Frustrated phase separation in two-dimensional charged systems

We study phase separation frustrated by the long-range Coulomb interaction in two dimensional electronic systems with emphasys in the case of a metallic and an insulating phase. We find that two-dimensional systems are more prone to mesoscopic frustrated phase separation than the three dimensional ones.Comment: 15 pages, 11 figure

HST/NICMOS Imaging of Disks and Envelopes Around Very Young Stars

We present HST/NICMOS observations with 0.1" (15 AU) resolution of six young stellar objects in the Taurus star-formation region. The targets of our survey are three Class I IRAS sources (IRAS 04016+2610, IRAS 04248+2612, and IRAS 04302+2247) and three low-luminosity stars (DG Tau B, Haro 6-5B, and CoKu Tau/1) associated with Herbig Haro jets. The broad-band images show that the near-infrared radiation from these sources is dominated by light scattered from dusty circumstellar material distributed in a region 10 - 15 times the size of our solar system. Although the detailed morphologies of the individual objects are unique, the observed young stellar objects share common features. All of the circumstellar reflection nebulae are crossed by dark lanes from 500 - 900 AU in extent and from less than 50 to 350 AU in apparent thickness. The absorption lanes extend perpendicular to known optical and millimeter outflows in these sources. We interpret the dark lanes as optically thick circumstellar disks seen in silhouette against bright reflection nebulosity. The bipolar reflection nebulae extending perpendicular to the dust lanes appear to be produced by scattering from the upper and lower surfaces of the disks and from dusty material within or on the walls of the outflow cavities. Out of five objects in which the central source is directly detected, two are found to be subarcsecond binaries. This mini-survey is the highest resolution near-infrared study to date of circumstellar environments around solar-type stars with age <= 1 Myr.Comment: 34 pages, 4 figures; also available at http://spider.ipac.caltech.edu/staff/brandner/topics/disks/disks.html ; accepted for publication in AJ (March 1999 issue

Near-Infrared Classification Spectroscopy: H-band Spectra of Fundamental MK Standards

We present a catalogue of H-band spectra for 85 stars of approximately solar abundance observed at a resolving power of 3000 with the KPNO Mayall 4m FTS. The atlas covers spectral types O7-M5 and luminosity classes I-V as defined on the MK system. We identify both atomic and molecular indices and line-ratios which are temperature and luminosity sensitive allowing spectral classification to be carried out in the H-band. The line ratios permit spectral classification in the presence of continuum excess emission, which is commonly found in pre-main sequence and evolved stars. We demonstrate that with spectra of R = 1000 obtained at SNR > 50 it is possible to derive spectral types within +- 2 subclasses for late-type stars. These data are available electronically through the Astronomical Data Center in addition to being served on the World-Wide-Web.Comment: To appear in the November 20, 1998 issue of ApJ (Volume 508, #1

Formation and Evolution of Planetary Systems: Cold Outer Disks Associated with Sun-like stars

We present the discovery of debris systems around three solar mass stars based upon observations performed with the Spitzer Space Telescope as part of a Legacy Science Program, ``the Formation and Evolution of Planetary Systems'' (FEPS). We also confirm the presence of debris around two other stars. All the stars exhibit infrared emission in excess of the expected photospheres in the 70 micron band, but are consistent with photospheric emission at <= 33 micron. This restricts the maximum temperature of debris in equilibrium with the stellar radiation to T < 70 K. We find that these sources are relatively old in the FEPS sample, in the age range 0.7 - 3 Gyr. Based on models of the spectral energy distributions, we suggest that these debris systems represent materials generated by collisions of planetesimal belts. We speculate on the nature of these systems through comparisons to our own Kuiper Belt, and on the likely planet(s) responsible for stirring the system and ultimately releasing dust through collisions. We further report observations of a nearby star HD 13974 (d =11 pc) that is indistinguishable from a bare photosphere at both 24 micron and 70 micron. The observations place strong upper limits on the presence of any cold dust in this nearby system (L_IR/L_* < 10^{-5.2}).Comment: 31 pages, 9 figures, accepted for publication in Ap

Isolated Hepatocyte Transplantation for Crigler-Najjar Syndrome Type 1:

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 × 10 9 hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean ± SD bilirubin level was 530 ± 38 µmol/L before and 359 ± 46 µmol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure

Insights From Liver-Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR-Agonist Pharmacodynamics in Humans

Background and Aims Genetically modified mice have been used extensively to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences. Approach and Results Fah(-/-), Rag2(-/-), and Il2rg(-/-) knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by a high ratio of low-density lipoprotein to high-density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low-density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level. Conclusions LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.Peer reviewe

Correction of a urea cycle defect after ex vivo gene editing of human hepatocytes

Ornithine transcarbamylase deficiency (OTCD) is a monogenic disease of ammonia metabolism in hepatocytes. Severe disease is frequently treated by orthotopic liver transplantation. An attractive approach is the correction of a patient's own cells to regenerate the liver with gene-repaired hepatocytes. This study investigates the efficacy and safety of ex vivo correction of primary human hepatocytes. Hepatocytes isolated from an OTCD patient were genetically corrected ex vivo, through the deletion of a mutant intronic splicing site achieving editing efficiencies >60% and the restoration of the urea cycle in vitro. The corrected hepatocytes were transplanted into the liver of FRGN mice and repopulated to high levels (>80%). Animals transplanted and liver repopulated with genetically edited patient hepatocytes displayed normal ammonia, enhanced clearance of an ammonia challenge and OTC enzyme activity, as well as lower urinary orotic acid when compared to mice repopulated with unedited patient hepatocytes. Gene expression was shown to be similar between mice transplanted with unedited or edited patient hepatocytes. Finally, a genome-wide screening by performing CIRCLE-seq and deep sequencing of >70 potential off-targets revealed no unspecific editing. Overall analysis of disease phenotype, gene expression, and possible off-target editing indicated that the gene editing of a severe genetic liver disease was safe and effective. Keywords: CRISPR; FRGN; ex vivo; genome editing; hepatocyte transplantation; liver-humanized mouse; primary hepatocytes; urea cycle disorder