On the geometry of the set of symmetric matrices with repeated eigenvalues

We investigate some geometric properties of the real algebraic variety \u394 of symmetric matrices with repeated eigenvalues. We explicitly compute the volume of its intersection with the sphere and prove a Eckart\u2013Young\u2013Mirsky-type theorem for the distance function from a generic matrix to points in \u394. We exhibit connections of our study to real algebraic geometry (computing the Euclidean distance degree of \u394) and random matrix theory

Biomass burning influence on high-latitude tropospheric ozone and reactive nitrogen in summer 2008: a multi-model analysis based on POLMIP simulations

We have evaluated tropospheric ozone enhancement in air dominated by biomass burning emissions at high latitudes (> 50° N) in July 2008, using 10 global chemical transport model simulations from the POLMIP multi-model comparison exercise. In model air masses dominated by fire emissions, ΔO3/ΔCO values ranged between 0.039 and 0.196 ppbv ppbv−1 (mean: 0.113 ppbv ppbv−1) in freshly fire-influenced air, and between 0.140 and 0.261 ppbv ppbv−1 (mean: 0.193 ppbv) in more aged fire-influenced air. These values are in broad agreement with the range of observational estimates from the literature. Model ΔPAN/ΔCO enhancement ratios show distinct groupings according to the meteorological data used to drive the models. ECMWF-forced models produce larger ΔPAN/ΔCO values (4.47 to 7.00 pptv ppbv−1) than GEOS5-forced models (1.87 to 3.28 pptv ppbv−1), which we show is likely linked to differences in efficiency of vertical transport during poleward export from mid-latitude source regions. Simulations of a large plume of biomass burning and anthropogenic emissions exported from towards the Arctic using a Lagrangian chemical transport model show that 4-day net ozone change in the plume is sensitive to differences in plume chemical composition and plume vertical position among the POLMIP models. In particular, Arctic ozone evolution in the plume is highly sensitive to initial concentrations of PAN, as well as oxygenated VOCs (acetone, acetaldehyde), due to their role in producing the peroxyacetyl radical PAN precursor. Vertical displacement is also important due to its effects on the stability of PAN, and subsequent effect on NOx abundance. In plumes where net ozone production is limited, we find that the lifetime of ozone in the plume is sensitive to hydrogen peroxide loading, due to the production of HOx from peroxide photolysis, and the key role of HO2 + O3 in controlling ozone loss. Overall, our results suggest that emissions from biomass burning lead to large-scale photochemical enhancement in high-latitude tropospheric ozone during summer

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4⁺ T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.</p> <p>Findings</p> <p>Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE.</p> <p>Conclusions</p> <p>DC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.</p

An Outbreak of Dengue Fever in St. Croix (US Virgin Islands), 2005

BACKGROUND: Periodic outbreaks of dengue fever occur in the United States Virgin Islands. In June 2005, an outbreak of dengue virus (DENV) serotype-2 with cases of dengue hemorrhagic fever (DHF) was detected in St. Croix, US Virgin Islands. The objective of this report is to describe this outbreak of DENV-2 and the findings of a case-control study examining risk factors for DHF. METHODOLOGY/PRINCIPAL FINDINGS: This is the largest dengue outbreak ever recorded in St. Croix, with 331 suspected dengue cases reported island-wide during 2005 (62.2 cases/10,000 population); 54% were hospitalized, 21% had at least one hemorrhagic manifestation, 28% had thrombocytopenia, 5% had DHF and 1 patient died. Eighty-nine laboratory-positive hospitalized patients were identified. Of these, there were 15 (17%) who met the WHO criteria for DHF (cases) and 74 (83%) who did not (controls). The only variable significantly associated with DHF on bivariate or multivariable analysis was age, with an adjusted odds ratio (95% confidence interval) of 1.033 (1.003,1.064). CONCLUSIONS/SIGNIFICANCE: During this outbreak of DENV-2, a high proportion of cases developed DHF and increasing age was significantly associated with DHF

Geometric methods on low-rank matrix and tensor manifolds

In this chapter we present numerical methods for low-rank matrix and tensor problems that explicitly make use of the geometry of rank constrained matrix and tensor spaces. We focus on two types of problems: The first are optimization problems, like matrix and tensor completion, solving linear systems and eigenvalue problems. Such problems can be solved by numerical optimization for manifolds, called Riemannian optimization methods. We will explain the basic elements of differential geometry in order to apply such methods efficiently to rank constrained matrix and tensor spaces. The second type of problem is ordinary differential equations, defined on matrix and tensor spaces. We show how their solution can be approximated by the dynamical low-rank principle, and discuss several numerical integrators that rely in an essential way on geometric properties that are characteristic to sets of low rank matrices and tensors

The CD3-Zeta Chimeric Antigen Receptor Overcomes TCR Hypo-Responsiveness of Human Terminal Late-Stage T Cells

