Dynamic nuclear polarization enhanced solid-state NMR studies of surface modification of gamma-alumina

Dynamic nuclear polarization (DNP) gives large (>100-fold) signal enhancements in solid-state NMR spectra via the transfer of spin polarization from unpaired electrons from radicals implanted in the sample. This means that the detailed information about local molecular environment available for bulk samples from solid-state NMR spectroscopy can now be obtained for dilute species, such as sites on the surfaces of catalysts and catalyst supports. In this paper we describe a DNP-enhanced solid-state NMR study of the widely used catalyst gamma-alumina which is often modified at the surface by the incorporation of alkaline earth oxides in order to control the availability of catalytically active penta-coordinate surface Al sites. DNP-enhanced 27Al solid-state NMR allows surface sites in gamma-alumina to be observed and their 27Al NMR parameters measured. In addition changes in the availability of different surface sites can be detected after incorporation of BaO

Dinámica poblacional de la oruga del cascabullo Helicoverpa gelotopoeon Dyar (Lepidoptera: Noctuidae) en el cultivo de garbanzo

El garbanzo (Cicer arietinum L.) es una fabácea de ciclo anual que fue introducida en la Argentina durante la etapa colonial, en el actual departamento cordobés de Cruz del Eje, y desde allí se expandió hacia el norte (Marginet Campos, 2001). Se la cultiva en invierno, principalmente en la región semiárida que comprende las provincias de Salta, Córdoba, Tucumán, Jujuy, Catamarca y San Luis (Carreras, 1999; García Medina et al., 2007).Fil: Scalora, Franco S.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Casmuz, Augusto S.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Cazado, Lucas Emiliano. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aralde, Marcos. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Aybar Guchea, Matias. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Fadda, Lucas. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Gómez, Mario. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Gómez, Horacio. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Tolosa, Gerardo. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Vera, Alejandro. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Gastaminza, Gerardo. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Willink, Eduardo. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Espeche, Clara M.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; Argentin

Evaluación de la eficacia de diferentes insecticidas químicos para el control de la oruga del cascabullo, Helicoverpa gelotopoeon Dyar (Lepidoptera: Noctuidae), en el cultivo de garbanzo

En la campaña 2010, la superficie cultivada con garbanzo en la Argentina fue de 40.000 ha, lo que significó un crecimiento del 150% con respecto a la campaña 2009 (Vizgarra et al., 2011). En la provincia de Tucumán y zonas de influencia (sudeste de Catamarca y oeste de Santiago del Estero), la superficie sembrada superó las 25.000 ha para la campaña 2011, producto del buen precio que tuvo esta legumbre en el 2010, que la posicionó como una interesante alternativa invernal (Vizgarra et al., 2012).Fil: Scalora, Franco S.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Casmuz, Augusto S.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Cazado, Lucas Emiliano. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán; ArgentinaFil: Aralde, Marcos R.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Aybar Guchea, Matías. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Fadda, Lucas A.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Gómez, Mario. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Gómez, César Horacio. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Tolosa, Gerardo J.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Vera, Martín A.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Gastaminza, Gerardo A.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Willink, Eduardo. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Vizgarra, Oscar N.. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; ArgentinaFil: Rodriguez, Walter. Gobierno de Tucumán. Ministerio de Desarrollo Productivo. Estación Experimental Agroindustrial Obispo Colombres; Argentin

Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson"s disease

Mutations in the PARK2 gene are associated with an autosomal recessive form of juvenile parkinsonism (AR-JP). These mutations affect parkin solubility and impair its E3 ligase activity, leading to a toxic accumulation of proteins within susceptible neurons that results in a slow but progressive neuronal degeneration and cell death. Here, we report that RTP801/REDD1, a pro-apoptotic negative regulator of survival kinases mTOR and Akt, is one of such parkin substrates. We observed that parkin knockdown elevated RTP801 in sympathetic neurons and neuronal PC12 cells, whereas ectopic parkin enhanced RTP801 poly-ubiquitination and proteasomal degradation. In parkin knockout mouse brains and in human fibroblasts from AR-JP patients with parkin mutations, RTP801 levels were elevated. Moreover, in human postmortem PD brains with mutated parkin, nigral neurons were highly positive for RTP801. Further consistent with the idea that RTP801 is a substrate for parkin, the two endogenous proteins interacted in reciprocal co-immunoprecipitates of cell lysates. A potential physiological role for parkin-mediated RTP801 degradation is indicated by observations that parkin protects neuronal cells from death caused by RTP801 overexpression by mediating its degradation, whereas parkin knockdown exacerbates such death. Similarly, parkin knockdown enhanced RTP801 induction in neuronal cells exposed to the Parkinson's disease mimetic 6-hydroxydopamine and increased sensitivity to this toxin. This response to parkin loss of function appeared to be mediated by RTP801 as it was abolished by RTP801 knockdown. Taken together these results indicate that RTP801 is a novel parkin substrate that may contribute to neurodegeneration caused by loss of parkin expression or activity

