This study shows that melanoma-associated fibroblasts (MAFs) suppress cytotoxic T lymphocyte (CTL) activity and reveals a pivotal role played by arginase in this phenomenon. MAFs and normal dermal ...fibroblasts (DFs) were isolated from surgically resected melanomas and identified as Melan-A-/gp100-/FAP+ cells. CTLs of healthy blood donors were activated in the presence of MAF- and DF-conditioned media (CM). Markers of successful CTL activation, cytotoxic degranulation, killing activity and immune checkpoint regulation were evaluated by flow cytometry, ELISPOT, and redirected killing assays. Soluble mediators responsible for MAF-mediated effects were identified by ELISA, flow cytometry, inhibitor assays, and knock-in experiments. In the presence of MAF-CM, activated/non-naïve CTLs displayed dysregulated ERK1/2 and NF-κB signaling, impeded CD69 and granzyme B production, impaired killing activity, and upregulated expression of the negative immune checkpoint receptors TIGIT and BTLA. Compared to DFs, MAFs displayed increased amounts of VISTA and HVEM, a known ligand of BTLA on T cells, increased
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-arginase activity and CXCL12 release. Transgenic arginase over-expression further increased, while selective arginase inhibition neutralized MAF-induced TIGIT and BTLA expression on CTLs. Our data indicate that MAF interfere with intracellular CTL signaling via soluble mediators leading to CTL anergy and modify immune checkpoint receptor availability via
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-arginine depletion.
Graphic abstract
Precision machining of automotive industrial parts is a highlighted topic in mechanical engineering due to the increased need for efficient and high-quality machining processes. This study is aimed ...to contribute to the field of surface topography evaluation by analyzing tribology-related topography parameters parallelly and finding connections between them. Hard machining experiments were carried out for the widely applied case-hardened material 16MnCr5 and the 3D topography of the machined surfaces was measured and analyzed. Based on a comprehensive design of experiments cubic response functions were determined for the analyzed parameters and the coefficients of determination were calculated. It was found that the cubic response function is reliable for predicting the topography parameter values and there are strong relationships between counterpart parameters under certain circumstances The findings could help clarify the roles of the analyzed parameters in some tribological properties within the analyzed cutting circumstances.
3D surface roughness measurement is still a less mature procedure than its 2D version. The size of the evaluation area is not as standardized as the measurement length in the 2D version. The purpose ...of this study is to introduce a method for minimizing the evaluated surface area. This could help industrial applications in minimizing the time and cost of measurements. Machining experiments (hard turning and infeed grinding) and surface roughness measurements were carried out for automotive industrial parts to demonstrate the introduced method. Some frequently used roughness parameters were analyzed. Basic statistical calculations were applied to analyze the relationship between the surface area and the roughness parameter values and regression analyses were applied to validate the results in case of the applied technological data. The main finding of the study is that minimum evaluation areas can be clearly designated and, depending on the different roughness parameter–procedure version, different evaluation sizes (Sa: 1.3 × 1.3 mm; Sq: 1.4 × 1.4 mm; Ssk and Sku: 2 × 2 m; Sp and Sv: 1.7 × 1.7 mm) are recommended.
The asymmetric height distribution of a machined surface can be useful from a tribological point of view in several cases. The purpose of this study is to analyze this asymmetry based on the 3D ...surface texture parameter skewness, providing technological parameter values that help in achieving favorable surfaces. A 16MnCr5 case-hardened steel (62–63 HRC) was machined by hard turning and grinding based on a comprehensive design of experiments and the topography of the surfaces was measured and analyzed. The texture parameter that informs about the height distribution of the surface points (skewness, Ssk) was compared to the volume parameters peak material volume (Vmp) and valley void volume (Vvv). The main finding is that negative Ssk values are found at low Vmp and Vvv values, which confirms the favorable tribological properties.
Several surface topography parameters are available for the quantification of tribological properties of machined surfaces. Although these parameters and their influences are widely studied, there ...are contradictory findings due to the nature of the topography parameters, i.e., the behavior of different materials and cutting tool interactions lead to relatively varying numerical results. A comprehensive study of these interactions can contribute to more exact industrial machining applications. In this study, tribology-related 3D topography parameters of hard-machined (hard-turned and ground) surfaces were analyzed. The machining experiments were carried out based on a detailed design of the experiment; the analyzed material was case-hardened low-carbon content steel, which is widely used for automotive, industrial components such as bearings or gears. From the topography data, response function, correlation, and relative deviation analyses were carried out for the analyzed topography parameters, and tribology maps were created to support the selection of optimal cutting parameter values.
