of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-αα (TNF-αα) were measured at 4, 12, and 24 h after induction of SAP. The pancreatic index and histopathologic observations were evaluated and the expression of intercellular adhesion molecule-1 (ICAM-1) and NF-κκB p65 in the pancreas, and the expression of ICAM-1 in the lungs were detected by immunohistochemistry. Results. LXA4 treated rats had lower serum levels of TNF-αα, IL-1, and IL-6 at all time points measured ( p < 0.05), but significantly differed in plasma amylase activity only at 24 h as compared with the SAP group. The pancreatic index and the scores of pancreatitic histopathologic evaluations were lower in the LXA4 group as compared to the SAP group. Immunohistochemistry showed that LXA4 attenuated the expression of ICAM-1 and NF-κκB p65 in the pancreas, as well as the expression of ICAM-1 in the lungs in animals with pancreatitis ( p < 0.05). Conclusions. We demonstrate that LXA4 has protective effects in experimental SAP, which may be achieved by inhibiting the NF-κκB signalling pathway, thereby reducing the production of proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

This paper proposes a topology optimization method integrating the variable trajectory constraints to design rigid and compliant hybrid mechanisms. The variable trajectory constraints are distributed in the design domain and are uniformly modeled by nonlinear spring model. Each of the variable trajectory constraints has an active or inactive state and different states map various mechanical properties of the nonlinear springs. The nonlinear relation between force and displacement of the spring is formulated. A new group of design variables denoting the states of the springs is introduced into the traditional density-based topology optimization model. The design variables representing the element density of the continuum structure and the states of the variable trajectory constraints are uniformly penalized to avoid intermediate values in order to obtain a physically realizable mechanism. Sensitivity analysis is performed by the adjoint equation method. To demonstrate the versatility and the generality of the proposed method, the typical numerical examples including linear, spline and circular trajectory constraints were implemented. The numerical comparisons between the nonlinear spring model and the actual trajectory constraints verify the accuracy. The proposed method expands the application of topology optimization and can be extensively employed to design the mechanisms integrating both the compliant members and rigid parts. [ABSTRACT FROM AUTHOR]

• A design method for the dielectric elastomer actuator is developed. • Structure of dielectric elastomer actuator is generated conveniently by curves. • Topology optimization is performed using genetic method. • Dielectric elastomer grippers are designed with expected performance. Dielectric elastomer (DE) grippers have attracted much attention in safety applications due to their intrinsic compliance, large deformation and high response speed. The performances of DE grippers can be influenced by the design of both the electrode patterns on the DE film and the film supporting frame. This paper presents a design scheme using Bezier curves for topology optimization of both electrode patterns and frame structures. Two kinds of DE grippers are designed to maximize the output displacements. Thereafter, the optimized DE grippers are fabricated and tested. The agreement between experiments and simulations is observed, which shows the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

The purpose of this study was to save heavy rare earth Dy in NdFeB production. By ways of optimizing preparation process and replacing Nd with Pr, Dy-free magnet with high coercivity was successfully prepared, the nominal composition is Pr14B6Co2.2Cu0.2Al1Fe76.7 (at %). The effect of Pr on magnetic performance and microstructure of the magnet were investigated systemically, alloy Nd13.65B6Co2.2Cu0.2Al1Fe76.9 (at %) was prepared by the same preparation process as comparison. The results indicated that magnet Pr14B6Co2.2Cu0.2Al1Fe76.7 has much higher coercivity than that of magnet Nd13.65B6Co2.2Cu0.2Al1Fe76.9. Microstructure investigation showed that the presence of small grains, thin and smooth RE-rich film, associated with higher coercivity. [ABSTRACT FROM AUTHOR]

This study proposes a new method to locate and measure the temperature of the hot spots caused by Joule Heating by measuring the free thermal expansion in-plane strain. It is demonstrated that the hotspot caused by the Joule heating in a thin metal film/plate structure can be measured by Phase shifting Moiré interferometry with continuous wavelet transform (PSMI/CWT) at the microscopic scale. A demonstration on a copper film is conducted to verify the theory under different current densities. A correlation between the current density and strain in two orthogonal directions (one in the direction of the current flow) is proposed. The method can also be used for the measurement of the Joule heating in the microscopic solid structures in the electronic packaging devices. It is shown that a linear relationship exists between current density squared and normal strains. [ABSTRACT FROM AUTHOR]

The silicon-based blocked-impurity-band (BIB) detectors play an irreplaceable role in long-wavelength and far-infrared detection applications from 2 to 40 μm, especially in astronomy. However, how to remove the anomalous sharp peaks in the spectral response of the planer structures is still unresolved. Here, we propose a tunneling current model to demonstrate the carrier transport mechanism in the planar structures. Specifically, the surface channel induced by dry etching on sidewalls of the mesa structures facilitates the photocarriers to bypass the interface barrier according to the model. Two structures with the same photosensitive area are fabricated and measured to characterize the role of the interface barrier. The disappearance of the sharp response peak at 31.8 μm in the measured photocurrent spectra of the mesa structure well confirms our model. Moreover, the manipulation of the localized energy level of the interface barrier is then utilized to optimize the mesa structure. A much lower dark current of the mesa structures is realized compared with that of the planar ones. Peak detectivity of 5.6 × 1012 Jones and uniformly broadband response among 2.5–40 μm are also achieved. We believe the results will find potential applications in the BIB detectors design. [ABSTRACT FROM AUTHOR]

This paper proposes a novel topology optimization method integrating the layout of the supports, links and material distribution to design partially compliant mechanisms. The potential supports and links are distributed in the design domain in initialization, each with an active or inactive state. The nonlinear spring model is implemented for the unified modeling of potential supports and links. The mechanical properties of springs are associated with the states of supports and links. Within the traditional density-based framework, a new group of design variables representing the states of supports and links is introduced into the topology optimization model. For obtaining a physically realizable mechanism, the design variables representing the element density of the structure and the states of supports or links are uniformly penalized for avoiding intermediate values. Sensitivity analysis is conducted by implementing the adjoint equation method. The versatility and flexibility of the proposed method are demonstrated via numerical examples and the accuracy of the nonlinear spring model is verified by comparison of results. • A novel method for designing partially compliant mechanisms. • Simultaneous optimization of supports, links and material distribution. • Unified modeling of supports and links by nonlinear spring model. • Sensitivity analysis for potential links is provided. [ABSTRACT FROM AUTHOR]

