Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons

Fibrillar αSynuclein is the major constituent of Lewy bodies and Lewy neurites, the protein deposits characteristic for Parkinson’s disease (PD). Multiplications of the αSynuclein gene, as well as point mutations cause familial PD. However, the exact role of αSynuclein in neurodegeneration remains uncertain. Recent research in invertebrates has suggested that oligomeric rather than fibrillizing αSynuclein mediates neurotoxicity. To investigate the impact of αSynuclein aggregation on the progression of neurodegeneration, we expressed variants with different fibrillation propensities in the rat substantia nigra (SN) by means of recombinant adeno-associated viral (AAV) vectors. The formation of proteinase K-resistant αSynuclein aggregates was correlated to the loss of nigral dopaminergic (DA) neurons and striatal fibers. Expression of two prefibrillar, structure-based design mutants of αSynuclein (i.e., A56P and A30P/A56P/A76P) resulted in less aggregate formation in nigral DA neurons as compared to human wild-type (WT) or the inherited A30P mutation. However, only the αSynuclein variants capable of forming fibrils (WT/A30P), but not the oligomeric αSynuclein species induced a sustained progressive loss of adult nigral DA neurons. These results demonstrate that divergent modes of αSynuclein neurotoxicity exist in invertebrate and mammalian DA neurons in vivo and suggest that fibrillation of αSynuclein promotes the progressive degeneration of nigral DA neurons as found in PD patients

Characterization of stochastic orders by L-functionals

Random variables may be compared with respect to their location by comparing certain functionals ad hoc, such as the mean or median, or by means of stochastic ordering based directly on the properties of the corresponding distribution functions. These alternative approaches are brought together in this paper. We focus on the class of L-functionals discussed by Bickel and Lehmann (1975) and characterize the comparison of random variables in terms of these measures by means of several stochastic orders based on iterated integrals, including the increasing convex orde

HIV-Induced Type I Interferon and Tryptophan Catabolism Drive T Cell Dysfunction Despite Phenotypic Activation

Infection by the human immunodeficiency virus (HIV) is characterized by functional impairment and chronic activation of T lymphocytes, the causes of which are largely unexplained. We cultured peripheral blood mononuclear cells (PBMC) from HIV-uninfected donors in the presence or absence of HIV. HIV exposure increased expression of the activation markers CD69 and CD38 on CD4 and CD8 T cells. IFN-α/β, produced by HIV-activated plasmacytoid dendritic cells (pDC), was necessary and sufficient for CD69 and CD38 upregulation, as the HIV-induced effect was inhibited by blockade of IFN-α/β receptor and mimicked by recombinant IFN-α/β. T cells from HIV-exposed PBMC showed reduced proliferation after T cell receptor stimulation, partially prevented by 1-methyl tryptophan, a competitive inhibitor of the immunesuppressive enzyme indoleamine (2,3)-dioxygenase (IDO), expressed by HIV-activated pDC. HIV-induced IDO inhibited CD4 T cell proliferation by cell cycle arrest in G1/S, and prevented CD8 T cell from entering the cell cycle by downmodulating the costimulatory receptor CD28. Finally, the expression of CHOP, a marker of the stress response activated by IDO, was upregulated by HIV in T cells in vitro and is increased in T cells from HIV-infected patients. Our data provide an in vitro model for HIV-induced T cell dysregulation and support the hypothesis that activation of pDC concomitantly contribute to phenotypic T cell activation and inhibition of T cell proliferative capacity during HIV infection

Supersymmetric QCD corrections to e+e−→tbˉH−e^+e^-\to t\bar{b}H^- and the Bernstein-Tkachov method of loop integration

The discovery of charged Higgs bosons is of particular importance, since their existence is predicted by supersymmetry and they are absent in the Standard Model (SM). If the charged Higgs bosons are too heavy to be produced in pairs at future linear colliders, single production associated with a top and a bottom quark is enhanced in parts of the parameter space. We present the next-to-leading-order calculation in supersymmetric QCD within the minimal supersymmetric SM (MSSM), completing a previous calculation of the SM-QCD corrections. In addition to the usual approach to perform the loop integration analytically, we apply a numerical approach based on the Bernstein-Tkachov theorem. In this framework, we avoid some of the generic problems connected with the analytical method.Comment: 14 pages, 6 figures, accepted for publication in Phys. Rev.

Do Gene Variants Influencing Adult Adiposity Affect Birth Weight? A Population-Based Study of 24 Loci in 4,744 Danish Individuals

Several obesity risk alleles affecting adult adiposity have been identified by the recent wave of genome wide association studies. We aimed to examine the potential effect of these variants on fetal body composition by investigating the variants in relation to birth weight and ponderal index of the newborn.Midwife records from the Danish State Archives provided information on mother's age, parity, as well as birth weight, birth length and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. Twenty-four risk alleles showing genome-wide associations with adult BMI and/or waist circumference were genotyped. None of the 24 risk variants tested showed an association with birth weight or ponderal index after correction for multiple testing. Birth weight was divided into three categories low (≤10(th) percentile), normal (10(th)-90(th) percentile) and high birth weight (≥90th percentile) to allow for non-linear associations. There was no difference in the number of risk alleles between the groups (p = 0.57). No interactions between each risk allele and birth weight in the prediction of adult BMI were observed. An obesity risk score was created by summing up risk alleles. The risk score did not associate with fetal body composition. Moreover there was no interaction between the risk score and birth weight/ponderal index in the prediction of adult BMI.24 common variants associated with adult adiposity did not affect or interact with birth weight among Danes suggesting that the effects of these variants predominantly arise in the post-natal life

A secretome profile indicative of oleate-induced proliferation of HepG2 hepatocellular carcinoma cells

Increased fatty acid (FA) is often observed in highly proliferative tumors. FAs have been shown to modulate the secretion of proteins from tumor cells, contributing to tumor survival. However, the secreted factors affected by FA have not been systematically explored. Here, we found that treatment of oleate, a monounsaturated omega-9 FA, promoted the proliferation of HepG2 cells. To examine the secreted factors associated with oleate-induced cell proliferation, we performed a comprehensive secretome profiling of oleate-treated and untreated HepG2 cells. A comparison of the secretomes identified 349 differentially secreted proteins (DSPs; 145 upregulated and 192 downregulated) in oleate-treated samples, compared to untreated samples. The functional enrichment and network analyses of the DSPs revealed that the 145 upregulated secreted proteins by oleate treatment were mainly associated with cell proliferation-related processes, such as lipid metabolism, inflammatory response, and ER stress. Based on the network models of the DSPs, we selected six DSPs (MIF, THBS1, PDIA3, APOA1, FASN, and EEF2) that can represent such processes related to cell proliferation. Thus, our results provided a secretome profile indicative of an oleate-induced proliferation of HepG2 cell

Hypereosinophilic syndromes

Hypereosinophilic syndromes (HES) constitute a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia (> 1.5 × 109/L for more than six consecutive months) associated with evidence of eosinophil-induced organ damage, where other causes of hypereosinophilia such as allergic, parasitic, and malignant disorders have been excluded. Prevalence is unknown. HES occur most frequently in young to middle-aged patients, but may concern any age group. Male predominance (4–9:1 ratio) has been reported in historic series but this is likely to reflect the quasi-exclusive male distribution of a sporadic hematopoietic stem cell mutation found in a recently characterized disease variant. Target-organ damage mediated by eosinophils is highly variable among patients, with involvement of skin, heart, lungs, and central and peripheral nervous systems in more than 50% of cases. Other frequently observed complications include hepato- and/or splenomegaly, eosinophilic gastroenteritis, and coagulation disorders. Recent advances in underlying pathogenesis have established that hypereosinophilia may be due either to primitive involvement of myeloid cells, essentially due to occurrence of an interstitial chromosomal deletion on 4q12 leading to creation of the FIP1L1-PDGFRA fusion gene (F/P+ variant), or to increased interleukin (IL)-5 production by a clonally expanded T cell population (lymphocytic variant), most frequently characterized by a CD3-CD4+ phenotype. Diagnosis of HES relies on observation of persistent and marked hypereosinophilia responsible for target-organ damage, and exclusion of underlying causes of hypereosinophilia, including allergic and parasitic disorders, solid and hematological malignancies, Churg-Strauss disease, and HTLV infection. Once these criteria are fulfilled, further testing for eventual pathogenic classification is warranted using appropriate cytogenetic and functional approaches. Therapeutic management should be adjusted to disease severity and eventual detection of pathogenic variants. For F/P+ patients, imatinib has undisputedly become first line therapy. For others, corticosteroids are generally administered initially, followed by agents such as hydroxycarbamide, interferon-alpha, and imatinib, for corticosteroid-resistant cases, as well as for corticosteroid-sparing purposes. Recent data suggest that mepolizumab, an anti-IL-5 antibody, is an effective corticosteroid-sparing agent for F/P-negative patients. Prognosis has improved significantly since definition of HES, and currently depends on development of irreversible heart failure, as well as eventual malignant transformation of myeloid or lymphoid cells

Inter-laboratory reproducibility of fast gas chromatography–electron impact–time of flight mass spectrometry (GC–EI–TOF/MS) based plant metabolomics

The application of gas chromatography–mass spectrometry (GC–MS) to the ‘global’ analysis of metabolites in complex samples (i.e. metabolomics) has now become routine. The generation of these data-rich profiles demands new strategies in data mining and standardisation of experimental and reporting aspects across laboratories. As part of the META-PHOR project’s (METAbolomics for Plants Health and OutReach: http://www.meta-phor.eu/) priorities towards robust technology development, a GC–MS ring experiment based upon three complex matrices (melon, broccoli and rice) was launched. All sample preparation, data processing, multivariate analyses and comparisons of major metabolite features followed standardised protocols, identical models of GC (Agilent 6890N) and TOF/MS (Leco Pegasus III) were also employed. In addition comprehensive GC×GC–TOF/MS was compared with 1 dimensional GC–TOF/MS. Comparisons of the paired data from the various laboratories were made with a single data processing and analysis method providing an unbiased assessment of analytical method variants and inter-laboratory reproducibility. A range of processing and statistical methods were also assessed with a single exemplary dataset revealing near equal performance between them. Further investigations of long-term reproducibility are required, though the future generation of global and valid metabolomics databases offers much promise

Interferon-Alpha Administration Enhances CD8+ T Cell Activation in HIV Infection

Type I interferons play important roles in innate immune defense. In HIV infection, type I interferons may delay disease progression by inhibiting viral replication while at the same time accelerating disease progression by contributing to chronic immune activation.To investigate the effects of type I interferons in HIV-infection, we obtained cryopreserved peripheral blood mononuclear cell samples from 10 subjects who participated in AIDS Clinical Trials Group Study 5192, a trial investigating the activity of systemic administration of IFNα for twelve weeks to patients with untreated HIV infection. Using flow cytometry, we examined changes in cell cycle status and expression of activation antigens by circulating T cells and their maturation subsets before, during and after IFNα treatment.The proportion of CD38+HLA-DR+CD8+ T cells increased from a mean of 11.7% at baseline to 24.1% after twelve weeks of interferon treatment (p = 0.006). These frequencies dropped to an average of 20.1% six weeks after the end of treatment. In contrast to CD8+ T cells, the frequencies of activated CD4+ T cells did not change with administration of type I interferon (mean percentage of CD38+DR+ cells = 2.62% at baseline and 2.17% after 12 weeks of interferon therapy). As plasma HIV levels fell with interferon therapy, this was correlated with a "paradoxical" increase in CD8+ T cell activation (p<0.001).Administration of type I interferon increased expression of the activation markers CD38 and HLA DR on CD8+ T cells but not on CD4+ T cells of HIV+ persons. These observations suggest that type I interferons may contribute to the high levels of CD8+ T cell activation that occur during HIV infection