Description: The phenotype associated to spontaneous mutation in the Tetratricopeptide Repeat Domain 7A (TTC7A) in the flaky skin ( fsn ) mice 1 combines gastric hyperplasia, hyperproliferative immune disorder and skin anomalies. All fsn mice progressively develop thick white scales and patchy alopecia that turns into papulo-squamous lesions, marked hyperkeratosis and hypergranulosis associated to a dermal mixed inflammatory infiltrate on skin biopsy 2,3 . To date, the fsn mouse constitutes a model for human psoriasis vulgaris 3 . This article is protected by copyright. All rights reserved.

Description: Plasmacytoid dendritic cells (pDCs) play an important role in innate and adaptive immunity and were shown to be identical to previously described natural IFN-α-producing (NIP) cells. Here, we describe two functionally distinct pDC subpopulations that are characterized by the differential expression of stem cell antigen-1 (Sca-1; Ly-6A/E). Sca-1 − pDCs are mainly found in the bone marrow, appear first during development, show a higher proliferative activity and represent the more precursor phenotype. Sca-1 + pDCs are mostly located in secondary lymphoid organs and represent a later developmental stage. Sca-1 − pDCs give rise to a Sca-1 + subset upon activation or in response to endogenous type I IFN. Interestingly, in contrast to Sca-1 − pDCs, Sca-1 + pDCs are defective in IFN-α production upon endosomal TLR9 stimulation, whereas lysosomal signaling via TLR9 is functional in both subsets. Gene expression analysis revealed that osteopontin (Opn) is strongly upregulated in Sca-1 − pDCs. These data provide evidence for the molecular basis of the observed functional heterogeneity, as the intracellular isoform of Opn couples TLR9 signaling to IFN-α expression. Taken together, our results indicate that Sca-1 − pDCs are an early developmental stage of pDCs with distinct innate functions representing the true murine NIP cell.

Description: Purpose To determine age- and gender-dependent whole-body adipose tissue and muscle volumes in healthy Swiss volunteers in Dixon MRI in comparison with anthropometric and bioelectrical impedance (BIA) measurements. Methods Fat–water-separated whole-body 3 Tesla MRI of 80 healthy volunteers (ages 20 to 62 years) with a body mass index (BMI) of 17.5 to 26.2 kg/m 2 (10 men, 10 women per decade). Age and gender-dependent volumes of total adipose tissue (TAT), visceral adipose tissue (VAT), total abdominal subcutaneous adipose tissue (ASAT) and total abdominal adipose tissue (TAAT), and the total lean muscle tissue (TLMT) normalized for body height were determined by semi-automatic segmentation, and correlated with anthropometric and BIA measurements as well as lifestyle parameters. Results The TAT, ASAT, VAT, and TLMT indexes (TATi, ASATi, VATi, and TLMTi, respectively) (L/m 2  ± standard deviation) for women/men were 6.4 ± 1.8/5.3 ± 1.7, 1.6 ± 0.7/1.2 ± 0.5, 0.4 ± 0.2/0.8 ± 0.5, and 5.6 ± 0.6/7.1 ± 0.7, respectively. The TATi correlated strongly with ASATi ( r  〉 0.93), VATi, BMI and BIA ( r  〉 0.70), and TAATi ( r  〉 0.96), and weak with TLMTi for both genders ( r  〉 –0.34). The VAT was the only parameter showing an age dependency ( r  〉 0.32). The BMI and BIA showed strong correlation with all MR-derived adipose tissue volumes. The TAT mass was estimated significantly lower from BIA than from MRI (both genders P  〈 .001; mean bias –5 kg). Conclusions The reported gender-specific MRI-based adipose tissue and muscle volumes might serve as normative values. The estimation of adipose tissue volumes was significantly lower from anthropometric and BIA measurements than from MRI. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Description: Purpose: To evaluate the feasibility of semiquantitative measurement of liver perfusion from analysis of ferucarbotran induced signal-dynamics in double-contrast liver MR-imaging (DC-MRI). Materials and Methods: In total 31 patients (21 men; 58 ± 10 years) including 18 patients with biopsy proven liver cirrhosis prospectively underwent clinically indicated DC-MRI at 1.5 Tesla (T) with dynamic T2*-weighted gradient-echo imaging after ferucarbotran bolus injection. Breathing artefacts in tissue and input time curves were reduced by Savitzky-Golay-filtering and semiquantitative perfusion maps were calculated using a model free approach. Hepatic blood flow index (HBFI) and splenic blood flow index (SBFI) were determined by normalization of arbitrary perfusion values to the perfusion of the erector spinae muscle resulting in a semiquantitative perfusion measure. Results: In 30 of 31 patients the evaluated protocol could successfully be applied. Mean HBF was 7.7 ± 2.46 (range, 4.6–12.8) and mean SBF was 13.20 ± 2.57 (range, 8.5–17.8). A significantly lower total HBF was seen in patients with cirrhotic livers as compared to patients with noncirrhotic livers ( P 〈 0.05). In contrast, similar SBF was observed in cirrhotic and noncirrhotic patients ( P = 0.11). Conclusion: Capturing the signal dynamics during bolus injection of ferucarbotran in DC-MRI of the liver allows for semiquantitative assessment of hepatic perfusion that may be helpful for a more precise characterisation of liver cirrhosis and focal liver lesions. J. Magn. Reson. Imaging 2012;. © 2012 Wiley Periodicals, Inc.

Description: Background : To quantitatively and qualitatively assess vastus medialis muscle atrophy in asymptomatic patients with anterior cruciate ligament reconstruction, using the nonoperated leg as control. Methods : Prospective Institutional Review Board approved study with written informed patient consent. Thirty-three asymptomatic patients (men, 21; women,12) with ACL-reconstruction underwent MR imaging of both legs (axial T1-weighted spin-echo and 3D spoiled dual gradient-echo sequences). Muscle volume and average fat-signal fraction (FSF) of the vastus medialis muscles were measured. Additionally, Goutallier classification was used to classify fatty muscle degeneration. Significant side differences were evaluated using the Wilcoxon test and, between volumes and FSF, using student t-tests with P -value 〈 0.05 and 〈 0.025, respectively. Results : The muscle volume was significantly smaller in the operated (mean ± SD, 430.6 ± 119.6 cm 3 ; range, 197.3 to 641.7 cm 3 ) than in the nonoperated leg (479.5 ± 124.8 cm 3 ; 261.4 to 658.9 cm 3 ) ( P  〈 0.001). Corresponding FSF was 6.3 ± 1.5% (3.9 to 9.2%) and 5.8 ± 0.9% (4.0 to 7.4%), respectively, with a nonsignificant ( P  〉 0.025) difference. The relative muscle-volume and FSF differences were −10.1 ± 8.6% (7.1 to −30.1%) and 10.9 ± 29.4% (39.7 to 40.1%). The qualitative assessment revealed no significant differences ( P  〉 0.1). Conclusion : A significant muscle volume loss of the vastus medialis muscle does exist in asymptomatic patients with ACL-reconstruction, but without fatty degeneration. J. Magn. Reson. Imaging 2014.

Description: Interference with tumor suppressor pathways by polyomavirus-encoded tumor antigens (T-Ags) can result in transformation. Consequently, it is thought that T-Ags encoded by Merkel cell polyomavirus (MCPyV), a virus integrated in ~90% of all Merkel cell carcinoma (MCC) cases, are major contributors to tumorigenesis. The MCPyV large T-Ag (LT-Ag) has preserved the key functional domains present in all family members but has also acquired unique regions that flank the LxCxE motif. As these regions may mediate unique functions, or may modulate those shared with T-Ags of other polyomaviruses, functional studies of MCPyV T-Ags are required. Here, we have performed a comparative study of full-length or MCC-derived truncated LT-Ags with regard to their biochemical characteristics, their ability to bind to retinoblastoma (Rb) and p53 proteins, and their transforming potential. We provide evidence that full-length MCPyV LT-Ag may not directly bind to p53 but nevertheless can significantly reduce p53-dependent transcription in reporter assays. Although early region expression constructs harboring either full-length or MCC-derived truncated LT-Ag genes can transform primary baby rat kidney cells, truncated LT-Ags do not bind to p53 or reduce p53-dependent transcription. Interestingly, shortened LT-Ags exhibit a very high binding affinity for Rb, as shown by coimmunoprecipitation and in vitro binding studies. Additionally, we show that truncated MCPyV LT-Ag proteins are expressed at higher levels than those for the wild-type protein and are able to partially relocalize Rb to the cytoplasm, indicating that truncated LT proteins may have gained additional features that distinguish them from the full-length protein. IMPORTANCE MCPyV is one of the 12 known polyomaviruses that naturally infect humans. Among these, it is of particular interest since it is the only human polyomavirus known to be involved in tumorigenesis. MCPyV is thought to be causally linked to MCC, a rare skin tumor. In these tumors, viral DNA is monoclonally integrated into the genome of the tumor cells in up to 90% of all MCC cases, and the integrated MCV genomes, furthermore, harbor signature mutations in the so-called early region that selectively abrogate viral replication while preserving cell cycle deregulating functions of the virus. This study describes comparative studies of early region T-Ag protein characteristics, their ability to bind to Rb and p53, and their transforming potential.

Description: The transcription factor GATA2 is required for expansion and differentiation of hematopoietic stem cells (HSCs). In mesenchymal stem cells (MSCs), GATA2 blocks adipogenesis, but its biological relevance and underlying genomic events are unknown. We report a dual function of GATA2 in bone homeostasis. GATA2 in MSCs binds near genes involved in skeletal system development and colocalizes with motifs for FOX and HOX transcription factors, known regulators of skeletal development. Ectopic GATA2 blocks osteoblastogenesis by interfering with SMAD1/5/8 activation. MSC-specific deletion of GATA2 in mice increases the numbers and differentiation capacity of bone-derived precursors, resulting in elevated bone formation. Surprisingly, MSC-specific GATA2 deficiency impairs the trabecularization and mechanical strength of bone, involving reduced MSC expression of the osteoclast inhibitor osteoprotegerin and increased osteoclast numbers. Thus, GATA2 affects bone turnover via MSC-autonomous and indirect effects. By regulating bone trabecularization, GATA2 expression in the osteogenic lineage may contribute to the anatomical and cellular microenvironment of the HSC niche required for hematopoiesis.