Chronic aristolochic acid nephropathy (CAAN) is characterized by widespread apoptosis and interstitial fibrosis, which severely impairs kidney function. mTOR is crucial for cell proliferation and protein synthesis. In the present study, the therapeutic effects of blockade of mTOR activity by rapamycin on aristolochic acid nephropathy were investigated. In vitro experiments to determine cell apoptosis and cell cycle alterations caused by aristolochic acid (AA)-induced injury were conducted on three groups of cells: Untreated control, AAI (treated with aristolochic acid I), and AAI + rapamycin (RMS). In vivo experiments were conducted in a CAAN mouse model. One group of mice was treated with AAI (the CAAN group), while another group was treated with AAI and rapamycin (the treatment group). Kidney function and pathological changes in these mice were assessed by serum creatinine and urea nitrogen analysis. Hematoxylin and eosin staining of renal tissue was performed to evaluate the treatment effects of rapamycin. Western blotting and immunohistochemical staining were used to explore the mechanisms by which rapamycin inhibited cell proliferation, apoptosis and tissue fibrosis. In the in vitro experiments, rapamycin prevented AAI-induced cell apoptosis and G2/M checkpoint cell cycle arrest. In the in vivo experiments, the treatment group exhibited lower serum creatinine and urea nitrogen, less extensive tubular atrophy and increased amount of glomerulus. Additionally, western blotting and immunohistochemical staining showed that the treatment group exhibited decreased expression levels of fibrosis-, proliferation- and apoptosis-related proteins compared with the CAAN group. The findings suggest that rapamycin can ameliorate kidney injury induced by AAI via blockade of mTOR, and thus could be a therapeutic strategy for patients with CAAN. [ABSTRACT FROM AUTHOR]

This paper develops a nonlinear stiffness mechanism to reduce the vibration of the suspended-load backpack and its peak force applied to human. The suspension system between the human and load is a mechanism with nonlinear force deflection behavior. Compared with the common linear vibration system, the nonlinear dynamics model of double-mass system actuated by human legs was established. An optimization formulation considering the static deflection constraint was established to reduce the peak force and obtain the target force deflection behavior. The optimization result reflects that the target force deflection behavior has the characteristic of high-static-low-dynamic stiffness and can significantly reduce the peak force imposed on human body compared with the generic backpack. The nonlinear stiffness mechanism is creatively designed by implementing a new design method based on topology optimization. Geometrically nonlinear finite element analysis is employed to obtain the reaction force of the mechanism under different displacement loads. A topology optimization model considering stress constraint was constructed based on the target nonlinear force deflection behavior. A test bench was built to test the practical force deflection behavior of the nonlinear stiffness mechanism. The experiments under different loads and speeds were conducted. The results show that the suspended-load backpack with the nonlinear stiffness mechanism reduces the peak dynamic force by 73.34% under the specified experimental circumstance and by 59.12% in all experimental conditions compared with the generic backpack. [Display omitted] • The nonlinear dynamics model of human and backpack system is presented. • The target force deflection behavior is obtained. • The nonlinear stiffness mechanism is designed by topology optimization. • The lightweight passive backpack can effectively reduce peak force. [ABSTRACT FROM AUTHOR]

Purpose. This study aimed to investigate the potential mechanism underlying the therapeutic effect of sildenafil in combination with islet transplantation for diabetic peripheral neuropathy. Methods. A streptozotocin-induced diabetic mouse model was established to evaluate the effects of islet transplantation and sildenafil intervention. The mice were subjected to different interventions for 6 weeks, and histopathological staining and immunohistochemistry techniques were employed to examine the pathological changes and protein expressions of BDNF, MBP, and cleaved caspase-3 in the sciatic nerve tissue. Moreover, RSC96 cells were cocultured with islet cells and sildenafil under high glucose conditions to investigate the potential involvement of the mTOR/S6K1 pathway, BDNF, and MBP proteins. Western blotting was used to detect protein expression in each group. Results. The results showed that islet transplantation can restore sciatic nerve injury in diabetic mice, and sildenafil can enhance the therapeutic effect of islet transplantation. In addition, the combination of sildenafil and islet cells significantly upregulated the expression levels of mTOR/S6K1, BDNF, and MBP in RSC96 cells under high glucose conditions. Conclusions. Islet transplantation can reverse sciatic nerve injury in diabetic mice, and islet cells exhibit a protective effect on RSC96 cells under high glucose conditions via the activation of the mTOR/S6K1 pathway. Sildenafil enhances the therapeutic effect of islet transplantation, which may represent a potential treatment strategy for diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Irreversible destruction of joints is the hallmark of rheumatoid arthritis (RA). Osteoclasts are the only bone‐resorbing cells and play an important role in joint rebuilding. BML‐111 (5(S),6(R),7‐trihydroxyheptanoic acid methyl ester, C8H16O5) is a synthetic lipoxin A4 agonist with antioxidant and anti‐inflammatory properties. The present study aimed to investigate the effect of BML‐111 on osteoclasts in vivo and in vitro, to investigate its therapeutic effect on joint destruction in RA. Cell Counting Kit‐8 assay and flow cytometry were used to exclude cytotoxic effects of BML‐111 to bone marrow‐derived macrophages (BMMs). Then, osteoclasts were differentiated in vitro from BMMs by used macrophage colony‐stimulating factor and receptor activator of nuclear factor‐κB ligand, and osteoclasts were observed following tartrate‐resistant acid phosphatase staining with or without BML‐111 treatment. Meanwhile, absorption pit assay and immunofluorescence staining of the fibrous actin ring were used to observe osteoclast function. Moreover, we examined mitogen‐activated protein kinase (MAPK) and nuclear factor‐κB (NF‐κB) activation. We established collagen‐induced arthritis in a rat model and, after treatment with BML‐111, joint swelling was measured and the knee joints were processed for histology. We also examined serum and tissue for osteoclastogenesis‐related markers. BML‐111 inhibited osteoclast formation and differentiation in a time‐ and concentration‐dependent manner, and downregulated the expression levels of MAPK and NF‐κB in vitro. Meanwhile, BML‐111 effectively alleviated joint structural damage and inhibited osteoclast formation in vivo. BML‐111 inhibited osteoclast formation and differentiation in vitro and in vivo, and delayed the progression of joint destruction. [ABSTRACT FROM AUTHOR]