Three-dimensional topography measurement is a focus area of precision machining because it provides detailed information on the functional behavior of contacting surfaces. The purpose of this study ...is to analyze how the process parameters and the edge geometry of the cutting insert influence the topographical characteristics of hardened 16MnCr5 steel surfaces and to determine the favorable combinations of technology parameter values based on the analyzed topography parameters (Ssk, Sku, Sz, Sa, Sk, Spk, Svk). A research question is whether the analyzed parameters can be substituted by each other or not. A hard turning experiment was carried out based on a full factorial design of experiments, and the areas of the machined surfaces were scanned and analyzed by analysis of variance, regression analysis (response function), and correlation analysis. It was found that there are strong correlations between the topography parameters that allow the substitution of one with another; the main influencing cutting parameter is the feed rate for both insert types. The contributions of the study are the numerical information with regard to the correlations among the topography parameters, as well as the extent of the influence of cutting parameters.
Despite turning could be replaced by grinding as a finishing machining process, it is considered not satisfactory for elongating the fatigue life of the component because of the produced tensile ...residual stresses and irregularities formed at the surface. Therefore, a complimentary operation should be applied after hard turning. Slide diamond burnishing process is a mechanical finishing operation used after hard turning to further decrease the surface roughness, introducing compressive residual stresses, increasing the microhardness, and refining the microstructure of the surface and subsurface layer of the workpiece. The main result is increasing the fatigue life of the rotating components subjected to cyclic loading. In this work, the simultaneous effect of changing the burnishing speed, feed, and force of slide diamond burnishing on surface roughness, residual stresses, and microhardness of 42CrMo4 hard-turned steel was studied. It was found that the effect of one parameter was highly affected by the others. As a result, the optimal burnishing parameters were specified, with which better surface quality was obtained than after grinding.
Plate bodies are facultative organelles occasionally described in the adult lungs of various species, including sheep and goat. They consist of multiple layers of plate-like cisterns with an electron ...dense middle bar. The present study was performed to elucidate the three-dimensional (3D) characteristics of this organelle and its presumed function in surfactant protein A (SP-A) biology. Archived material of four adult goat lungs and PFA-fixed lung samples of two adult sheep lungs were used for the morphological and immunocytochemical parts of this study, respectively. 3D imaging was performed by electron tomography and focused ion beam scanning electron microscopy (FIB-SEM). Immuno gold labeling was used to analyze whether plate bodies are positive for SP-A. Transmission electron microscopy revealed the presence of plate bodies in three of four goat lungs and in both sheep lungs. Electron tomography and FIB-SEM characterized the plate bodies as layers of two up to over ten layers of membranous cisterns with the characteristic electron dense middle bar. The membranes of the plates were in connection with the rough endoplasmic reticulum and showed vesicular inclusions in the middle of the plates and a vesicular network at the sides of the organelle. Immuno gold labeling revealed the presence of SP-A in the vesicular network of plate bodies but not in the characteristic plates themselves. In conclusion, the present study clearly proves the connection of plate bodies with the rough endoplasmic reticulum and the presence of a vesicular network as part of the organelle involved in SP-A trafficking.
Fragmentation of health data and biomedical research data is a major obstacle for precision medicine based on data-driven decisions. The development of personalized medicine requires the efficient ...exploitation of health data resources that are extraordinary in size and complexity, but highly fragmented, as well as technologies that enable data sharing across institutions and even borders. Biobanks are both sample archives and data integration centers. The analysis of large biobank data warehouses in federated datasets promises to yield conclusions with higher statistical power. A prerequisite for data sharing is harmonization, i.e., the mapping of the unique clinical and molecular characteristics of samples into a unified data model and standard codes. These databases, which are aligned to a common schema, then make healthcare information available for privacy-preserving federated data sharing and learning. The re-evaluation of sensitive health data is inconceivable without the protection of privacy, the legal and conceptual framework for which is set out in the GDPR (General Data Protection Regulation) and the FAIR (findable, accessible, interoperable, reusable) principles. For biobanks in Europe, the BBMRI-ERIC (Biobanking and Biomolecular Research Infrastructure - European Research Infrastructure Consortium) research infrastructure develops common guidelines, which the Hungarian BBMRI Node joined in 2021. As the first step, a federation of biobanks can connect fragmented datasets, providing high-quality data sets motivated by multiple research goals. Extending the approach to real-word data could also allow for higher level evaluation of data generated in the real world of patient care, and thus take the evidence generated in clinical trials within a rigorous framework to a new level. In this publication, we present the potential of federated data sharing in the context of the Semmelweis University Biobanks joint project. Orv Hetil. 2023; 164(21): 811-819.
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