Clinical Features and Genetic Analysis of 20 Chinese Patients with X-Linked Hyper-IgM Syndrome

X-linked hyper-IgM syndrome (XHIGM) is one type of primary immunodeficiency diseases, resulting from defects in the CD40 ligand/CD40 signaling pathways. We retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to 2013. The median onset age of these patients was 8.5 months (range: 20 days–21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%), neutropenia (14 patients, 70%), oral ulcer (13 patients, 65%), and protracted diarrhea (13 patients, 65%). Six patients had BCGitis. Six patients received hematopoietic stem cell transplantations and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations in CD40L gene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. We compared with reported mutation results and used bioinformatics software to predict the effects of mutations on the target protein. These mutations reflected the heterogeneity of CD40L gene and expanded our understanding of XHIGM

Inducible nitric oxide synthase gene targeting

Nitric oxide (NO) is a critical mediator of a variety of biological functions, including vascular and muscle relaxation, platelet aggregation, neuronal-cell function, microbicidal and tumoricidal activity, and a range of immunopathologies. NO is derived from L-arginine and molecular oxygen in a reaction catalysed by NO synthase (NOS). Three isoforms of NOS have been identified; neuronal constitutive NOS (ncNOS), endothelial constitutive NOS (ecNOS), and inducible NOS (iNOS). ncNOS and ecNOS are calcium-dependent, present constitutively in a variety of tissues and produce physiological concentrations of NO. However, large amounts NO are produced by iNOS which are expressed in cells such as macrophage after stimulation with a number of cytokines, including interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), and bacterial lipopolysaccharide (LPS). Findings of iNOS biological functions are based mainly on experiments using L-arginine analogues such as L-NG monomethyl arginine (L-NMMA) which competitively inhibits NO Synthase. These inhibitors are not NOS isoform selective and have differential bioavailability, and hence often render interpretation of results difficult. To directly define the iNOS biological functions, I constructed a strain of iNOS gene targeted mice. The first step of a gene targeting experiment is typically cDNA cloning and sequencing. A cDNA library was constructed in the vector λ ZAPII using mRNA isolated from J774 macrophages activated with IFN-? and LPS. Six independent positive colonies were found in the screen with both 5' and 3' specific probes and were subcloned in pBluescript. A full-length iNOS cDNA was constructed using the clones isolated from the library. Double strand cDNA sequence analysis showed that the J774 iNOS clone was identical to that of the Raw 264.7 macrophages iNOS cDNA sequence. A replacement-type targeting construct was prepared from 129/sv genomic DNA. A single targeted clone was identified amongst 636 screened after two independent electroporations of the CGR8 embryonic stem cell line. Gene replacement was detected by both 5' and 3' specific external probes. Five of ten chimeras generated gave germ line transmission. No homozygous mice were found by Southern blot analysis with 5' and 3' external probe in the offspring from heterozygous mice (FI) breedings. The iNOS gene had been altered by replacement with gene targeting construct and 5' iNOS gene translocation which could be detected by internal probe Southern blot analysis. Using the internal probe, mutant homozygous, heterozygous and wild-type mice were found in the offspring from heterozygous breedings. The ratio of these three genotypes was 21:47:25. Northern blot analysis with 5' iNOS cDNA probe showed that a large messenger appeared in the macrophages of homozygous mice when the cells were activated with IFN-γ and LPS in vitro. However there was no detectable iNOS protein translation by western blot analysis using monoclonal or polyclonal anti-iNOS antibodies. (Abstract shortened by ProQuest.

Luttinger-volume violating Fermi liquid in the pseudogap phase of the cuprate superconductors

Based on the NMR measurements on Bi$_2$Sr$_{2-x}$La$_x$CuO$_{6+\delta}$ (La-Bi2201) in strong magnetic fields, we identify the non-superconducting pseudogap phase in the cuprates as a Luttinger-volume violating Fermi liquid (LvvFL). This state is a zero temperature quantum liquid that does not break translational symmetry, and yet, the Fermi surface encloses a volume smaller than the large one given by the Luttinger theorem. The particle number enclosed by the small Fermi surface in the LvvFL equals the doping level $p$, not the total electron number $n_e=1-p$. Both the phase string theory and the dopon theory are introduced to describe the LvvFL. For the dopon theory, we can obtain a semi-quantitative agreement with the NMR experiments.Comment: The final version in PR

IL-15 augments TCR-induced CD4⁺ T cell expansion in vitro by inhibiting the suppressive function of CD25High CD4⁺ T cells

Due to its critical role in NK cell differentiation and CD8(+) T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+) T cells. The increased levels of IL-15 found in several CD4(+) T cell-driven (auto-) immune diseases prompted us to examine how IL-15 influences murine CD4(+) T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+) and CD8+ T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+) T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15R alpha was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15R beta, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4(+) T cell suppression by a gradually expanding CD25(High)CD4(+) T cell subset that expresses Foxp3 and originates from CD4(+)CD25(+) Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology

Perturbation bounds for constrained and weighted least squares problems

AbstractWe derive perturbation bounds for the constrained and weighted linear least squares (LS) problems. Both the full rank and rank-deficient cases are considered. The analysis generalizes some results of earlier works

Fluid-structure interaction modeling on a 3D ray-strengthened caudal fin

In this paper, we present a numerical model capable of solving the fluid-structure interaction problems involved in the dynamics of skeleton-reinforced fish fins. In this model, the fluid dynamics is simulated by solving the Navier-Stokes equations using a finite-volume method based on an overset, multi-block structured grid system. The bony rays embedded in the fin are modeled as nonlinear Euler-Bernoulli beams. To demonstrate the capability of this model, we numerically investigate the effect of various ray stiffness distributions on the deformation and propulsion performance of a 3D caudal fin. Our numerical results show that with specific ray stiffness distributions, certain caudal fin deformation patterns observed in real fish (e.g. the cupping deformation) can be reproduced through passive structural deformations. Among the four different stiffness distributions (uniform, cupping, W-shape and heterocercal) considered here, we find that the cupping distribution requires the least power expenditure. The uniform distribution, on the other hand, performs the best in terms of thrust generation and efficiency. The uniform stiffness distribution, per se, also leads to 'cupping' deformation patterns with relatively smaller phase differences between various rays. The present model paves the way for future work on dynamics of skeleton-reinforced membranes