Sedum sarmentosum Bunge possesses excellent anti-inflammatory properties and was used in the treatment of inflammatory diseases. The aim of the present study was to investigate the efficiency of Sedum sarmentosum Bunge extract (SSBE) on severe acute pancreatitis-associated (SAP-associated) acute lung injury (ALI) in rats and to explore the underlying mechanisms. Here, we used a sodium taurocholate-induced SAP rat model to determine the role of SSBE in ALI. During the course of pancreatitis, the expressions of phosphorylated phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt) and nuclear factor-kappa B (NF-κB) p65 in the lungs were upregulated. Meanwhile, a parallel increase in the levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the lungs was observed after the induction of SAP. Treatment with SSBE significantly reduced the expression of p-Akt and p-p65 in the lungs and attenuated the severity of SAP-associated ALI compared to the SAP group at 12 h and 24 h. In summary, this study showed that SSBE has beneficial effects on SAP-associated ALI, probably through the PI3-K/Akt signaling pathways by suppressing the NF-κB activities. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) have been reported to be involved in many important biological processes including proliferation, apoptosis, differentiation, and survival. Recently, nuclear paraspeckle assembly transcript 1 (NEAT1), a novel lncRNA, serves as a crucial regulator in tumors. However, the biological role of NEAT1 in liver fibrosis is largely unknown. In this study, the role of NEAT1 was explored in primary mouse hepatic stellate cells (HSCs) and carbon tetrachloride (CCl)-induced mouse liver fibrosis models. We found that NEAT1 expression was significantly increased in CCl-induced mice and activated HSCs. Loss of NEAT1 suppressed liver fibrosis in vivo and in vitro. Conversely, NEAT1 overexpression accelerated HSC activation, including increased cell proliferation and collagen expression. Further studies indicated that the microRNA-122 (miR-122)-Kruppel-like factor 6 (KLF6) axis was involved in the effects of NEAT1 on HSC activation. The effects of NEAT1 on HSC activation were almost blocked down by miR-122 mimics or KLF6 knockdown. Interestingly, both NEAT1 and KLF6 are targets of miR-122. In addition, miR-122 led to a significant reduction in NEAT1 level while NEAT1 overexpression resulted in the suppression of miR-122 expression. Pull-down assay confirmed a direct interaction between miR-122 and NEAT1. NEAT1 contributes to HSC activation via the miR-122-KLF6 axis. In human fibrotic liver samples, increased NEAT1 levels positively correlated with liver fibrosis markers. In conclusion, we disclose a novel NEAT1-miR-122-KLF6 signaling cascade and its implication in liver fibrosis. Key messages: [ABSTRACT FROM AUTHOR]

Background/Aims: Wnt/β-catenin pathway is involved in liver fibrosis and microRNAs (miRNAs) are considered as key regulators of the activation of hepatic stellate cells (HSCs). A recent study showed the protective role of miR-378a-3p against cardiac fibrosis. However, whether miR-378a-3p suppresses Wnt/β-catenin pathway in liver fibrosis is largely unknown. Methods: miR-378a-3p expression was detected in carbon tetrachloride-induced liver fibrosis and activated HSCs. Effects of miR-378a-3p overexpression on HSC activation and Wnt/β-catenin pathway were analyzed. Bioinformatic analysis was employed to identify the potential targets of miR-378a-3p. Serum miR-378a-3p expression was analyzed in patients with cirrhosis. Results: Reduced miR-378a-3p expression was observed in the fibrotic liver tissues and activated HSCs. Up-regulation of miR-378a-3p inhibited HSC activation including cell proliferation, α-smooth muscle actin (α-SMA) and collagen expression. Moreover, miR- 378a-3p overexpression resulted in Wnt/β-catenin pathway inactivation. Luciferase reporter assays demonstrated that Wnt10a, a member of Wnt/β-catenin pathway, was confirmed to be a target of miR-378a-3p. By contrast, miR-378a-3p inhibitor contributed to HSC activation, with an increase in cell proliferation, α-SMA and collagen expression. But all these effects were blocked down by silencing of Wnt10a. Notably, sera from patients with cirrhosis contained lower levels of miR-378a-3p than sera from healthy controls. Receiver operating characteristic curve analysis suggested that serum miR-378a-3p differentiated liver cirrhosis patients from healthy controls, with an area under the curve of ROC curve of 0.916. Conclusion: miR-378a- 3p suppresses HSC activation, at least in part, via targeting of Wnt10a, supporting its potential utility as a novel therapeutic target for liver fibrosis. [ABSTRACT FROM AUTHOR]

Previously, we found that long intergenic noncoding RNA-p21 (lincRNA-p21) inhibits hepatic stellate cell (HSC) activation and liver fibrosis via p21. However, the underlying mechanism of the antifibrotic role of lincRNA-p21 in liver fibrosis remains largely unknown. Here, we found that lincRNA-p21 expression was significantly downregulated during liver fibrosis. In LX-2 cells, the reduction of lincRNA-p21 induced by TGF-β1 was in a dose- and time-dependent manner. lincRNA-p21 expression was reduced in liver tissues from patients with liver cirrhosis when compared with that of healthy controls. Notably, lincRNA-p21 overexpression contributed to the suppression of HSC activation. lincRNA-p21 suppressed HSC proliferation and induced a significant reduction in α-SMA and type I collagen. All these effects induced by lincRNA-p21 were blocked down by the loss of PTEN, suggesting that lincRNA-p21 suppressed HSC activation via PTEN. Further study demonstrated that microRNA-181b (miR-181b) was involved in the effects of lincRNA-p21 on HSC activation. The effects of lincRNA-p21 on PTEN expression and HSC activation were inhibited by miR-181b mimics. We demonstrated that lincRNA-p21 enhanced PTEN expression by competitively binding miR-181b. In conclusion, our results disclose a novel lincRNA-p21-miR-181b-PTEN signaling cascade in liver fibrosis and suggest lincRNA-p21 as a promising molecular target for antifibrosis therapy. [ABSTRACT FROM AUTHOR]

Compliant mechanisms with corrugated flexure units have been attracting increasing attention due to their large range of motion. However, most research has considered in-plane compliance, whereas the out-of-plane performance, which affects the load-carrying ability, has seldom been studied. In this paper, an analytical model for the spatial compliance of a corrugated flexure translational joint is formulated. The in-plane compliance of the corrugated flexure translational joint is modeled by the Maxwell–Mohr method and compliance matrix method. For the out-of-plane compliance, a modification method is proposed for the closed-form analytical solution based on a finite element analysis with shell elements. The corrugated flexure translational joint is further optimized to achieve a high in-plane and out-of-plane off-axis stiffness ratio, low first-order natural frequency, and large range of motion. Experiments were conducted to verify the effectiveness of the method. • The spatial compliance of a corrugated flexure beam is formulated. • For out-of-plane compliance, a modification method is proposed with shell elements. • The corrugated flexure translational joint was further optimized. • The experimental results have good agreement with the analytical solution. [ABSTRACT FROM AUTHOR]

We designed a high-viscosity antimicrobial hydrogel patch (HDC-bFGF), using 1,4-butanediol dimethacrylate as the cross-linking agent, with cross-linked hyaluronic acid serving as the backbone. Additionally, dopamine and chitosan were incorporated as cross-linkers, and the surface was spray-coated with microspheres containing bFGF. This hydrogel patch possesses anti-inflammatory, antioxidant, antimicrobial, and angiogenesis-promoting properties, which can accelerate the healing of wounds. It significantly accelerated the healing of infected wounds in an acute wound model in mice. [Display omitted] The current wound healing process faces numerous challenges such as bacterial infection, inflammation and oxidative stress. However, wound dressings used to promote wound healing, are not well suited to meet the clinical needs. Hyaluronic acid (HA) not only has excellent water absorption and good biocompatibility but facilitates cell function and tissue regeneration. Dopamine, on the other hand, increases the overall viscosity of the hydrogel and possesses antioxidant property. Furthermore, chitosan exhibits outstanding performance in antimicrobial, anti-inflammatory and antioxidant activities. Basic fibroblast growth factor (bFGF) is conducive to cell proliferation and migration, vascular regeneration and wound healing. Hence, we designed an all-in-one hydrogel patch containing dopamine and chitosan framed by hyaluronic acid (HDC) with sprayed gelatin methacryloyl (GelMA) microspheres loaded with bFGF (HDC-bFGF). The hydrogel patch exhibits excellent adhesive, anti-inflammatory, antioxidant and antibacterial properties. In vitro experiments, the HDC-bFGF hydrogel patch not only showed significant inhibitory effect on RAW cell inflammation and Staphylococcus aureus (S. aureus) growth but also effectively scavenged free radicals, in addition to promoting the migration of 3 T3 cells. In the mice acute infected wound model, the HDC-bFGF hydrogel patch adhered to the wound surface greatly accelerated the healing process via its anti-inflammatory and antioxidant activities, bacterial inhibition and pro-vascularization effects. Therefore, the multifunctional HDC-bFGF hydrogel patch holds great promise for clinical application. [ABSTRACT FROM AUTHOR]

Periplocin, a natural compound, has been shown to induce apoptosis in a variety of cancer cells. However, no research has been conducted to demonstrate that Periplocin has a regulatory effect on autophagy. This study is aimed to determine the effect of Periplocin treatment on autophagy in human pancreatic cancer cells, as well as the underlying mechanisms. Pancreatic cancer cells were treated with different concentrations of Periplocin, and real-time cell analysis (RTCA), colony formation assay, and Ki67 immunofluorescence detection were used to determine cell proliferation. Autophagy protein was detected by immunofluorescence and western blotting. Western blotting was also used to detect the caspase family of apoptotic proteins. Flow cytometry and TUNEL staining were used to detect cell apoptosis. Following treatment with Periplocin, the expression of autophagy genes was detected using RNA-seq. In vivo examination of the effect of Periplocin on autophagy in pancreatic was performed using a xenograft model. Periplocin inhibits the proliferation of CFPAC1 and PANC1 cells and induces autophagy by regulating the AMPK/mTOR pathway. Using the AMPK inhibitor Compound C(CC), both the Periplocin-induced inhibition of cell proliferation and autophagy activation was reduced, which further verified this conclusion. Periplocin inhibits CFPAC1 xenograft tumor growth in nude mice and increases tumor cell autophagy. Collectively, these results have shown that Periplocin promotes autophagy in human pancreatic cancer cells by regulating the AMPK/mTOR pathway. [ABSTRACT FROM AUTHOR]

At present, the number of diabetes patients has exceeded 537 million worldwide and this number continues to increase. Stem cell therapy represents a new direction for the treatment of diabetes; the use of stem cells overcomes some shortcomings associated with traditional therapies. Functional β cells play an important role in the pathogenesis of diabetes. As therapeutic targets, functional β cells are restored by a variety of stem cells, including pluripotent stem cells, mesenchymal cells, and urine-derived stem cells. Although all types of stem cells have their own characteristics, they mainly promote the repair and regeneration of β cells through directional differentiation, immunomodulation, and paracrine signaling after homing to the injured site. However, stem cell therapy still faces many obstacles, such as low long-term cell survival rate after transplantation, low maintenance time of blood glucose homeostasis, immune rejection, and tumorigenesis. Recently, genetically edited pluripotent stem cells and the cotransplantation of mesenchymal stem cells and islet cells have made significant progress in improving the efficacy of stem cell transplantation processes, also providing powerful tools for the study of the mechanisms underlying diabetes and disease modeling. In this review, we first focused on: (1) stem cells as a pool for the differentiation of insulin-producing cells; (2) stem cells as a source for regenerative repair of damaged islets and as a potential cotransplanted population with islets; (3) the potential of combining gene editing with stem cell therapy; and (4) selection of the stem cell transplantation approach. Based on these topics, we discuss the challenges within the field of adapting stem cell-supported and stem cell-derived transplantations and the promising routes for overcoming these problems. [ABSTRACT FROM AUTHOR]

The airflow and dispersion of a pollutant in a complex urban area of Beijing, China, were numerically examined by coupling a Computational Fluid Dynamics (CFD) model with a mesoscale weather model. The models used were Open Source Field Operation and Manipulation (OpenFOAM) software package and Weather Research and Forecasting (WRF) model. OpenFOAM was firstly validated against wind-tunnel experiment data. Then, the WRF model was integrated for 42 h starting from 0800 LST 08 September 2009, and the coupled model was used to compute the flow fields at 1000 LST and 1400 LST 09 September 2009. During the WRF-simulated period, a high pressure system was dominant over the Beijing area. The WRF-simulated local circulations were characterized by mountain valley winds, which matched well with observations. Results from the coupled model simulation demonstrated that the airflows around actual buildings were quite different from the ambient wind on the boundary provided by the WRF model, and the pollutant dispersion pattern was complicated under the influence of buildings. A higher concentration level of the pollutant near the surface was found in both the step-down and step-up notches, but the reason for this higher level in each configurations was different: in the former, it was caused by weaker vertical flow, while in the latter it was caused by a downward-shifted vortex. Overall, the results of this study suggest that the coupled WRF-OpenFOAM model is an important tool that can be used for studying and predicting urban flow and dispersions in densely built-up areas. [ABSTRACT FROM AUTHOR]

Objective. Abnormal signaling pathways play a crucial role in the mechanisms of podocyte injury in diabetic nephropathy. They also affect the recovery of podocytes after islet transplantation (IT). However, the specific signaling abnormalities that affect the therapeutic effect of IT on podocytes remains unclear. The purpose of this study was to assess whether the RhoA/ROCK/NF-κB signaling pathway is related to podocyte restoration after IT. Methods. A mouse model of diabetic nephropathy was established in vivo using streptozotocin. The mice were then subsequently reared for 4 weeks after islet transplantation to determine the effect of IT. Islet cells, CCG-1423 (RhoA Inhibitor), and fasudil (ROCK inhibitor) were then cocultured with podocytes in vitro to assess their protective effects on podocyte injury induced by high glucose (HG). Protein expression levels of RhoA, ROCK1, synaptopodin, IL-6, and MCP-1 in kidney tissues were then measured using immunohistochemistry and Western blotting techniques. Results. Islet transplantation reduced the expression levels of RhoA/ROCK1 and that of related inflammatory factors such as IL-6 and MCP-1 in the kidney podocytes of diabetic nephropathy. In the same line, islet cells reduced the expression of RhoA, ROCK1, and pp65 in immortalized podocytes under high glucose (35.0 mmol/L glucose) conditions. Conclusions. Islet transplantation can reverse podocyte injury in diabetes nephropathy by inhibiting the RhoA/ROCK1 signaling pathway. Islet cells have a strong protective effect on podocytes treated with high glucose (35.0 mmol/L glucose). Discovery of signaling pathways affecting podocyte recovery is helpful for individualized efficacy evaluation and targeted therapy of islet transplantation patients. [ABSTRACT FROM AUTHOR]

Background: Periplocin is a monomeric compound that exhibits anti‐tumor activities. It is extracted from Cortex Periplocae. Objective: This study aimed at determining the effect of periplocin treatment on the apoptosis and proliferation of human pancreatic cancer cells, and to elucidate on its mechanisms of action. Methods: PANC1 and cfpac1 cells were treated with periplocin. Cell proliferation was detected by RTCA, Ki67 immunofluorescence, and a clonogenic assay. The transwell assay was used to examine cell migration and invasion functions. The expression of apoptosis‐associated proteins was detected by flow cytometry and western blotting. Total RNA was extracted from the treated and untreated group of PANC1 cells for RNA‐seq detection and analysis. Differentially expressed genes were screened for GO biological process and KEGG pathway analysis. Finally, CFPAC1 cells were subcutaneously inoculated into BALB / c nude mice to assess tumor growth. Results: Periplocin inhibited the proliferation of PANC1 and CFPAC1 cells and induced their apoptosis by activating the AMPK/mTOR pathway and inhibiting p70 S6K. It also attenuated the cell migration, invasion, and inhibited the growth of cfpac1 xenografts in nude mice. Conclusions: Periplocin inhibits human pancreatic cancer cell proliferation and induces their apoptosis by activating the AMPK / mTOR pathway. [ABSTRACT FROM AUTHOR]

Improving the functionality of soft continuum manipulators to expand their application space has always been an important development direction for soft robotics. It remains very challenging to calculate the deformations of soft materials and predict the basic structure of soft fingers under complex objective functions and constraints. This work develops a cable-driven soft robotic gripper with multi-input and multi-output using topology optimization considering geometric nonlinearity, which not only performs adaptive grasping but also enables finer manipulations such as rotating or panning the target. A scheme that can describe adaptive grasping behavior is proposed, which converts the contact between the clamping surface and the object into a boundary condition to circumvent complex contact nonlinearities. An additive hyperelasticity technique is used to overcome numerical instabilities, and the finite element analysis is performed in ANSYS. Numerical simulations and experimental results are performed to demonstrate the effectiveness of the optimization algorithm and to illustrate the application potential of the proposed gripper. [ABSTRACT FROM AUTHOR]

Tubulointerstitial fibrosis (TIF) is a common final endpoint of chronic allograft nephropathy. Over the years, several hypotheses have been developed to explain the progression of TIF, including mechanisms such as inflammation, epithelial-mesenchymal transition, senescence, chronic hypoxia and reactive oxygen species. Furthermore, TIF is reportedly induced by the 'damage-proliferation-death' cycle. In the present study, an AA renal fibrosis model was established in vitro to investigate whether the vicious proliferation-death cycle is a pathophysiological process of TIF following chronic injury to the kidneys. Results from the present study revealed that cell death was associated with the entrance of cells into the cell cycle. Genetic knockdown of p21 was observed to increase cell cycle progression and the proliferative rate of cells, which overall promoted increased rates of cell death. In addition, the activation of the DNA damage response (DDR) signaling pathway was demonstrated to be crucial to the initiation of the vicious cycle of 'proliferation-death'. Ataxia telangiectasia mutated (ATM) is an important molecule of the DDR and the genetic knockdown of ATM induced apoptosis, increased cell proliferation and promoted cell death. The increase in apoptosis was suggested to be due to the decreased expression levels of p21 observed following the genetic knockdown of ATM. In conclusion, the present study suggested that the crosstalk between the ATM and p21 protein may serve an important role in the regulation of the 'proliferation-death' cycle in the progress of chronic tubulointerstitial injury. [ABSTRACT FROM AUTHOR]

Observational data from two field campaigns in the Amazon forest were used to study the vertical structure of turbulence above the forest. The analysis was performed using the reduced turbulent kinetic energy (TKE) budget and its associated two-dimensional phase space. Results revealed the existence of two regions within the roughness sublayer in which the TKE budget cannot be explained by the canonical flat-terrain TKE budgets in the canopy roughness sublayer or in the lower portion of the convective ABL. Data analysis also suggested that deviations from horizontal homogeneity have a large contribution to the TKE budget. Results from LES of a model canopy over idealized topography presented similar features, leading to the conclusion that flow distortions caused by topography are responsible for the observed features in theTKEbudget. These results support the conclusion that the boundary layer above the Amazon forest is strongly impacted by the gentle topography underneath. [ABSTRACT FROM AUTHOR]

The effects of hydriding degree on the microstructure and magnetic properties of sintered NdFeB magnets have been studied. The degree of crushing depends on the absorption content of hydrogen and affects the magnetic properties of final magnet. Insertion of hydrogen atoms leads to a significant increase of the unit cell volume. And the crush mechanism depends on the internal stress resulting from differences in the expansion rates of the two phases. The remanence of final magnets increases monotonously while the coercivity decreases sharply with the increasing of hydriding degree, attributed to the strip fracture features and the morphology of particles. [ABSTRACT FROM AUTHOR]

Adipose-derived mesenchymal stem cells (ASCs) play a positive role in tissue injury repair and regeneration. The aim of this study was to determine whether ASCs could ameliorate chronic pancreatitis (CP) induced by the injection of dibutyltin dichloride (DBTC) and to elucidate its potential mechanisms. Furthermore, this study also explored whether there was a significant difference if the ASCs were injected via the inferior vena cava or the left gastric artery. CP was induced in rats by a single intravenous administration of DBTC, and the accumulation of collagen and apoptotic rates of pancreatic acinar cells were analyzed. According to the results, ASCs markedly reduced DBTC-induced pancreatic damage and collagen deposition in the rat model of CP. Moreover, ASCs significantly decreased pancreatic cell apoptosis by regulating the expression levels of caspase-3, BAX and Bcl-2. These effects were observed regardless of whether the injection was in the inferior vena cava or the left gastric artery. It was also found that the expression levels of phosphorylated PI3K, AKT and mTOR in pancreatic tissues of the DBTC-induced CP model group were significantly increased, while the expression levels of phosphorylated PI3K, AKT and mTOR in the two treatment groups were markedly decreased. ASCs noticeably suppressed the PI3K/AKT/mTOR pathway in the pancreatic tissue of DBTC-induced CP. This study indicated that ASCs protect against pancreatic fibrosis by modulating the PI3K/AKT/mTOR pathway, and have the potential to be a new strategy for the treatment of CP in the future. [ABSTRACT FROM AUTHOR]

Objective. Posttransplantation diabetes mellitus (PTDM) is a known complication of transplantation that affects the prognosis. Tacrolimus (Tac or FK506) is a widely used immunosuppressant that has been reported to be a risk factor for PTDM and to further induce complications in heart and skeletal muscles, but the mechanism is still largely unknown. In our preliminary experiments, we found that after Tac treatment, blood glucose increased, and the weight of skeletal muscle declined. Here, we hypothesize that tacrolimus can induce PTDM and influence the atrophy of skeletal muscle. Methods. We designed preliminary experiments to establish a tacrolimus-induced PTDM model. Gene expression profiles in quadriceps muscle from this rat model were characterized by oligonucleotide microarrays. Then, differences in gene expression profiles in muscle from PTDM rats that received tacrolimus and control subjects were analyzed by using GeneSpring GX 11.0 software (Agilent). Functional annotation and enrichment analysis of differentially expressed genes (DEGs) helped us identify clues for the side effects of tacrolimus. Results. Our experiments found that the quadriceps in tacrolimus-induced PTDM group were smaller than those in the control group. The study identified 275 DEGs that may be responsible for insulin resistance and the progression of PTDM, including 86 upregulated genes and 199 downregulated genes. GO and KEGG functional analysis of the DEGs showed a significant correlation between PTDM and muscle development. PPI network analysis screened eight hub genes and found that they were related to troponin and tropomyosin. Conclusions. This study explored the molecular mechanism of muscle atrophy in a tacrolimus-induced PTDM model by bioinformatics analyses. We identified 275 DEGs and identified significant biomarkers for predicting the development and progression of tacrolimus-induced PTDM. [ABSTRACT FROM AUTHOR]

The aim of the present study was to explore the role of ataxia-telangiectasia mutated (ATM) in lipopolysaccharide (LPS)-induced in vitro model of septic acute kidney injury (AKI) and the association between ATM, tubular epithelial inflammatory response and autophagy. The renal tubular epithelial cell HK-2 cell line was cultured and passaged, with HK-2 cell injury induced by LPS. The effects of LPS on HK-2 cell morphology, viability, ATM expression and inflammation were observed. Lentiviral vectors encoding ATM shRNA were constructed to knock down ATM expression in HK-2 cells. The efficiency of ATM knockdown in HK-2 cells was detected by western blot analysis and reverse transcription-quantitative PCR (RT-qPCR). HK-2 cells transfected with the ATM shRNA lentivirus were used for subsequent experiments. Following ATM knockdown, corresponding controls were set up, and the effects of ATM on inflammation and autophagy were detected in HK-2 cells using RT-qPCR, western blotting and ELISA. After LPS stimulation, the HK-2 cells were rounded into a slender or fusiform shape with poorly defined outlines. LPS treatment reduced cell viability in a partly dose-dependent manner. LPS increased the expression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6, with the levels reaching its highest value at 10 µg/ml. IL-6 and IL-1β expression increased with increasing LPS concentration. These findings suggest that LPS reduced HK-2 cell viability whilst increasing the expression of inflammatory factors. Following transfection with ATM shRNA, expression levels of key autophagy indicators microtubule associated protein 1 light chain 3α I/II ratio and beclin-1 in the two ATM shRNA groups were also significantly reduced compared with the NC shRNA group. In summary, downregulation of ATM expression in HK-2 cells reduced LPS-induced inflammation and autophagy in sepsis-induced AKI in vitro, suggesting that LPS may induce autophagy in HK-2 cells through the ATM pathway leading to the upregulation of inflammatory factors. [ABSTRACT FROM AUTHOR]

