Anatomy of germinal centers in mouse spleen, with special reference to \u27follicular dendritic cells\u27

Lymphocyte proliferation in germinal centers (GC\u27s) is thought to be triggered by antigen retained extracellularly on the surface of special \u27dendritic\u27 cells. The anatomy and function of these cells have not been studied directly or in detail. We therefore examined mouse spleen GC\u27s developing in response to sheep erythrocyte stimulation. We found that distinctive \u27follicular dendritic cells\u27 (FDC\u27s) were present in both the GC and adjacent mantle region of secondary follicles. The large, irregularly shaped nucleus, containing little heterochromatin, allowed for the light microscope (LM) identification of FDC\u27s. By EM, the cell was stellate in shape sending out long, thin sheets of cytoplasm which could fold and coil into complex arrays. The processes were coated extracellularly by an amorphous electron-dense material of varying thickness, as well as particulates including variable numbers of virions. The FDC cytoplasm lacked organelles of active secretory and endocytic cells, such as well-developed rough endoplasmic reticulum (RER) and lysosomes. These anatomical features readily distinguished FDC\u27s from other cell types, even those that were extended in shape. To pursue these descriptive findings, we injected three electron-dense tracers i.v. and sacrificed the mice 1 h-10 days thereafter. Colloidal carbon, colloidal thorium dioxide (cThO2), and soluble horseradish perixidase (HRP) were actively sequestered into the vacuolar system of macrophages but were interiorized only in trace amounts by FDC\u27s. Therefore, FDC\u27s are not macrophages by cytologic and functional criteria. FDC\u27s did display a unique property. Both colloidal carbon and thorium dioxide, which are nonimmunogens, could be visualized extracellularly on the cell surface for several days. The meaning of this is unclear, but the association of colloid with FDC\u27s appeared to slow the movement of particulates through the extracellular space into the GC proper. FDC\u27s were not readily identified in splenic white pulp lacking GC\u27s. They must develop de novo then, possibly from novel dendritic cells that we have identified in vitro

Distribution of horseradish peroxidase (HRP)- anti-HRP immune complexes in mouse spleen with special reference to follicular dendritic cells

The distribution of immune complexes has been studied in mouse spleen stimulated to contain many germinal centers (GC′s). Horseradish peroxidase (HRP)-anti-HRP complexes were used as an appropriately precise and sensitive model. We were primarily interested in the relative abilities of three cell types to interact with complexes: lymphocytes, macrophages, and follicular dendritic cells (FDC′s). The latter are distinctive, nonendocytic, stellate cells located primarily at the transition of mantle and GC zones of 2° lymphoid follicles (Chen, L. L., J. C. Adams, and R. M. Steinman, 1978, J. Cell Biol. 77: 148). Binding of immune complexes to lymphocytes could not be visualized in situ. Macrophages avidly interiorized complexes into lysosomes, but did not retain them extracellularly. In contrast, FDC′s could retain HRP-anti-HRP extracellularly under appropriate conditions, but did not endocytose them. Cytochemical reactivity accumulated progressively on FDC′s 1-6 h after administration of complexes i.v., remained stable in amount and location for 1 day, and then was progressively lost over a 1- to 5-day period. Several variables in the association of complexes with macrophages and FDC′s were pursued. Only 1 /xg of complexed HRP had to be administered to visualize binding to both cell types. Macrophages interiorized complexes formed in a wide range of HRP/anti-HRP ratios, while FDC′s associated with complexes formed in HRP excess only. Quantitative studies with [125I]HRP-anti-HRP demonstrated that 20 of the splenic load of HRP associated with FDC′s. Complexes formed with an F(ab′)2 anti-HRP were distributed primarily in macrophages. When the levels of the third component of serum complement were depleted by prior treatment with cobra venom factor, uptake of complexes by macrophages was reduced some 50 whereas association with FDC′s was abolished. The fact that antigen excess complexes are retained extracellularly strengthens the idea that they are immunogenic. Finally, the association of complexes with FDC′s seems to retard the entry of antigen into the GC proper

