Numerical simulations are used in this work to investigate aspects of microstructure and microsegregation during rapid solidification of a Ni-based superalloy in a laser powder bed fusion additive ...manufacturing process. Thermal modeling by finite element analysis simulates the laser melt pool, with surface temperatures in agreement with in situ thermographic measurements on Inconel 625. Geometric and thermal features of the simulated melt pools are extracted and used in subsequent mesoscale simulations. Solidification in the melt pool is simulated on two length scales. For the multicomponent alloy Inconel 625, microsegregation between dendrite arms is calculated using the Scheil-Gulliver solidification model and DICTRA software. Phase-field simulations, using Ni–Nb as a binary analogue to Inconel 625, produced microstructures with primary cellular/dendritic arm spacings in agreement with measured spacings in experimentally observed microstructures and a lesser extent of microsegregation than predicted by DICTRA simulations. The composition profiles are used to compare thermodynamic driving forces for nucleation against experimentally observed precipitates identified by electron and X-ray diffraction analyses. Our analysis lists the precipitates that may form from FCC phase of enriched interdendritic compositions and compares these against experimentally observed phases from 1 h heat treatments at two temperatures: stress relief at 1143 K (870 °C) or homogenization at 1423 K (1150 °C).
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The development of additive manufacturing has allowed for increased flexibility and complexity of designs over formative and subtractive manufacturing. However, a limiting factor of additive ...manufacturing is the as-built surface quality as well as the difficulty in maintaining an acceptable surface roughness in overhanging structures. In order to optimize surface roughness in these structures, samples covering a range of overhang angles and process parameters were built in a laser powder bed fusion system. Analysis of the surface roughness was then performed to determine a relationship between process parameters, angle of the overhanging surface, and surface roughness. It was found that the analysis of surface roughness metrics, such as Rpc, Rsm, and Rc, can indicate a shift between surfaces dominated by partially melted powder particles and surfaces dominated by material from the re-solidified melt track.
Laser powder bed fusion (L-PBF) additive manufacturing (AM) requires the careful selection of laser process parameters for each feedstock material and machine, which is a laborious process. Scaling ...laws based on the laser power, speed, and spot size; melt pool geometry; and thermophysical properties can potentially reduce this effort by transferring knowledge from one material and/or laser system to another. Laser spot size is one critical parameter that is less well studied for scaling laws compared to laser power and scan speed. Consequently, single track laser scans were generated with a spot size (D4σ) range of 50 μm to 322 μm and melt pool aspect ratio (depth over spot radius) range from 0.1 to 7.0. These were characterized by in-situ thermography, cross-sectioning, and optical microscopy. Scaling laws from literature were applied and evaluated based on melt pool depth predictions. Scaling laws that contain a minimum of three dimensionless parameters and account for changing absorption between conduction and keyhole mode provide the most accurate melt pool depth predictions (<35% difference from experiments), which is comparable to thermal simulation results from literature for a select number of cases.
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•Effect of laser spot size on melt pool morphology was systematically studied.•Scaling laws provide a basis to compare the effect of laser spot size on melt pool depth.•Absorption coefficients are critical for accurate melt pool depth predictions.•Melt pool depth predictions from scaling laws show comparable accuracy to more complex simulation predictions.
Additive manufacturing technologies are increasingly used in the development of new products. However, variations in part quality in terms of material properties, dimensional tolerances, surface ...roughness and defects limit its broader acceptance. Process control today based on heuristics and experimental data yields limited improvement in part quality. In an effort to identify the needed measurement science for real-time closed-loop control of additive manufacturing (AM) processes, this paper presents a literature review on the current AM control schemes, process measurements and modelling and simulation methods as it applies to the powder bed fusion process, though results from other processes are reviewed where applicable. We present our research findings to identify the correlations between process parameters, process signatures and product quality. We also present research recommendations on the key control issues to serve as a technical basis for standards development in this area. Complimentary details to this paper with summary tables, range of values, preliminary correlations and correlation figures can be accessed from a National Institute of Standards and Technology Report (
http://nvlpubs.nist.gov/nistpubs/ir/2015/NIST.IR.8036.pdf
). This paper is developed based on the report.
Currently, no evidence-based guidelines exist for treatment of children with monogenic steroid-resistant nephrotic syndrome. A retrospective study on 141 patients from Malakasioti et al. revealed ...that 27.6% responded to calcineurin inhibitor (CNI) treatment, and 75% of responders maintained stable kidney function. Virtually all CNI nonresponders developed progressive loss of kidney function. This study emphasized roles for CNIs in patients with monogenic steroid-resistant nephrotic syndrome, and the need for future studies to identify CNI response biomarkers.
We previously reported that mutations in the anillin (
) gene cause familial forms of FSGS. ANLN is an F-actin binding protein that modulates podocyte cell motility and interacts with the ...phosphoinositide 3-kinase (PI3K) pathway through the slit diaphragm adaptor protein CD2-associated protein (CD2AP). However, it is unclear how the
mutations cause the FSGS phenotype. We hypothesized that the R431C mutation exerts its pathogenic effects by uncoupling ANLN from CD2AP.
We conducted
complementation assays in zebrafish to determine the effect of the previously identified missense
variants,
and
during development. We also performed
functional assays using human podocyte cell lines stably expressing wild-type ANLN (
) or
.
Experiments in
-deficient zebrafish embryos showed a loss-of-function effect for each
variant. In human podocyte lines, expression of
increased cell migration, proliferation, and apoptosis. Biochemical characterization of
-expressing podocytes revealed hyperactivation of the PI3K/AKT/mTOR/p70S6K/Rac1 signaling axis and activation of mTOR-driven endoplasmic reticulum stress in
-expressing podocytes. Inhibition of mTOR, GSK-3
, Rac1, or calcineurin ameliorated the effects of
. Additionally, inhibition of the calcineurin/NFAT pathway reduced the expression of endogenous ANLN and mTOR.
The
mutation causes multiple derangements in podocyte function through hyperactivation of PI3K/AKT/mTOR/p70S6K/Rac1 signaling. Our findings suggest that the benefits of calcineurin inhibition in FSGS may be due, in part, to the suppression of ANLN and mTOR. Moreover, these studies illustrate that rational therapeutic targets for familial FSGS can be identified through biochemical characterization of dysregulated podocyte phenotypes.
Steroid-resistant nephrotic syndrome (SRNS) is the most severe form of childhood nephrotic syndrome with an increased risk of progression to chronic kidney disease stage 5. Research endeavors to date ...have identified more than 80 genes that are associated with SRNS. Most of these genes regulate the structure and function of the podocyte, the visceral epithelial cells of the glomerulus. Although individuals of African ancestry have the highest prevalence of SRNS, especially those from Sub-Saharan Africa (SSA), with rates as high as 30–40% of all cases of nephrotic syndrome, studies focusing on the characterization and understanding of the genetic basis of SRNS in the region are negligible compared with Europe and North America. Therefore, it remains unclear if some of the variants in SRNS genes that are deemed pathogenic for SRNS are truly disease causing, and if the leading causes of monogenic nephrotic syndrome in other populations are the same for children in SSA with SRNS. Other implications of this lack of genetic data for SRNS in the region include the exclusion of children from the region from clinical trials aimed at identifying potential novel therapeutic agents for this severe form of nephrotic syndrome. This review underlines a need for concerted efforts to advance the genetic basis of SRNS in children in SSA. Such endeavors will complement global efforts at understanding the genetic basis of nephrotic syndrome.
Otx and Mitf transcription factors have been implicated in the development of the retinal pigmented epithelium (RPE), but the relationship between these factors and their specific roles in the ...development of the RPE have not been fully defined. The role of the three Otx transcription factors (Otx1a, Otx1b, and Otx2) and two Mitf transcription factors (Mitfa and Mitfb) in the development of the zebrafish RPE was explored in these experiments. The loss of Otx activity through morpholino knockdown produced variable eye defects, ranging from delayed RPE pigmentation to severe coloboma, depending on the combination of Otx factors that were targeted. Expression analysis through in situ hybridization demonstrates that otx transcription factors are necessary for the proper expression of mitfa and mitfb while Mitf transcription factors are not required for the expression of otx genes. Surprisingly, the loss of Mitf activity in mitfa, mitfb, or double mitf mutant zebrafish had no effect on RPE pigmentation or development. Moreover, histological analysis revealed that retinal lamination is unaffected in mitf mutants, as well as in otx morphants, even in regions lacking RPE. Otx and Mitf combined loss of function experiments suggest that mitfa and mitfb may still influence zebrafish RPE development. This is further supported by the ability of mitfa to induce pigmentation in the zebrafish retina when misexpressed. These findings suggest that one or more Otx targets in addition to mitfa and mitfb, possibly another mitf family member, are necessary for development of the RPE in zebrafish.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Advances in genome science in the last 20 years have led to the discovery of over 50 single gene causes and genetic risk loci for steroid resistant nephrotic syndrome (SRNS). Despite these advances, ...the genetic architecture of childhood steroid sensitive nephrotic syndrome (SSNS) remains poorly understood due in large part to the varying clinical course of SSNS over time. Recent exome and genome wide association studies from well-defined cohorts of children with SSNS identified variants in multiple MHC class II molecules such as HLA-DQA1 and HLA-DQB1 as risk factors for SSNS, thus stressing the central role of adaptive immunity in the pathogenesis of SSNS. However, evidence suggests that unknown second hit risk loci outside of the MHC locus and environmental factors also make significant contributions to disease. In this review, we examine what is currently known about the genetics of SSNS, the implications of recent findings on our understanding of pathogenesis of SSNS, and how we can utilize these results and findings from future studies to improve the management of children with nephrotic syndrome.
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