Testicular structural and functional impairment is a serious complication in male diabetes mellitus (DM) patients that leads to impaired fertility in adulthood. In contrast to other endocrine therapies, islet transplantation (IT) can effectively prevent and even reverse diabetic nephropathy and myocardial damage. However, whether IT can alleviate diabetes-induced testicular injury remains unclear. In this study, we sought to investigate the effect of IT on diabetes-induced testicular damage. A diabetic rat model was established by streptozotocin injection. DM, IT, and insulin treatment (INS) groups were compared after 4 weeks of respective treatment. We confirmed that IT could effectively attenuate diabetes-induced testicular damage and recover sperm counts more extensively compared with INS in diabetic rats. In addition, significantly higher levels of superoxide dismutase (SOD) activity and lower contents of malondialdehyde (MDA) were detected in the testes of the IT group versus diabetic rats. Mechanism studies revealed that IT significantly activates the expression of Nrf-2, HO-1, and NQO-1 and inhibits upregulation of the NF-κB expression in response to DM, while INS only exhibit slight impact on the protein expression. Therefore, we speculate that IT may prevent the progression of testicular damage by downregulating oxidative stress and inhibiting inflammation via Nrf-2/HO-1 and NF-κB pathways. [ABSTRACT FROM AUTHOR]

• A novel bistable mechanism with a maximized difference between switching forces in forward and backward direction is designed using topology optimization. • An approximate expression of the sensitivity is deduced to obtain the derivatives from ANSYS during topology optimization. • The experimental studies indicate that the optimized mechanism is more robust to external disturbances than the conventional mechanisms based on inclined straight beams or preshaped curved beams. A small bistable mechanism with a strong robustness to external disturbances is eagerly desired in many practical applications. The difference between the switching forces in forward and backward directions is a critical parameter influencing the robustness. However, the difference decreases with the size of bistable mechanisms. This study designs robust bistable mechanisms with maximized differences between the reaction forces at the desired critical points using topology optimization. The reaction forces are obtained by finite element analysis (FEA). Geometric constraints of the minimum length scale in topology optimization are employed to reduce the requirement on fabrication. An additive hyperelasticity technique is utilized to ensure the convergence of the nonlinear finite element problems. An approximate expression of the sensitivity is deduced to obtain the derivatives from ANSYS. The experimental studies indicate that the optimized mechanism is more stable than the conventional mechanisms based on inclined straight beams or preshaped curved beams. [ABSTRACT FROM AUTHOR]

Our previous studies verified the potent anti-inflammatory effects against severe acute pancreatitis (SAP) of AT-Lipoxin A4 and their analogues. However, the anti-inflammatory effects of AT-Lipoxin A4 on SAP-associated lung injury are not thoroughly known. We used western blot, polymerase chain reaction (PCR), and immunofluorescence to investigate the downregulation of TNF-α signals in cellular and animal models of SAP-associated lung injury following AT-Lipoxin A4 intervention. In vitro, we found that AT-Lipoxin A4 markedly suppressed protein expression in TNF-α signals in human pulmonary microvascular endothelial cell, such as tumor necrosis factor receptor-associated factor 2 (TRAF2), TNF-R1-associated death domain (TRADD), receptor-interacting protein (RIP), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, AT-Lipoxin A4 inhibited downstream signals activated by TNF-α, including NF-κB/p65, JNK/MAPK, and ERK/MAPK. In vivo, AT-Lipoxin A4 significantly decreased pathological scores of the pancreas and lungs and the serum levels of IL-6 and TNF-α. Immunofluorescence, western blotting, and real-time PCR assay showed that AT-Lipoxin A4 significantly attenuated the expression of TNF-R1, TRADD, TRAF2, and RIP in the lungs of SAP rats. In addition, the activation of NF-κB was also downregulated by AT-Lipoxin A4 administration as compared with SAP rats. AT-Lipoxin A4 could inhibit the production of proinflammatory mediators and activation of TNF-α downstream signals such as NF-κB and MAPK. Downregulation of TNF-α signals by AT-Lipoxin A4 may be a significant mechanism in the attenuation of SAP-associated lung injury. [ABSTRACT FROM AUTHOR]

Highlights • Acute lung injury is the most common complications of acute pancreatitis with significant morbidity and mortality rates. • LXA4 exerts protective eff ;ects on AP-induced ALI. • LXA4 can reduce alveolar fluid exudation and maintain the clearance of alveolar fluid. Abstract An essential component of acute pancreatitis(AP)-induced acute lung injury(ALI) is the inflammation that is part of the body's systemic inflammatory response to a variety of systemic stimuli. Lipoxins(LXs) are considered important endogenous lipids that mediate the resolution of inflammation. In previous studies, we found that Lipoxin A4 (LXA4) reduced AP-induced pulmonary oedema and TNF-α production in lung. However, the underlying mechanism remains unclear. Due to the above studies, we investigated the aquaporin, matrix metalloprotein, apoptosis and PKC/SSeCKS signal pathway in cellular and animal models of AP-associated lung injury following LXA4 intervention. In this study, we first proved LXA4 could effectively promote F-actin reconstruction and regulate its expression in pulmonary microvascular endothelial cells both in vivo and vitro via suppressing PKC/SSeCKS signalling pathway. Next, we found that LXA4 attenuated cell growth inhibition and apoptosis in lung tissues of AP-ALI mice and HPMECs. Additionally, we demonstrated that LXA4 could regulate the expression of AQP-5 and MMP-9 to stabilize the permeability of pulmonary microvascular endothelial cell. In summary, our results suggest that the anti-inflammatory eff ;ects of LXA4 may be due to the inhibition of both the PKC/SSeCKS pathway and apoptosis to reduce alveolar fluid exudation and to the regulation of AQP-5 and MMP-9 expression to maintain the clearance of alveolar fluid. Thus, LXA4 is capable of exerting protective eff ;ects on AP-induced ALI. [ABSTRACT FROM AUTHOR]