Adoptive therapy of malignant diseases with tumor-specific cytotoxic T cells showed remarkable efficacy in recent trials. Repetitive T cell receptor (TCR) engagement of target antigen, however, inevitably ends up in hypo-responsive cells with terminally differentiated KLRG-1+ CD57+ CD7− phenotype limiting their therapeutic efficacy. We here revealed that hypo-responsiveness of CMV-specific late-stage CD8+ T cells is due to reduced TCR synapse formation compared to younger cells. Membrane anchoring of TCR components contributes to T cell hypo-responsiveness since dislocation of galectin-3 from the synapse by swainsonine restored both TCR synapse formation and T cell response. Transgenic expression of a CD3-zeta signaling chimeric antigen receptor (CAR) recovered hypo-responsive T cells to full effector functions indicating that the defect is restricted to TCR membrane components while synapse formation of the transgenic CAR was not blocked. CAR engineered late-stage T cells released cytokines and mediated redirected cytotoxicity as efficiently as younger effector T cells. Our data provide a rationale for TCR independent, CAR mediated activation in the adoptive cell therapy to avoid hypo-responsiveness of late-stage T cells upon repetitive antigen encounter

In silico evolution of signaling networks using rule-based models: bistable response dynamics

One of the ultimate goals in biology is to understand the design principles of biological systems. Such principles, if they exist, can help us better understand complex, natural biological systems and guide the engineering of de novo ones. Towards deciphering design principles, in silico evolution of biological systems with proper abstraction is a promising approach. Here, we demonstrate the application of in silico evolution combined with rule-based modelling for exploring design principles of cellular signaling networks. This application is based on a computational platform, called BioJazz, which allows in silico evolution of signaling networks with unbounded complexity. We provide a detailed introduction to BioJazz architecture and implementation and describe how it can be used to evolve and/or design signaling networks with defined dynamics. For the latter, we evolve signaling networks with switch-like response dynamics and demonstrate how BioJazz can result in new biological insights on network structures that can endow bistable response dynamics. This example also demonstrated both the power of BioJazz in evolving and designing signaling networks and its limitations at the current stage of development.Comment: 24 pages, 7 figure

Epidermal Stem Cells Are Defined by Global Histone Modifications that Are Altered by Myc-Induced Differentiation

Activation of Myc induces epidermal stem cells to exit their niche and differentiate into sebocytes and interfollicular epidermis, a process that is associated with widespread changes in gene transcription. We have identified chromatin modifications that are characteristic of epidermal stem cells and investigated the effects of Myc activation. Quiescent stem cells in the interfollicular epidermis and the hair follicle bulge had high levels of tri-methylated histone H3 at lysine 9 and H4 at lysine 20. Chromatin in both stem cell populations was hypoacteylated at histone H4 and lacked mono-methylation of histone H4 at lysine 20. Myc-induced exit from the stem cell niche correlated with increased acetylation at histone H4 and transiently increased mono-methylation at lysine 20. The latter was replaced by epigenetic modifications that are largely associated with chromatin silencing: di-methylation at histone H3 lysine 9 and histone H4 lysine 20. These modifications correlated with changes in the specific histone methyltransferases Set8 and Ash-1. The Myc-induced switch from mono- to di-methylated H4K20 required HDAC activity and was blocked by the HDAC inhibitor trichostatin A (TSA). TSA treatment induced a similar epidermal phenotype to activation of Myc, and activation of Myc in the presence of TSA resulted in massive stimulation of terminal differentiation. We conclude that Myc-induced chromatin modifications play a major role in Myc-induced exit from the stem cell compartment

Candida albicans Possesses Sap7 as a Pepstatin A-Insensitive Secreted Aspartic Protease

BACKGROUND: Candida albicans, a commensal organism, is a part of the normal flora of healthy individuals. However, once the host immunity is compromised, C. albicans opportunistically causes recurrent superficial or fatal systemic candidiasis. Secreted aspartic proteases (Sap), encoded by 10 types of SAP genes, have been suggested to contribute to various virulence processes. Thus, it is important to elucidate their biochemical properties for better understanding of the molecular mechanisms that how Sap isozymes damage host tissues. METHODOLOGY/PRINCIPAL FINDINGS: The SAP7 gene was cloned from C. albicans SC5314 and heterogeneously produced by Pichia pastoris. Measurement of Sap7 proteolytic activity using the FRETS-25Ala library showed that Sap7 was a pepstatin A-insensitive protease. To understand why Sap7 was insensitive to pepstatin A, alanine substitution mutants of Sap7 were constructed. We found that M242A and T467A mutants had normal proteolytic activity and sensitivity to pepstatin A. M242 and T467 were located in close proximity to the entrance to an active site, and alanine substitution at these positions widened the entrance. Our results suggest that this alteration might allow increased accessibility of pepstatin A to the active site. This inference was supported by the observation that the T467A mutant has stronger proteolytic activity than the wild type. CONCLUSIONS/SIGNIFICANCE: We found that Sap7 was a pepstatin A-insensitive protease, and that M242 and T467 restricted the accessibility of pepstatin A to the active site. This finding will lead to the development of a novel protease inhibitor beyond pepstatin A. Such a novel inhibitor will be an important research tool as well as pharmaceutical agent for patients suffering from candidiasis

Paradoxical Effects of Rapamycin on Experimental House Dust Mite-Induced Asthma

The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma