Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1

Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation-dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-κB/SOD2 antioxidant pathway. Neuronal PKD1 inactivation by pharmacological inhibition or lentiviral silencing in vitro, or by genetic inactivation in neurons in vivo, strongly enhances excitotoxic neuronal death. In contrast, expression of an active dephosphorylation-resistant PKD1 mutant potentiates the IKK/NF-κB/SOD2 oxidative stress detoxification pathway and confers neuroprotection from in vitro and in vivo excitotoxicity. Our results indicate that PKD1 inactivation underlies excitotoxicity-induced neuronal death and suggest that PKD1 inactivation may be critical for the accumulation of oxidation-induced neuronal damage during aging and in neurodegenerative disorders

Depletion of abscisic acid levels in roots of flooded Carrizo citrange (Poncirus trifoliata L. Raf. x Citrus sinensis L. Osb.) plants is a stress-specific response associated to the differential expression of PYR/PYL/RCAR receptors

[EN] Soil flooding reduces root abscisic acid (ABA) levels in citrus, conversely to what happens under drought. Despite this reduction, microarray analyses suggested the existence of a residual ABA signaling in roots of flooded Carrizo citrange seedlings. The comparison of ABA metabolism and signaling in roots of flooded and water stressed plants of Carrizo citrange revealed that the hormone depletion was linked to the upregulation of CsAOG, involved in ABA glycosyl ester (ABAGE) synthesis, and to a moderate induction of catabolism (CsCYP707A, an ABA 8'-hydroxylase) and buildup of dehydrophaseic acid (DPA). Drought strongly induced both ABA biosynthesis and catabolism (CsNCED1, 9-cis-neoxanthin epoxycarotenoid dioxygenase 1, and CsCYP707A) rendering a significant hormone accumulation. In roots of flooded plants, restoration of control ABA levels after stress release was associated to the upregulation of CsBGLU18 (an ABA beta-glycosidase) that cleaves ABAGE. Transcriptional profile of ABA receptor genes revealed a different induction in response to soil flooding (CsPYL5) or drought (CsPYL8). These two receptor genes along with CsPYL1 were cloned and expressed in a heterologous system. Recombinant CsPYL5 inhibited Delta NHAB1 activity in vitro at lower ABA concentrations than CsPYL8 or CsPYL1, suggesting its better performance under soil flooding conditions. Both stress conditions induced ABA-responsive genes CsABI5 and CsDREB2A similarly, suggesting the occurrence of ABA signaling in roots of flooded citrus seedlings. The impact of reduced ABA levels in flooded roots on CsPYL5 expression along with its higher hormone affinity reinforce the role of this ABA receptor under soil-flooding conditions and explain the expression of certain ABA-responsive genes.This work was supported by Ministerio de Economia y Competitividad (MINECO), Fondo Europeo de Desarrollo Regional (FEDER) and Universitat Jaume I through grants No. AGL201676574-R, UJI-B2016-23/UJI-B2016-24 to A.G-C. and V.A. and MINECO, FEDER and Consejo Superior de Investigaciones Cientificas (CSIC) through grant BIO2014-52537-R to P.L.R. S.I.Z. and M.M. were supported by predoctoral grants from Universitat Jaume I and Generalitat Valenciana, respectively. M.G.G. was recipient of a "JAE-DOC" contract from the CSIC. 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Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial

OBJECTIVES: To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis. METHODS: Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology International Trials Organization (PRINTO) MTX trial. Bivariate and logistic regression analyses were used to identify baseline predictors of poor response according to the American College of Rheumatology pediatric (ACR-ped) 30 and 70 criteria. RESULTS: In all, 405/563 (71.9%) of patients were women; median age at onset and disease duration were 4.3 and 1.4 years, respectively, with anti-nuclear antibody (ANA) detected in 259/537 (48.2%) patients. With multivariate logistic regression analysis, the most important determinants of ACR-ped 70 non-responders were: disease duration > 1.3 years (OR 1.93), ANA negativity (OR 1.77), Childhood Health Assessment Questionnaire (CHAQ) disability index > 1.125 (OR 1.65) and the presence of right and left wrist activity (OR 1.55). Predictors of ACR-ped 30 non-responders were: ANA negativity (OR 1.92), CHAQ disability index > 1.14 (OR 2.18) and a parent's evaluation of child's overall well-being < or = 4.69 (OR 2.2). CONCLUSION: The subgroup of patients with longer disease duration, ANA negativity, higher disability and presence of wrist activity were significantly associated with a poorer response to a 6-month MTX course

