A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers

Use of isomaltulose to formulate healthy spreadable strawberry products. Application of response surface methodology

Response surface methodology (RSM) was applied to optimize the formulation of a 50 Brix spreadable strawberry product with healthier sugars and a high percentage of fruit. A central composite design was applied to analyse the influence of four independent variables on the quality parameters. Each of the variables was analysed at five different levels (X1: % of isomaltulose (0, 12.5, 25, 37.5 and 50%), X2: % of pectin (0.5, 1, 1.5, 2 and 2.5%), X3: % of citric acid (0, 0.25, 0.5, 0.75 and 1%) and X4: time of thermal treatment (0, 5 10, 15 and 20 min). Physicochemical properties, microbiological stability, antioxidant properties (anthocyanin content and antioxidant activity) as well as optical and mechanical properties were considered for the optimization. The influence of storage time on the above parameters was also evaluated. Percentages of pectin and citric acid were the variables that most influenced the measured parameters. In general terms, high levels of these two variables (2% pectin; 0.75% citric acid) resulted in greater antioxidant activity, consistency and adhesiveness values. The optimal formulation to obtain a spreadable strawberry product was fresh strawberry, 50% fructose, 50% isomaltulose, 1% citric acid and 1.5% pectin; the ingredients were mixed, and heated to 85 1C, and the product was stable after 90 days stored at room temperature.Authors would like to thank Direccion General de Investigacion del Ministerio de Ciencia y Tecnologia (AGL2008-01745/ALI) as well as the Universitat Politecnica de Valencia for the financial support given to this investigation.Peinado Pardo, I.; Rosa Barbosa, EM.; Heredia Gutiérrez, AB.; Andrés Grau, AM. (2015). Use of isomaltulose to formulate healthy spreadable strawberry products. Application of response surface methodology. Food Bioscience. 9:47-59. https://doi.org/10.1016/j.fbio.2014.08.002S4759

Bees increase seed set of wild plants while the proportion of arable land has a variable effect on pollination in European agricultural landscapes

Background and aims - Agricultural intensification and loss of farmland heterogeneity have contributed to population declines of wild bees and other pollinators, which may have caused subsequent declines in insect-pollinated wild plants. Material and methods - Using data from 37 studies on 22 pollinator-dependent wild plant species across Europe, we investigated whether flower visitation and seed set of insect-pollinated plants decline with an increasing proportion of arable land within 1 km. Key results - Seed set increased with increasing flower visitation by bees, most of which were wild bees, but not with increasing flower visitation by other insects. Increasing proportion of arable land had a strongly variable effect on seed set and flower visitation by bees across studies. Conclusion - Factors such as landscape configuration, local habitat quality, and temporally changing resource availability (e.g. due to mass-flowering crops or honey bee hives) could have modified the effect of arable land on pollination. While our results highlight that the persistence of wild bees is crucial to maintain plant diversity, we also show that pollen limitation due to declining bee populations in homogenized agricultural landscapes is not a universal driver causing parallel losses of bees and insect-pollinated plants.Peer reviewe

Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy

Background: Glatiramer acetate therapy is thought to be effective for multiple sclerosis (MS) by promoting TH2 cytokine deviation, possibly in the brain, but the exact mechanism and site of action are incompletely understood. Determining the site of action and effect of glatiramer on cell trafficking is of major importance in designing rational combination therapy clinical trials. Objective: To determine whether glatiramer therapy will also act in the peripheral blood through bystander modulation of chemokine receptor (CKR) expression and cytokine production on T lymphocytes. Design: Before-and-after trial. Setting: A university MS specialty center. Patients: Ten patients with relapsing-remitting MS. Interventions: Treatment with glatiramer for 12 months and serial phlebotomy. Main Outcome Measures: Cytokine production, CKR expression, and cell migration. Results: The glatiramer-reactive T cells were TH2 cytokine biased, consistent with previous studies. We found a significant reduction in the expression of the TH1 inflammation associated with the CKRs CXCR3, CXCR6, and CCR5 on glatiramer- and myelin-reactive T cells generated from patients with MS receiving glatiramer therapy vs baseline. Conversely, expression of the lymph node-homing CKR, CCR7, was markedly enhanced on the glatiramer-reactive T cells derived from patients with MS undergoing glatiramer therapy. There was a reduction in the percentage of CD4+ glatiramer-reactive T cells and an increase in the number of CD8+ glatiramer-reactive T cells. Conclusions: Glatiramer may suppress autoreactive CD4+ effector memory T cells and enhance CD8+ regulatory responses, and bystander modulation of CKRs may occur in the periphery. ©2005 American Medical Association. All rights reserved.Link_to_subscribed_fulltex

Inflammatory signals increase Fas ligand expression by inner ear cells

There is considerable evidence that hearing and vestibular function can be influenced by immune processes. The inner ear has evolved mechanisms, such as the blood-labyrinthine barrier that limit immune responses and autoimmune processes to reduce the potential for damage to cochlear cells. Recently, expression of Fas ligand (FasL) in some non-lymphoid tissue, as in the anterior chamber of the eye, has been hypothesized to play a role in protection of sensitive organs from activated T-cells. We show that under resting conditions, cochlear cells express little or no FasL. However, after exposure to interferon-gamma in vitro, FasL is induced in many neonatal cochlear cells. In addition, we show that FasL is upregulated in adult cochlear cells after induction of a sterile labyrinthitis in vivo. The induction of FasL by inflammation may serve to limit cochlear immune responses, and to protect sensorineural tissue from immune and autoimmune damage

Ras/MEK But Not p38 Signaling Mediates NT-3-Induced Neurite Extension from Spiral Ganglion Neurons

Neurotrophin (NT)-3 is expressed in the neuronal target tissue of the developing rat cochlea and has been shown to promote the survival and neurite outgrowth of spiral ganglion (SG) neurons, suggesting a role for this protein during the innervation of the organ of Corti. In other neurons, NT-3 can mediate neuritogenesis and survival via a number of intracellular signal pathways. To date, the intracellular transduction pathways involved in the mediation of NT-3 effects have not been investigated in SG neurons. To determine whether the activities of NT-3 on SG neurons are dependent on the activation of mitogen-activated protein kinase kinases (MEK)/extracellular-signal-regulated kinases (ERK), Ras, and/or p38, SG explants from postnatal-day 4 rats were cultured with NT-3 and increasing concentrations of the MEK inhibitor U0126, the Ras farnesyl-transferase inhibitor (FTI)-277, and the p38 inhibitor SB203580. After fixation and immunocytochemical labeling, neurite growth was evaluated. A dose-dependent decrease of the effects of NT-3 on length and number of processes was observed in the U0126- and FTI-277-treated SG neurons. In contrast, SB203580 had no significant effect on NT-3-mediated stimulation of neurite growth, in terms of either number or length. The results suggest that NT-3 effects on SG neurons are mediated primarily by the Ras/MEK/ERK signaling pathway