Kidney segmentation using 3D U-Net localized with Expectation Maximization

Kidney volume is greatly affected in several renal diseases. Precise and automatic segmentation of the kidney can help determine kidney size and evaluate renal function. Fully convolutional neural networks have been used to segment organs from large biomedical 3D images. While these networks demonstrate state-of-the-art segmentation performances, they do not immediately translate to small foreground objects, small sample sizes, and anisotropic resolution in MRI datasets. In this paper we propose a new framework to address some of the challenges for segmenting 3D MRI. These methods were implemented on preclinical MRI for segmenting kidneys in an animal model of lupus nephritis. Our implementation strategy is twofold: 1) to utilize additional MRI diffusion images to detect the general kidney area, and 2) to reduce the 3D U-Net kernels to handle small sample sizes. Using this approach, a Dice similarity coefficient of 0.88 was achieved with a limited dataset of n=196. This segmentation strategy with careful optimization can be applied to various renal injuries or other organ systems

Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse

Mia3’s contribution to protein secretion is broader than previously realized—its absence impairs collagen deposition and normal development of cartilage and bone

Host-Detrimental Role of Esx-1-Mediated Inflammasome Activation in Mycobacterial Infection

The Esx-1 (type VII) secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium marinum. However, the molecular events and host-pathogen interactions underlying Esx-1-mediated virulence in vivo remain unclear. Here we address this problem in a non-lethal mouse model of M. marinum infection that allows detailed quantitative analysis of disease progression. M. marinum established local infection in mouse tails, with Esx-1-dependent formation of caseating granulomas similar to those formed in human tuberculosis, and bone deterioration reminiscent of skeletal tuberculosis. Analysis of tails infected with wild type or Esx-1-deficient bacteria showed that Esx-1 enhanced generation of proinflammatory cytokines, including the secreted form of IL-1β, suggesting that Esx-1 promotes inflammasome activation in vivo. In vitro experiments indicated that Esx-1-dependent inflammasome activation required the host NLRP3 and ASC proteins. Infection of wild type and ASC-deficient mice demonstrated that Esx-1-dependent inflammasome activation exacerbated disease without restricting bacterial growth, indicating a host-detrimental role of this inflammatory pathway in mycobacterial infection. These findings define an immunoregulatory role for Esx-1 in a specific host-pathogen interaction in vivo, and indicate that the Esx-1 secretion system promotes disease and inflammation through its ability to activate the inflammasome

Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia.

The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders

Secreted sulfatases Sulf1 and Sulf2 have overlapping yet essential roles in mouse neonatal survival.

BackgroundHeparan sulfate proteoglycans (HSPGs) use highly sulfated polysaccharide side-chains to interact with several key growth factors and morphogens, thereby regulating their accessibility and biological activity. Various sulfotransferases and sulfatases with differing specificities control the pattern of HSPG sulfation, which is functionally critical. Among these enzymes in the mouse are two secreted 6-O-endosulfatases, Sulf1 and Sulf2, which modify HSPGs in the extracellular matrix and on the cell surface. The roles of Sulf1 and Sulf2 during normal development are not well understood.Methods/resultsTo investigate the importance of Sulf1 and Sulf2 for embryonic development, we generated mice genetically deficient in these genes and assessed the phenotypes of the resulting secreted sulfatase-deficient mice. Surprisingly, despite the established crucial role of HSPG interactions during development, neither Sulf1- nor Sulf2-deficient mice showed significant developmental flaws. In contrast, mice deficient in both Sulf1and Sulf2 exhibited highly penetrant neonatal lethality. Loss of viability was associated with multiple, although subtle, developmental defects, including skeletal and renal abnormalities.ConclusionsThese results show that Sulf1 and Sulf2 play overlapping yet critical roles in mouse development and are redundant and essential for neonatal survival

R1MAb2 induces FGF23 production.

<p>(<b>A and B</b>) Serum FGF23 (A) and PTH (B) levels in male C57BL/6 mice intraperioneally injected with R1MAb2 or isotype control (Control IgG) at 1 mg/kg. The same animals described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057322#pone-0057322-g001" target="_blank">Figure 1C</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057322#pone-0057322-g002" target="_blank">Figure 2</a> were analyzed at 48 hour post injection. N = 8 mice/group. (<b>C</b>) Serum FGF23 levels in female <i>db/db</i> mice intraperioneally injected with R1MAb1 or isotype control (Control IgG) at 2 mg/kg. The samples were collected at 7 days post injection. N = 6 mice/group. (<b>D and E</b>) Serum FGF23 levels (D) and phosphate levels (E) in male C57BL/6 mice intraperioneally injected with an indicated antibody at 1 mg/kg. The samples were collected at 3 days post injection. N = 8 mice/group. (<b>F</b>) FGF23 levels in culture medium after treatment of differentiate rat osteoblast with vitamin D (100 nM), R1MAb1, or isotype control IgG (26.7 nM). The cells were incubated for 48 hours in the presence of the indicated ligand. N = 6 samples/treatment. (A–F) * p<0.05, **G) Differentiated rat osteoblasts were treated with R1MAb2, or isotype control IgG (26.7 nM), for 1 hour and subjected to Western blot analysis to examine phosphorylation of MAPK pathway proteins, CREB and STAT3.</p