R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils

Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1–2% of all cases of Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2—either in its kinase domain (e.g. G2019S) with modest effect or its ROC-COR GTPase domain (e.g. R1441G/H) with large effect on LRRK2 kinase activity. We have previously reported assays to interrogate LRRK2 kinase pathway activity in human bio-samples measuring phosphorylation of its endogenous substrate Rab10, that mirrors LRRK2 kinase activation status. Here, we isolated neutrophils from fresh peripheral blood from 101 participants including 42 LRRK2 mutation carriers (21 with the G2019S and 21 with the R1441G mutations), 27 patients with idiopathic PD, and 32 controls. Using a dual approach, LRRK2 dependent Rab10 phosphorylation at Threonine 73 (pRab10(Thr73)) was measured by quantitative multiplexed immunoblotting for pRab10(Thr73)/total Rab10 as well as targeted mass-spectrometry for absolute pRab10(Thr73) occupancy. We found a significant over fourfold increase in pRab10(Thr73) phosphorylation in carriers of the LRRK2 R1441G mutation irrespective of clinical disease status. The effect of the LRRK2 G2019S mutation did not reach statistical significance. Furthermore, we show that LRRK2 phosphorylation at Serine 935 is not a marker for LRRK2 kinase activity in human neutrophils. When analysing pRab10(Thr73) phosphorylation in post-mortem brain samples, we observed overall high variability irrespective of clinical and LRRK2 mutation status and attributed this mainly to the adverse effect of the peri- and post-mortem period on the stability of posttranslational modifications such as protein phosphorylation. Overall, in vivo LRRK2 dependent pRab10(Thr73) phosphorylation in human peripheral blood neutrophils is a specific, robust and promising biomarker for significant LRRK2 kinase hyperactivation, as with the LRRK2 R1441G mutation. Additional readouts and/or assays may be needed to increase sensitivity to detect modest LRRK2 kinase activation, as with the LRRK2 G2019S mutation. Our assays could be useful for patient stratification and target engagement studies for LRRK2 kinase inhibitors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-021-02325-z

123I-MIBG cardiac uptake and smell identification in parkinsonian patients with LRRK2 mutations

Reduced uptake of 123I- metaiodobenzylguanidine (MIBG) on cardiac gammagraphy and impaired odor identification are markers of neurodegenerative diseases with Lewy bodies (LB) as a pathological hallmark, such as idiopathic Parkinson’s disease (IPD). LRRK2 patients present with a clinical syndrome indistinguishable from IPD, but LB have not been found in some cases. Patients with such mutations could behave differently than patients with IPD with respect to MIBG cardiac uptake and olfaction. We studied 14 LRRK2 patients, 14 IPD patients matched by age, gender, disease duration and severity, and 13 age and gender matched control subjects. Olfaction was analyzed through the University of Pennsylvania Smell Identification Test (UPSIT). MIBG cardiac uptake was evaluated through the H/M ratio. The late H/M was 1.44 ± 0.31 for LRRK2 patients, 1.19 ± 0.15 for PD patients, and 1.67 ± 0.16 for control subjects. LRRK2 patients presented lower but not statistically significant MIBG cardiac uptake than controls (p = 0.08) and significant higher uptake than PD patients (p = 0.04). UPSIT mean scores were 21.5 ± 7.3 for LRRK2 patients, 18.7 ± 6.2 for IPD patients and 29.7 ± 5.7 for control subjects. UPSIT score was lower in both LRRK2 and PD than in controls. In LRRK2 patients a positive correlation was found between myocardial MIBG uptake and UPSIT scores, (R = 0.801, p < 0.001). In LRRK2 patients, MIBG cardiac uptake was less impaired than in PD; a positive correlation between MIBG cardiac uptake and UPSIT scores was observed. As MIBG cardiac reduced uptake and impaired odor identification are markers of LB pathology, this findings may represent neuropathological heterogeneity among LRRK2 patients

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease

BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. CONCLUSION: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD

Embracing monogenic Parkinson's disease: the MJFF Global Genetic PD Cohort

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014info:eu-repo/semantics/publishedVersio

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals