1,475 research outputs found
Osteopontin upregulation in rotavirus-induced murine biliary atresia requires replicating virus but is not necessary for development of biliary atresia
AbstractBiliary atresia (BA) is a progressive fibro-inflammatory pediatric liver disease in which osteopontin (OPN), a glycoprotein with inflammatory and fibrogenic activity, may play a pathogenic role. The current studies were conducted in a mouse model of rotavirus-induced BA to test the hypotheses that live but not inactivated rotavirus causes antigenemia, upregulation of hepatic OPN expression, and induction of BA and fibrosis; and that OPN is necessary for development of BA. Prolonged or transient antigenemia developed in mice inoculated with live or inactivated virus, respectively, but only live virus upregulated hepatic OPN and caused BA and fibrosis. OPN was expressed in intra- and extrahepatic bile ducts in healthy mice and in mice with BA. OPN-deficient mice, similar to WT mice, developed BA. Together, these data show that live but not inactivated rotavirus causes upregulation of hepatic OPN expression and BA but that OPN is not necessary for development of BA
Representation Of The Antebellum South In The House Of Representatives: Measuring The Impact Of The Three-Fifths Clause
Percolation and jamming in random sequential adsorption of linear segments on square lattice
We present the results of study of random sequential adsorption of linear
segments (needles) on sites of a square lattice. We show that the percolation
threshold is a nonmonotonic function of the length of the adsorbed needle,
showing a minimum for a certain length of the needles, while the jamming
threshold decreases to a constant with a power law. The ratio of the two
thresholds is also nonmonotonic and it remains constant only in a restricted
range of the needles length. We determine the values of the correlation length
exponent for percolation, jamming and their ratio
Bipotential Adult Liver Progenitors Are Derived from Chronically Injured Mature Hepatocytes
SummaryAdult liver progenitor cells are biliary-like epithelial cells that emerge only under injury conditions in the periportal region of the liver. They exhibit phenotypes of both hepatocytes and bile ducts. However, their origin and their significance to injury repair remain unclear. Here, we used a chimeric lineage tracing system to demonstrate that hepatocytes contribute to the progenitor pool. RNA-sequencing, ultrastructural analysis, and in vitro progenitor assays revealed that hepatocyte-derived progenitors were distinct from their biliary-derived counterparts. In vivo lineage tracing and serial transplantation assays showed that hepatocyte-derived proliferative ducts retained a memory of their origin and differentiated back into hepatocytes upon cessation of injury. Similarly, human hepatocytes in chimeric mice also gave rise to biliary progenitors in vivo. We conclude that human and mouse hepatocytes can undergo reversible ductal metaplasia in response to injury, expand as ducts, and subsequently contribute to restoration of the hepatocyte mass
Sterols sense swelling in lipid bilayers
In the mimetic membrane system of phosphatidylcholine bilayers, thickening
(pre-critical behavior, anomalous swelling) of the bilayers is observed, in the
vicinity of the main transition, which is non-linear with temperature. The
sterols cholesterol and androsten are used as sensors in a time-resolved
simultaneous small- and wide angle x-ray diffraction study to investigate the
cause of the thickening. We observe precritical behavior in the pure lipid
system, as well as with sterol concentrations less than 15%. To describe the
precritical behavior we introduce a theory of precritical phenomena.The good
temperature resolution of the data shows that a theory of the influence of
fluctuations needs modification. The main cause of the critical behavior
appears to be a changing hydration of the bilayer.Comment: 11 pages, 7 ps figures included, to appear in Phys.Rev.
Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children\u27s Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children\u27s Oncology Group.
Purpose To determine whether the pattern of lung nodules in children with metastatic hepatoblastoma (HB) correlates with outcome. Methods Thirty-two patients with metastatic HB were enrolled on Children\u27s Oncology Group Protocol AHEP0731 and treated with vincristine and irinotecan (VI). Responders to VI received two additional cycles of VI intermixed with six cycles of cisplatin/fluorouracil/vincristine/doxorubicin (C5VD), and nonresponders received six cycles of C5VD alone. Patients were imaged after every two cycles and at the conclusion of therapy. All computed tomography scans and pathology reports were centrally reviewed, and information was collected regarding lung nodule number, size, laterality, timing of resolution, and pulmonary surgery. Results Among the 29 evaluable patients, only 31% met Response Evaluation Criteria in Solid Tumors (RECIST) for measurable metastatic disease. The presence of measurable disease by RECIST, the sum of nodule diameters greater than or equal to the cumulative cohort median size, bilateral disease, and ≥ 10 nodules were each associated with an increased risk for an event-free survival event ( P = .48, P = .08, P = .065, P = .03, respectively), with nodule number meeting statistical significance. Ten patients underwent pulmonary resection/metastasectomy at various time points, the benefit of which could not be determined because of small patient numbers. Conclusion Children with metastatic HB have a poor prognosis. Overall tumor burden may be an important prognostic factor for these patients. Lesions that fail to meet RECIST size criteria (ie, those \u3c 10 mm) at diagnosis may contain viable tumor, whereas residual lesions at the end of therapy may constitute eradicated tumor/scar tissue. Patients may benefit from risk stratification on the basis of the burden of lung metastatic disease at diagnosis
Robust high-dimensional precision matrix estimation
The dependency structure of multivariate data can be analyzed using the
covariance matrix . In many fields the precision matrix
is even more informative. As the sample covariance estimator is singular in
high-dimensions, it cannot be used to obtain a precision matrix estimator. A
popular high-dimensional estimator is the graphical lasso, but it lacks
robustness. We consider the high-dimensional independent contamination model.
Here, even a small percentage of contaminated cells in the data matrix may lead
to a high percentage of contaminated rows. Downweighting entire observations,
which is done by traditional robust procedures, would then results in a loss of
information. In this paper, we formally prove that replacing the sample
covariance matrix in the graphical lasso with an elementwise robust covariance
matrix leads to an elementwise robust, sparse precision matrix estimator
computable in high-dimensions. Examples of such elementwise robust covariance
estimators are given. The final precision matrix estimator is positive
definite, has a high breakdown point under elementwise contamination and can be
computed fast
Theoretical and numerical studies of chemisorption on a line with precursor layer diffusion
We consider a model for random deposition of monomers on a line with
extrinsic precursor states. As the adsorbate coverage increases, the system
develops non-trivial correlations due to the diffusion mediated deposition
mechanism. In a numeric simulation, we study various quantities describing the
evolution of the island structure. We propose a simple, self-consistent theory
which incorporates pair correlations. The results for the correlations, island
density number, average island size and probabilities of island nucleation,
growth and coagulation show good agreement with the simulation data.Comment: 17 pages(LaTeX), 11 figures(1 PS file, uuencoded), submmited to Phys.
Rev.
Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome
Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome
NR1H4-related Progressive Familial Intrahepatic Cholestasis 5: Further Evidence for Rapidly Progressive Liver Failure.
Pathogenic sequence variants in the nuclear bile acid receptor FXR, encoded by NR1H4, have been reported in a small number of children with low-GGT cholestasis progressing to liver failure. We describe three additional children from two unrelated families with cholestasis and liver failure due to pathologic variants in NR1H4. One patient underwent liver transplantation and has had good clinical outcomes in six years of follow-up. While that patient has biochemical evidence of increased bile acid synthetic activity, he has not experienced post-transplant diarrhea or allograft steatosis, as has been reported among other transplanted patients
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