A Spatio-Temporal Model Reveals Self-Limiting FcɛRI Cross-Linking by Multivalent Antigens

Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (FcɛRI) in the plasma membrane of mast cells. However, understanding of the mechanisms of FcɛRI aggregation remains incomplete. Experimental reports indicate that FcɛRI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse FcɛRI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens

Expansion of radiative cooling of the laser induced plasma

To study the expansion and cooling process of the laser induced plasma generated by nanosecond pulsed laser ablation, experiments have been conducted which measure the position of the external shockwaves and the temperature of the vapor plumes. The positions of external shockwaves were determined by a femtosecond laser time-resolved imaging system. Vapor plume temperature was determined from spectroscopic measurements of the plasma emission lines. A model which considers the mass, momentum, and energy conservation of the region affected by the laser energy was developed. It shows good agreement to the experimental data

Metal particles produced by laser ablation for ICP-MSmeasurements

Pulsed laser ablation (266nm) was used to generate metal particles of Zn and Al alloys using femtosecond (150 fs) and nanosecond (4 ns) laser pulses with identical fluences of 50 J cm{sup -2}. Characterization of particles and correlation with Inductively Coupled Plasma Mass Spectrometer (ICP-MS) performance was investigated. Particles produced by nanosecond laser ablation were mainly primary particles with irregular shape and hard agglomerates (without internal voids). Particles produced by femtosecond laser ablation consisted of spherical primary particles and soft agglomerates formed from numerous small particles. Examination of the craters by white light interferometric microscopy showed that there is a rim of material surrounding the craters formed after nanosecond laser ablation. The determination of the crater volume by white light interferometric microscopy, considering the rim of material surrounding ablation craters, revealed that the volume ratio (fs/ns) of the craters on the selected samples was approximately 9 (Zn), 7 (NIST627 alloy) and 5 (NIST1711 alloy) times more ablated mass with femtosecond pulsed ablation compared to nanosecond pulsed ablation. In addition, an increase of Al concentration from 0 to 5% in Zn base alloys caused a large increase in the diameter of the particles, up to 65% while using nanosecond laser pulses. When the ablated particles were carried in argon into an ICP-MS, the Zn and Al signals intensities were greater by factors of {approx} 50 and {approx} 12 for fs vs. ns ablation. Femtosecond pulsed ablation also reduced temporal fluctuations in the {sup 66}Zn transient signal by a factor of ten compared to nanosecond laser pulses

Lineage Divergence and Historical Gene Flow in the Chinese Horseshoe Bat (Rhinolophus sinicus)

PMCID: PMC3581519This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Synthesis and structures of new borophosphates (B1-xMx)PO4 (M=Mn,Fe,Co,Ni,Cu) with orthorhombic low-cristobalite type

The first reported (B1-xMx)PO4 (M = Mn, Fe, Co, Ni, Cu) compounds were synthesized by high temperature solid state methods and the structures refined from X-ray powder data. The transition metal substitutions on the boron site stabilized the structure to the orthorhombic low-cristobalite type with average volumes per tetrahedral unit 30% larger than that in BPO4 and novel catalytic properties are expected. The magnetic data indicate the 3+ valences thr the metals

The patatin-containing phospholipase A pPLAIIα modulates oxylipin formation and water loss in Arabidopsis thaliana

The patatin-related phospholipase A (pPLA) hydrolyzes membrane glycerolipids to produce monoacyl compounds and free fatty acids. Phospholipids are cleaved by pPLAIIα at the sn-1 and sn-2 positions, and galactolipids, including those containing oxophytodienoic acids, can also serve as substrates. Ablation of pPLAIIα decreased lysophosphatidylcholine and lysophosphatidylethanolamine levels, but increased free linolenic acid. pPLAIIα-deficient plants displayed a higher level of jasmonic acid and methyl jasmonate, as well as the oxylipin-biosynthetic intermediates 13-hydroperoxylinolenic acid and 12-oxophytodienoic acid than wild-type plants. The expression of genes involved in oxylipin production was also higher in the pPLAIIα-deficient mutant than in wild-type plants. The mutant plants lost water faster than wild type plants did. The stomata of wild type and mutant plants responded similarly to abscisic acid. In response to desiccation, the mutant and wild type leaves produced abscisic acid at the same rate, but after 4 h of desiccation, the jasmonic acid level was much higher in mutant than wild-type leaves. These results indicate that pPLAIIα negatively regulates oxylipin production and suggest a role in the removal of oxidatively modified fatty acids from membranes

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva

BackgroundCorticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood.MethodsWe investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn.ResultsMaternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, β = 0.64, SE = 0.30).ConclusionIn our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood

Wnt signaling in breast cancer: have we come full circle?

Since the original identification of Wnt1 as a mammary oncogene in mouse mammary tumor virus infected mice, questions have been asked about its relevance to human breast cancer. Wnt1 is now known to be one of a large family of Wnt genes encoding structurally similar secreted signaling proteins, several of which are functionally redundant. The principal intracellular signaling pathway activated by these proteins has been elucidated in recent years. Components of this pathway include proto-oncogene products, such as β-catenin, and tumor suppressor proteins such as APC. Although WNT1 itself has not been implicated in human breast neoplasms, it has been reported that other WNT genes are sometimes overexpressed in human breast cancer and there is growing evidence that downstream components of the Wnt signaling pathway are activated in a significant proportion of breast tumors

Elevated levels of Dickkopf-related protein 3 in seminal plasma of prostate cancer patients

<p>Abstract</p> <p>Background</p> <p>Expression of Dkk-3, a secreted putative tumor suppressor, is altered in age-related proliferative disorders of the human prostate. We now investigated the suitability of Dkk-3 as a diagnostic biomarker for prostate cancer (PCa) in seminal plasma (SP).</p> <p>Methods</p> <p>SP samples were obtained from 81 patients prior to TRUS-guided prostate biopsies on the basis of elevated serum prostate-specific antigen (PSA; > 4 ng/mL) levels and/or abnormal digital rectal examination. A sensitive indirect immunoenzymometric assay for Dkk-3 was developed and characterized in detail. SP Dkk-3 and PSA levels were determined and normalized to total SP protein. The diagnostic accuracies of single markers including serum PSA and multivariate models to discriminate patients with positive (N = 40) and negative (N = 41) biopsy findings were investigated.</p> <p>Results</p> <p>Biopsy-confirmed PCa showed significantly higher SP Dkk-3 levels (100.9 ± 12.3 vs. 69.2 ± 9.4 fmol/mg; <it>p </it>= 0.026). Diagnostic accuracy (AUC) of SP Dkk-3 levels (0.633) was enhanced in multivariate models by including serum PSA (model A; AUC 0.658) or both, serum and SP PSA levels (model B; AUC 0.710). In a subpopulation with clinical follow-up > 3 years post-biopsy to ensure veracity of negative biopsy status (positive biopsy N = 21; negative biopsy N = 25) AUCs for SP Dkk-3, model A and B increased to 0.667, 0.724 and 0.777, respectively.</p> <p>Conclusions</p> <p>In multivariate models to detect PCa, inclusion of SP Dkk-3 levels, which were significantly elevated in biopsy-confirmed PCa patients, improved the diagnostic performance compared with serum PSA only.</p