Pregnancy outcomes for women with rare autoimmune diseases

Objective: To examine pregnancy outcomes and pregnancy-related health service utilisation among women with rare autoimmune diseases. Methods: This population-based cohort study of an Australian obstetric population (New South Wales 2001-2011) used birth records linked to hospital records for identification of rare autoimmune diseases including systemic vasculitis, vasculitis limited to skin, systemic sclerosis, dermatopolymyositis and other systemic involvement of connective tissue. We excluded births to women with systemic lupus erythematosus or rheumatoid arthritis and births >6 months before the first documented diagnosis of the rare autoimmune disease. Modified Poisson regression was used to compare study outcomes between women with autoimmune diseases and the general obstetric population. Results: There were 991,701 births including 409 (0.04%) births to 293 women with rare autoimmune diseases. Of the 409 pregnancies, 202 (49%) delivered by cesarean delivery and 72 (18%) were preterm; these rates were significantly higher than those in the general obstetric population (28% and 7% respectively). Compared to the general population, women with autoimmune diseases had higher rates of hypertensive disorders, antepartum hemorrhage and severe maternal morbidity, and required longer hospitalization at delivery and more hospital admissions and tertiary obstetric care. Compared to other infants, those whose mothers had a rare autoimmune disease were at increased risk of admission to neonatal intensive care unit, severe neonatal morbidity and perinatal death. Conclusions: Women with rare autoimmune diseases were at increased risk of having both maternal complications and adverse neonatal outcomes; their pregnancies should be closely monitored.NHMRC; Rolf Edgar Lake Postdoctoral Fellowship, University of Sydne

Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy.

PurposeTo report potentially pathogenic mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes in two individuals with clinically diagnosed Meesmann corneal dystrophy (MECD).MethodsSlit-lamp examination was performed on the probands and available family members to identify characteristic features of MECD. After informed consent was obtained, saliva samples were obtained as a source of genomic DNA, and screening of KRT3 and KRT12 was performed. Potentially pathogenic variants were screened for in 200 control chromosomes. PolyPhen-2, SIFT, and PANTHER were used to predict the functional impact of identified variants. Short tandem repeat genotyping was performed to confirm paternity.ResultsSlit-lamp examination of the first proband demonstrated bilateral, diffusely distributed, clear epithelial microcysts, consistent with MECD. Screening of KRT3 revealed a heterozygous missense variant in exon 1, c.250C>T (p.(Arg84Trp)), which has a minor allele frequency of 0.0076 and was not identified in 200 control chromosomes. In silico analysis with PolyPhen-2 and PANTHER predicted the variant to be damaging to protein function; however, SIFT analysis predicted tolerance of the variant. The second proband demonstrated bilateral, diffusely distributed epithelial opacities that appeared gray-white on direct illumination and translucent on retroillumination. Neither parent demonstrated corneal opacities. Screening of KRT12 revealed a novel heterozygous insertion/deletion variant in exon 6, c.1288_1293delinsAGCCCT (p.(Arg430_Arg431delinsSerPro)). This variant was not present in either of the proband's parents or in 200 control chromosomes and was predicted to be damaging by PolyPhen-2, PANTHER, and SIFT. Haplotype analysis confirmed paternity of the second proband, indicating that the variant arose de novo.ConclusionsWe present a novel KRT12 mutation, representing the first de novo mutation and the first indel in KRT12 associated with MECD. In addition, we report a variant of uncertain significance in KRT3 in an individual with MECD. Although the potential pathogenicity of this variant is unknown, it is the first variant affecting the head domain of K3 to be reported in an individual with MECD and suggests that disease-causing variants associated with MECD may not be restricted to primary sequence alterations of either the helix-initiation or helix-termination motifs of K3 and K12

Tumor Necrosis Factor-Alpha Inhibitory Therapy for Non-Infectious Autoimmune Uveitis

Biologic agents represent a mainstay in the treatment of refractory non-infectious, immune-mediated uveitis. Tumor necrosis factor (TNF)-α inhibitors have demonstrated efficacy in inducing and sustaining disease remission in numerous systemic inflammatory disorders and their associated uveitic entities. In particular, studies have shown that infliximab and adalimumab can induce steroid-free disease remission in patients with Behçet’s disease and juvenile arthritis as treatments that are superior to conventional disease-modifying immunosuppressive agents. Patients receiving anti-TNF-α therapy may experience adverse events and should be closely monitored for the development of opportunistic infections, reactivation of tuberculosis and hepatitis, demyelinating disease and neuropathies, as well as malignancies

Doped graphene nanohole arrays for flexible transparent conductors

Graphene nanohole arrays (GNAs) were fabricated using nanoimprint lithography. The improved optical transmittance of GNAs is primarily due to the reduced surface coverage of graphene from the nanohole fabrication. Importantly, the exposed edges of the nanoholes provided effective sites for chemical doping using thionyl chloride was shown to enhance the conductance by a factor of 15–18 in contrast to only 2-4 for unpatterned graphene. GNAs can provide a unique scheme for improving both optical transmittance and electrical conductivity of graphene-based transparent conductors

SeaWiFS technical report series. Volume 9: The simulated SeaWiFS data set, version 1

Data system development activities for the Sea-viewing Wide Field-of-view Sensor (SeaWiFS) must begin well before the scheduled 1994 launch. To assist in these activities, it is essential to develop a simulated SeaWiFS data set as soon as possible. Realism is of paramount importance in this data set, including SeaWiFS spectral bands, orbital and scanning characteristics, and known data structures. Development of the simulated data set can assist in identification of problem areas that can be addressed and solved before the actual data are received. This paper describes the creation of the first version of the simulated SeaWiFS data set. The data set includes the spectral band, orbital, and scanning characteristics of the SeaWiFS sensor and SeaStar spacecraft. The information is output in the data structure as it is stored onboard. Thus, it is a level-0 data set which can be taken from start to finish through a prototype data system. The data set is complete and correct at the time of printing, although the values in the telemetry fields are left blank. The structure of the telemetry fields, however, is incorporated. Also, no account for clouds has been included. However, this version facilitates early prototyping activities by the SeaWiFS data system, providing a realistic data set to assess performance

Ambipolar Field Effect in Topological Insulator Nanoplates of (BixSb1-x)2Te3

Topological insulators represent a new state of quantum matter attractive to both fundamental physics and technological applications such as spintronics and quantum information processing. In a topological insulator, the bulk energy gap is traversed by spin-momentum locked surface states forming an odd number of surface bands that possesses unique electronic properties. However, transport measurements have often been dominated by residual bulk carriers from crystal defects or environmental doping which mask the topological surface contribution. Here we demonstrate (BixSb1-x)2Te3 as a tunable topological insulator system to manipulate bulk conductivity by varying the Bi/Sb composition ratio. (BixSb1-x)2Te3 ternary compounds are confirmed as topological insulators for the entire composition range by angle resolved photoemission spectroscopy (ARPES) measurements and ab initio calculations. Additionally, we observe a clear ambipolar gating effect similar to that observed in graphene using nanoplates of (BixSb1-x)2Te3 in field-effect-transistor (FET) devices. The manipulation of carrier type and concentration in topological insulator nanostructures demonstrated in this study paves the way for implementation of topological insulators in nanoelectronics and spintronics.Comment: 7 pages, 4 figure

Rapid Surface Oxidation as a Source of Surface Degradation Factor for Bi2Se3

Bi2Se3 is a topological insulator with metallic surface states residing in a large bulk bandgap. It is believed that Bi2Se3 gets additional n-type doping after exposure to atmosphere, thereby reducing the relative contribution of surface states in total conductivity. In this letter, transport measurements on Bi2Se3 nanoribbons provide additional evidence of such environmental doping process. Systematic surface composition analyses by X-ray photoelectron spectroscopy reveal fast formation and continuous growth of native oxide on Bi2Se3 under ambient conditions. In addition to n-type doping at the surface, such surface oxidation is likely the material origin of the degradation of topological surface states. Appropriate surface passivation or encapsulation may be required to probe topological surface states of Bi2Se3 by transport measurements

The Chandra Source Catalog

The Chandra Source Catalog (CSC) is a general purpose virtual X-ray astrophysics facility that provides access to a carefully selected set of generally useful quantities for individual X-ray sources, and is designed to satisfy the needs of a broad-based group of scientists, including those who may be less familiar with astronomical data analysis in the X-ray regime. The first release of the CSC includes information about 94,676 distinct X-ray sources detected in a subset of public ACIS imaging observations from roughly the first eight years of the Chandra mission. This release of the catalog includes point and compact sources with observed spatial extents <~ 30''. The catalog (1) provides access to the best estimates of the X-ray source properties for detected sources, with good scientific fidelity, and directly supports scientific analysis using the individual source data; (2) facilitates analysis of a wide range of statistical properties for classes of X-ray sources; and (3) provides efficient access to calibrated observational data and ancillary data products for individual X-ray sources, so that users can perform detailed further analysis using existing tools. The catalog includes real X-ray sources detected with flux estimates that are at least 3 times their estimated 1 sigma uncertainties in at least one energy band, while maintaining the number of spurious sources at a level of <~ 1 false source per field for a 100 ks observation. For each detected source, the CSC provides commonly tabulated quantities, including source position, extent, multi-band fluxes, hardness ratios, and variability statistics, derived from the observations in which the source is detected. In addition to these traditional catalog elements, for each X-ray source the CSC includes an extensive set of file-based data products that can be manipulated interactively.Comment: To appear in The Astrophysical Journal Supplement Series, 53 pages, 27 figure