The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour-associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2-like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia-inducible factor-1α (HIF-1α), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase-9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF-1 and phosphorylated-signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2-like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF-1α and STAT3 signalling pathways. [ABSTRACT FROM AUTHOR]

Gefitinib is effective for patients with non-small cell lung cancer (NSCLC) with a mutation in the epidermal growth factor receptor (EGFR) gene, which makes the detection of EGFR mutations a critical step prior to determining a treatment schedule. Therefore, the present study determined the EGFR mutation status in patients with NSCLC using an allele refractory mutation system (ARMS) and analyzed the detection ratio for different specimen types. A total of 1,596 NSCLS samples were collected and EGFR gene mutations were detected on exons 18–21 using ARMS and direct sequencing. The concordance of two methods reached 89.21%, with a total mutation rate of 45.55% (727/1,596), in which the mutation rate in lung adenocarcinoma samples was markedly increased compared with squamous cell carcinoma (51.77 vs. 8.68%). In patients with lung adenocarcinoma, EGFR mutations were more frequent in female patients than male patients (65.53 vs. 39.80%, P<0.01); there was no observable difference depending on age. Similar results were obtained for squamous cell carcinoma. In the present study, certain rare mutations were also identified; these may be subjects for further study. The impact of different sample types on the consistency between the methods was determined to be insignificant. ARMS is a more applicable approach for large-scale clinical detection than direct sequencing, and we hypothesize that ARMS may replace direct sequencing if the drawbacks of ARMS, including its narrow detection range, can be amended. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common cancers diagnosed worldwide. However, the mechanism underlying HCC pathogenesis remains unknown. In the present study, TRIM24 was found increased in human HCC clinical samples and positively correlated with HCC tumor grade. Furthermore, TRIM24 knockdown inhibits proliferation and migration in a human HCC cell line in vitro while also inhibiting tumor growth in vivo. Mechanistically, TRIM24 appears to promote liver tumor development via AMPK signaling as AMPK knockdown alleviated the in vitro and in vivo effects of TRIM24 knockdown in a human HCC cell line. Taken together, these data enhance our understanding of HCC development in addition to highlighting TRIM24-regulated AMPK signaling as a potential therapeutic target for HCC treatment. [ABSTRACT FROM AUTHOR]

The identification and characterization of long non‐coding RNAs (lncRNAs) in diverse biological process has currently developed rapidly. LncRNA‐PVT1, located adjacent to the MYC locus on chromosomal region 8q24, has been reported to be associated with many biological processes. However, the function and mechanism of PVT1 in pancreatic carcinoma (PC) is poorly understood. In this present study, we first measured the level of PVT1 in the PC cell lines and tissues by quantitative real‐time PCR (qRT‐PCR), and then employed loss‐of‐function and gain‐of‐function approaches to explore the association between PVT1 expression levels and PC cell proliferation/migration ability. Furthermore, bioinformatics analysis was utilized to show that PVT1 contains binding site for miR‐448 and an inverse correlation between PVT1 and miR‐448 was obtained in PC specimens. Additionally, dual luciferase reporter assay, RNA‐binding protein immunoprecipitation (RIP) and applied biotin‐avidin pulldown system were applied to further confirm that PVT1 directly bind with microRNA binding site harboring in the PVT1 sequence. Then, SERBP1 was identified as a target of miR‐448 according to the gene expression array analysis of PC clinical samples. Together, we revealed that PVT1 functions as an endogenous “sponge” by competing for miR‐448 binding to regulate the miRNA target SERBP1 and, therefore, promotes the proliferation and migration of PC cells. [ABSTRACT FROM AUTHOR]

Background/Aims: The activation of hepatic stellate cells (HSCs) is considered as a pivotal event in liver fibrosis and epithelial-mesenchymal transition (EMT) process has been reported to be involved in HSC activation. It is known that microRNAs (miRNAs) play a pro-fibrotic or anti-fibrotic role in HSC activation. Recently, emerging studies show that miR-30a is down-regulated in human cancers and over-expression of miR-30a inhibits tumor growth and invasion via suppressing EMT process. However, whether miR-30a could regulate EMT process in HSC activation is still unclear. Methods: miR-30a expression was quantified using real-time PCR in carbon tetrachloride (CCl4)-induced rat liver fibrosis, activated HSCs and patients with cirrhosis. Roles of miR-30a in liver fibrosis in vivo and in vitro were also analyzed. Luciferase activity assays were performed to examine the binding of miR-30a to the 3′-untranslated region of snail family transcriptional repressor 1 (Snai1). Results: miR-30a was down-regulated in human cirrhotic tissues. In CCl4 rats, reduced miR-30a was found in fibrotic liver tissues as well as isolated HSCs. There was a significant reduction in miR-30a in primary HSCs during culture days. miR-30a over-expression resulted in the suppression of CCl4-induced liver fibrosis. Restoration of miR-30a led to the inhibition of HSC activation including cell proliferation, α-SMA and collagen expression. Notably, miR-30a inhibited EMT process, with a reduction in TGF-β1 and Vimentin as well as an increase in GFAP and E-cadherin. miR-30a induced a significant reduction in Snai1 protein expression when compared with the control. Interestingly, Snail protein expression was increased during liver fibrosis, indicating that there may be a negative correlation between miR-30a level and Snai1 protein expression. Further studies demonstrated that Snai1 was a target of miR-30a. Conclusion: Our results suggest that miR-30a inhibits EMT process, at least in part, via reduction of Snai1, leading to the suppression of HSC activation in liver fibrosis. [ABSTRACT FROM AUTHOR]