Myeloid-related protein 8/14 complex describes microcirculatory alterations in patients with type 2 diabetes and nephropathy

<p>Abstract</p> <p>Background</p> <p>Inflammation contributes to cardiovascular complications in type 2 diabetes, which are often characterized by microvascular alterations. We investigated whether myeloid-related protein 8/14 complex (MRP8/14) secreted by transmigrating monocytes and granulocytes may represent a biomarker for microvascular alterations in patients with type 2 diabetes and nephropathy.</p> <p>Methods</p> <p>MRP8/14 was measured in 43 patients with type 2 diabetes and nephropathy. Additionally, the inflammatory markers Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were quantified. To detect microvascular alterations proteinuria and retinal vessel caliber were used as classical and novel marker, respectively. Proteinuria was quantified by protein-creatinine ratio (PCR); retinal vessel caliber was quantified after retina photography on digitalized retina pictures.</p> <p>Results</p> <p>MRP8/14 was positively associated with inflammation (<it>r </it>= 0.57), proteinuria (<it>r </it>= 0.40) and retinal arterial caliber (<it>r </it>= 0.48). Type 2 diabetic patients with MRP8/14 values above the median of 5.8 μg/ml demonstrated higher proteinuria and larger retinal artery caliber than patients with MRP8/14 values below the median (logPCR: -0.51 ± 0.52 versus -0.96 ± 0.46, <it>P </it>< 0.01; retinal artery lumen (μm): 178.3 ± 14.1 versus 162.7 ± 14.9 <it>P </it>< 0.01). Both groups did not differ with regard to metabolic factors and blood pressure. MRP8/14 was an independent predictor of retinal artery caliber in multivariate stepwise regression analysis (<it>β </it>= 0.607) and was positively associated with IL-6 (<it>r </it>= 0.57, <it>P </it>< 0.001) and TNF-α (<it>r </it>= 0.36, <it>P </it>< 0.05).</p> <p>Conclusion</p> <p>MRP8/14 – a marker for transendothelial migration – describes not only the state of inflammation in diabetic nephropathy, but additionally the degree of microvascular alterations in the glomerular and retinal bed. Therefore, MRP8/14 may be a potentially selective novel biomarker for microcirculatory defects in diabetic nephropathy.</p

Study on the Impact of Filter Layer Permeability on Revetment Top Layer Stability under Wave Action

Abstract: In the design of revetment engineering under wave action, to resist the wave action, the pattern of top layer-filter layer-core (subsoil) is often adopted. In general, the structure of top layer is usually single discrete blocks, typically accropode blocks, four-leg square hollow blocks and barrier boards, and also acropode, riprap, paved rock blocks or concrete slabs with smaller waves. Such top layer has been provided with many research findings on its stability and is widely used in engineering. Setting a filter layer between the top layer and the lower dike core mainly has two functions: (1) giving certain permeability, to minimize the hydrodynamic load directly acting on the lower foundation soil; (2) giving certain hydraulic tightness, to prevent fine sediment of the lower foundation soil from being washed out. This paper is focused on a special filter layer with geotextile as its upper structure and coarse aggregate as its lower structure. By simulating geotextile with different permeability and coarse aggregate with different size, the pressure of top of cover layer and the down side of the geotextile is tested under wave actions, and compared with theoretical analysis, in this way, how the permeability of geotextile impacts the stability of top layer is studied. The research shows that when the filter layer under the geotextile has high permeability and the geotextile&apos;s permeability gets poorer, the uplift force to geotextile and the top layer will be increased under wave action, which will cause damage to the top layer when it is greater than the vertical component of the underwater gravity along the slope surface

Gefitinib for Epidermal Growth Factor Receptor Activated Osteoarthritis Subpopulation Treatment

Osteoarthritis (OA) is a leading cause of physical disability among aging populations, with no available drugs able to efficiently restore the balance between cartilage matrix synthesis and degradation. Also, OA has not been accurately classified into subpopulations, hindering the development toward personalized precision medicine.In the present study, we identified a subpopulation of OA patients displaying high activation level of epidermal growth factor receptor (EGFR). With Col2a1-creERT2; Egfrf/f mice, it was found that the activation of EGFR, indicated by EGFR phosphorylation (pEGFR), led to the destruction of joints. Excitingly, EGFR inhibition prohibited cartilage matrix degeneration and promoted cartilage regeneration. The Food and Drug Administration (FDA)-approved drug gefitinib could efficiently inhibit EGFR functions in OA joints and restore cartilage structure and function in the mouse model as well as the clinical case report.Overall, our findings suggested the concept of the EGFR activated OA subpopulation and illustrated the mechanism of EGFR signaling in regulating cartilage homeostasis. Gefitinib could be a promising disease-modifying drug for this OA subpopulation treatment. Keywords: Osteoarthritis, Disease subpopulation, Epidermal growth factor receptor, Gefitini

Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis

Changes in the stiffness of chondrocyte extracellular matrix (ECM) are involved in the pathological progression of osteoarthritis (OA). However, the downstream responses of cartilage ECM stiffness are still unclear. YAP (Yes-associated protein) has been extensively studied as a mechanotransducer, we thus hypothesized that by targeting the downstream molecule activity of ECM stiffness could maintain chondrocyte phenotype and prevent cartilage degeneration in OA. Here, we showed that human cartilage matrix stiffened during pathological progression of OA, and the chondrocyte YAP activity was associated with ECM stiffness. We then mimicked the physiological and pathological stiffness of human cartilage by using PDMS-based substrates, and found that YAP was activated in chondrocytes seeded on stiff substrate, gradually losing their phenotype. In addition, it was observed that YAP was also significantly activated in mice OA development, and conditional knockout (cKO) of YAP in mice preserved collagen II expression and protected cartilage from degeneration in the OA model. Furthermore, intra-articular injection of YAP-selective inhibitor, Verteporfin, significantly maintained cartilage homeostasis in mice OA model. This study indicates that the application of mechanotransducer-targeted drugs could be a potential therapeutic approach for cartilage repair in OA.</p

Observations of Forbush Decreases of Cosmic-Ray Electrons and Positrons with the Dark Matter Particle Explorer

The Forbush decrease (FD) represents the rapid decrease of the intensities of charged particles accompanied with the coronal mass ejections or high-speed streams from coronal holes. It has been mainly explored with the ground-based neutron monitor network, which indirectly measures the integrated intensities of all species of cosmic rays by counting secondary neutrons produced from interaction between atmospheric atoms and cosmic rays. The space-based experiments can resolve the species of particles but the energy ranges are limited by the relatively small acceptances except for the most abundant particles like protons and helium. Therefore, the FD of cosmic-ray electrons and positrons have just been investigated by the PAMELA experiment in the low-energy range (<5 GeV) with limited statistics. In this paper, we study the FD event that occurred in 2017 September with the electron and positron data recorded by the Dark Matter Particle Explorer. The evolution of the FDs from 2 GeV to 20 GeV with a time resolution of 6 hr are given. We observe two solar energetic particle events in the time profile of the intensity of cosmic rays, the earlier, and weaker, one has not been shown in the neutron monitor data. Furthermore, both the amplitude and recovery time of fluxes of electrons and positrons show clear energy dependence, which is important in probing the disturbances of the interplanetary environment by the coronal mass ejections