The phenylpropanoid pathway inhibitor piperonylic acid induces broad‐spectrum pest and disease resistance in plants

Although many phenylpropanoid pathway-derived molecules act as physical and chemical barriers to pests and pathogens, comparatively little is known about their role in regulating plant immunity. To explore this research field, we transiently perturbed the phenylpropanoid pathway through application of the CINNAMIC ACID-4-HYDROXYLASE (C4H) inhibitor piperonylic acid (PA). Using bioassays involving diverse pests and pathogens, we show that transient C4H inhibition triggers systemic, broad-spectrum resistance in higher plants without affecting growth. PA treatment enhances tomato (Solanum lycopersicum) resistance in field and laboratory conditions, thereby illustrating the potential of phenylpropanoid pathway perturbation in crop protection. At the molecular level, transcriptome and metabolome analyses reveal that transient C4H inhibition in tomato reprograms phenylpropanoid and flavonoid metabolism, systemically induces immune signalling and pathogenesis-related genes, and locally affects reactive oxygen species metabolism. Furthermore, C4H inhibition primes cell wall modification and phenolic compound accumulation in response to root-knot nematode infection. Although PA treatment induces local accumulation of the phytohormone salicylic acid, the PA resistance phenotype is preserved in tomato plants expressing the salicylic acid-degrading NahG construct. Together, our results demonstrate that transient phenylpropanoid pathway perturbation is a conserved inducer of plant resistance and thus highlight the crucial regulatory role of this pathway in plant immunity

An Integrated View of Whole-Tree Hydraulic Architecture. Does Stomatal or Hydraulic Conductance Determine Whole Tree Transpiration? - Fig 8

<p>(A) Diameter, (B) density and (C) total lumen area of xylem vessels of taproot and basal stem in cross sections of <i>Poncirus trifoliata</i> (PT) and Cleopatra mandarin (CM) seedlings. Histological data correspond to the mean of six independent plants (n = 6) of each rootstock. The value for each plant is the mean of three visual fields of three sections from three samples per root and stem. Different letters indicate statistically significant differences (P <0.05) (LSD test).</p

Patient-Reported Outcomes Among Patients Ages Two to Seventeen Years With Polyarticular-Course Juvenile Idiopathic Arthritis Treated With Subcutaneous Abatacept: Two-Year Results From an International Phase III Study

Objective: To describe longitudinal changes in patient-reported outcomes (PROs) in children with polyarticular-course juvenile idiopathic arthritis (pJIA) treated with subcutaneous abatacept. Methods: Secondary analysis of a single-arm, open-label 24-month study of patients ages 6-17 years and 2-5 years. PROs included Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), parent global assessment of child well-being (PaGA), pain assessment, and Activity Limitation Questionnaire (ALQ). Clinical outcomes included 50% or greater improvement in JIA American College of Rheumatology (ACR) criteria, clinically inactive disease, and Juvenile Arthritis Disease Activity Score. Results: For the 6- to 17-year-old (n = 173) and 2- to 5-year-old (n = 46) cohorts, respectively, median (Q1, Q3) changes from baseline in CHAQ-DI at months 4 and 24 were -0.3 (-0.8, 0.0) and -0.5 (-1.0, -0.1), and -0.4 (-0.8, 0.0) and -0.5 (-1.0--0.1). Median pain scores were below cutoff threshold for clinically relevant pain (<35 mm) by month 1 (6 to 17 years, 32.3 mm; 2 to 5 years, 25.7 mm), reaching a nadir at month 24 (6 to 17 years, 6.0 mm; 2 to 5 years, 2.0 mm). For the 6- to 17-year-old and 2- to 5-year-old cohorts, respectively, median PaGA scores were 47.8 (n = 172) and 42.1 (n = 46) at baseline and 6.3 (n = 107) and 2.0 (n = 37) at month 24. In both cohorts, ALQ components improved from baseline to month 4 and were largely maintained to month 24. Clinical outcomes improved through to month 24. Conclusion: Early and sustained PRO improvements were reported in this phase III, open-label trial of subcutaneous abatacept in patients with pJIA