Lentivector Transduction Improves Outcomes Over Transplantation of Human HSCs Alone in NOD/SCID/Fabry Mice

Fabry disease is a lysosomal storage disorder caused by a deficiency of a-galactosidase A (a-gal A) activity that results in progressive globotriaosylceramide (Gb(3)) deposition. We created a fully congenic nonobese diabetic (NOD)/severe combined immunodeficiency (SCID)/Fabry murine line to facilitate the in vivo assessment of human cell-directed therapies for Fabry disease. This pure line was generated after 11 generations of backcrosses and was found, as expected, to have a reduced immune compartment and background a-gal A activity. Next, we transplanted normal human CD34(+) cells transduced with a control (lentiviral vector-enhanced green fluorescent protein (LV-eGFP)) or a therapeutic bicistronic LV (LV-a-gal A/internal ribosome entry site (IRES)/hCD25). While both experimental groups showed similar engraftment levels, only the therapeutic group displayed a significant increase in plasma a-gal A activity. Gb(3) quantification at 12 weeks revealed metabolic correction in the spleen, lung, and liver for both groups. Importantly, only in the therapeutically-transduced cohort was a significant Gb(3) reduction found in the heart and kidney, key target organs for the amelioration of Fabry disease in humans.Fil: Pacienza, Natalia Alejandra. University Health Network; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Yoshimitsu, Makoto. Kagoshima University; Japón. University Health Network; CanadáFil: Mizue, Nobuo. University Health Network; CanadáFil: Au, Bryan C. Y.. University Health Network; CanadáFil: Wang, James C. M.. University Health Network; CanadáFil: Fan, Xin. University Health Network; CanadáFil: Takenaka, Toshihiro. Kagoshima University; JapónFil: Medin, Jeffrey A. University Health Network; Canadá. University of Toronto; Canad

P-wave tomography of the mantle beneath the South Pacific Superswell revealed by joint ocean floor and islands broadband seismic experiments

International audienceThree-dimensional P-wave velocity structure of the mantle beneath the South Pacific Superswell is determined through passive broadband seismic experiments on the ocean floor and islands between 2003 and 2005. We collected approximately 1500 relative times of long-period teleseismic P-waves by using a waveform cross-correlation. We analyzed this data set with relative time tomography to depths of 2000 km. The resultant structure shows lateral heterogeneity of approximately +/- 2%, in which a distinct low velocity region is found beneath the center of the Superswell at a depth of 1600 km. At 1200km depth, an elongated low velocity region is found beneath the Society to Pitcairn hotspots. At 800 km depth, two linear low velocity regions are located beneath Tuamotu and Austral islands. Isolated low velocity regions are identified beneath the Society, Marquesas, and Macdonald hotspots at 400 km depth. Our new tomographic images reveal that the large low velocity region rooted in the deep lower mantle is split into two sheets at 1200 km depth and these terminate at approximately 800 km depth. This feature appears to be consistent with the characteristics of a thermo-chemical pile or dome

Multimodel uncertainty changes in simulated river flows induced by human impact parameterizations

Human impacts increasingly affect the global hydrological cycle and indeed dominate hydrological changes in some regions. Hydrologists have sought to identify the human-impact-induced hydrological variations via parameterizing anthropogenic water uses in global hydrological models (GHMs). The consequently increased model complexity is likely to introduce additional uncertainty among GHMs. Here, using four GHMs, between-model uncertainties are quantified in terms of the ratio of signal to noise (SNR) for average river flow during 1971–2000 simulated in two experiments, with representation of human impacts (VARSOC) and without (NOSOC). It is the first quantitative investigation of between-model uncertainty resulted from the inclusion of human impact parameterizations. Results show that the between-model uncertainties in terms of SNRs in the VARSOC annual flow are larger (about 2% for global and varied magnitude for different basins) than those in the NOSOC, which are particularly significant in most areas of Asia and northern areas to the Mediterranean Sea. The SNR differences are mostly negative (-20% to 5%, indicating higher uncertainty) for basin-averaged annual flow. The VARSOC high flow shows slightly lower uncertainties than NOSOC simulations, with SNR differences mostly ranging from -20% to 20%. The uncertainty differences between the two experiments are significantly related to the fraction of irrigation areas of basins. The large additional uncertainties in VARSOC simulations introduced by the inclusion of parameterizations of human impacts raise the urgent need of GHMs development regarding a better understanding of human impacts. Differences in the parameterizations of irrigation, reservoir regulation and water withdrawals are discussed towards potential directions of improvements for future GHM development. We also discuss the advantages of statistical approaches to reduce the between-model uncertainties, and the importance of calibration of GHMs for not only better performances of historical simulations but also more robust and confidential future projections of hydrological changes under a changing environment

An unusual association of diffuse adenomyomatosis with dysplastic adenoma in chronic calculous cholecystitis: case presentation

<p>Abstract</p> <p>Background</p> <p>Gallbladder adenomyomatosis is an epithelial proliferation and hypertrophy of the muscularis mucosae of the gallbladder. Rokitansky-Aschoff sinuses are a characteristic of this condition. The segmental adenomyomatosis has a higher risk of developing into gallbladder carcinoma, especially in the fundal region of elderly patients.</p> <p>We report the case of a patient affected by chronic calculous cholecystitis with diffuse adenomyomatosis associated with dysplastic adenoma.</p> <p>Case presentation</p> <p>An 81-year-old woman presented at our hospital with a 1-year history of intermittent pain localized at the right upper abdominal quadrant, without diffusion to any other body part. On physical examination the abdomen was soft, not distended, and tender to palpation in the right upper quadrant. Murphy sign was negative. Laboratory tests were normal. The patient was scheduled for a laparoscopic cholecystectomy, and neither endoscopic ultrasonographic scan nor magnetic resonance imaging was performed. The operation, performed after obtaining informed consent, was uncomplicated and the intra-operative pathological examination showed no malignancy. The definitive pathological examination of the gallbladder showed: multiple stones of cholesterol origin; diffuse mucosal adenomyomatosis; and a 1.1 cm pedunculated mass localized at the fundus, whose surface was lumpy. This mass was diagnosed as an adenoma with multiple areas of severe dysplasia.</p> <p>Conclusions</p> <p>The adenoma of the gallbladder, together with the dysplasia, represents a biological carcinogenetic model. Carcinoma has rarely been reported in adenomyomatosis. Degenerative risk suggests surgery should be mandatory when there is a concomitant presence of large adenoma and adenomyomatosis.</p

Phosphorylation of centromeric histone H3 variant regulates chromosome segregation in S. cerevisiae

The centromeric histone H3 variant (CenH3) is essential for chromosome segregation in eukaryotes. We have identified posttranslational modifications of S. cerevisiae CenH3, Cse4. Functional characterization of cse4 phosphorylation mutants showed growth and chromosome segregation defects when combined with kinetochore mutants okp1 and ame1. Using a phosphoserine-specific antibody we showed that the association of phosphorylated Cse4 with centromeres is increased in response to defective microtubule attachment or reduced cohesion. We determined that evolutionarily conserved Ipl1/Aurora B contributes to phosphorylation of Cse4, as levels of phosphorylated Cse4 were reduced at centromeres in ipl1 strains in vivo and in vitro assays showed phosphorylation of Cse4 by Ipl1. Consistent with these results we observed that a phosphomimetic cse4-4SD mutant suppressed the temperature sensitive growth of ipl1-2 and Ipl1 substrate mutants dam1 spc34 and ndc80 that are defective for chromosome biorientation. Furthermore, cell biology approaches using a GFP labeled chromosome showed that cse4-4SD suppressed chromosome segregation defects in dam1 spc34 strains. Based these results we propose that phosphorylation of Cse4 destabilizes defective kinetochores to promote biorientation and ensure faithful chromosome segregation. Taken together, our study provides a detailed analysis, in vivo and in vitro, of Cse4 phosphorylation and its role in promoting faithful chromosome segregation

Consensus report from the 8th International Forum for Liver Magnetic Resonance Imaging.

ObjectivesThe 8th International Forum for Liver Magnetic Resonance Imaging (MRI), held in Basel, Switzerland, in October 2017, brought together clinical and academic radiologists from around the world to discuss developments in and reach consensus on key issues in the field of gadoxetic acid-enhanced liver MRI since the previous Forum held in 2013.MethodsTwo main themes in liver MRI were considered in detail at the Forum: the use of gadoxetic acid for contrast-enhanced MRI in patients with liver cirrhosis and the technical performance of gadoxetic acid-enhanced liver MRI, both opportunities and challenges. This article summarises the expert presentations and the delegate voting on consensus statements discussed at the Forum.Results and conclusionsIt was concluded that gadoxetic acid-enhanced MRI has higher sensitivity for the diagnosis of hepatocellular carcinoma (HCC), when compared with multidetector CT, by utilising features of hyperenhancement in the arterial phase and hypointensity in the hepatobiliary phase (HBP). Recent HCC management guidelines recognise an increasing role for gadoxetic acid-enhanced MRI in early diagnosis and monitoring post-resection. Additional research is needed to define the role of HBP in predicting microvascular invasion, to better define washout during the transitional phase in gadoxetic acid-enhanced MRI for HCC diagnosis, and to reduce the artefacts encountered in the arterial phase. Technical developments are being directed to shortening the MRI protocol for reducing time and patient discomfort and toward utilising faster imaging and non-Cartesian free-breathing approaches that have the potential to improve multiphasic dynamic imaging.Key points• Gadoxetic acid-enhanced MRI provides higher diagnostic sensitivity than CT for diagnosing HCC. • Gadoxetic acid-enhanced MRI has roles in early-HCC diagnosis and monitoring post-resection response. • Faster imaging and free-breathing approaches have potential to improve multiphasic dynamic imaging

Observation of the in-plane magnetic field-induced phase transitions in FeSe

We investigate the thermodynamic properties of FeSe under the in-plane magnetic fields using torque magnetometry, specific heat, magnetocaloric measurements. Below the upper critical field Hc2, we observed the field-induced anomalies at H1 ~ 15 T and H2 ~ 22 T near H//ab and below a characteristic temperature T* ~ 2 K. The transition magnetic fields H1 and H2 exhibit negligible dependence on both temperature and field orientation. This contrasts with the strong temperature and angle dependence of Hc2, suggesting that these anomalies are attributed to the field-induced phase transitions, originating from the inherent spin-density-wave instability of quasiparticles near the superconducting gap minima or possible Flude-Ferrell-Larkin-Ovchinnikov state in the highly spin-polarized Fermi surfaces. Our observations imply that FeSe, an atypical multiband superconductor with extremely small Fermi energies, represents a unique model system for stabilizing unusual superconducting orders beyond the Pauli limit.Comment: 8 pages, 4 figures, submitte

Relationship between silent brain infarction and chronic kidney disease

Background. The presence of silent brain infarction (SBI) increases the risk of symptomatic stroke and dementia. The association between SBI and chronic kidney disease (CKD) has not been clarified. Moreover, little is known about what factors are related to SBI in CKD patients and whether the prevalence of SBI differs in CKD stage or cause of CKD