EXO modifies sucrose and trehalose responses and connects the extracellular carbon status to growth

Plants have the capacity to adapt growth to changing environmental conditions. This implies the modulation of metabolism according to the availability of carbon (C). Particular interest in the response to the C availability is based on the increasing atmospheric levels of CO2. Several regulatory pathways that link the C status to growth have emerged. The extracellular EXO protein is essential for cell expansion and promotes shoot and root growth. Homologous proteins were identified in evolutionarily distant green plants. We show here that the EXO protein connects growth with C responses. The exo mutant displayed altered responses to exogenous sucrose supplemented to the growth medium. Impaired growth of the mutant in synthetic medium was associated with the accumulation of starch and anthocyanins, altered expression of sugar-responsive genes, and increased abscisic acid levels. Thus, EXO modulates several responses related to the C availability. Growth retardation on medium supplemented with 2-deoxy-glucose, mannose, and palatinose was similar to the wild type. Trehalose feeding stimulated root growth and shoot biomass production of exo plants whereas it inhibited growth of the wild type. The phenotypic features of the exo mutant suggest that apoplastic processes coordinate growth and C responses

Effects of Alpha-Lipoic Acid and Myoinositol Supplementation on the Oocyte Enviroment of Obese Infertile Women

INTRODUCTION Obesity is characterized by increased inflammation and oxidative stress, resulting in adverse effects on women reproductive potential. Antioxidant supplementation may exert a positive effect on the obese ovarian environment. Indeed, we preliminarily observed a reduction of mitochondrial (mt) DNA content, a marker of oxidative stress, in granulosa cells of obese infertile women supplemented with Sinopol\uae (Laborest SpA), composed by alpha-lipoic acid (ALA) 800 mg, myoinositol (MYO) 2 g, folic acid (FA) 400 ug. This suggested a potential role of Sinopol\uae in reducing oxidative stress in the obese ovarian environment. Here we analyzed Total Antioxidant Capacity (TAC) in follicular fluid and mtDNA levels in granulosa cells, in a larger population of infertile women undergoing in vitro fertilization (IVF). METHODS 19 normal weight (NW) and 24 obese (OB) infertile women were enrolled in our IVF center. Infertility was investigated and a non-ovarian diagnosis was made. Patients did not present any additional pathology. All women were provided with FA and among them 15 OB (OB-SIN) were also supplemented with ALA and MYO, for 2 months before ovarian stimulation. Follicular fluid (FF) and granulosa cells (GC) were collected after oocyte retrieval. TAC was measured in FF by enzymatic assay, mtDNA levels evaluated in GC by Real-time PCR. Results were compared by ANOVA and correlations assessed by Pearson\u2019s correlation (SPSS; IBM). RESULTS OB groups had similar BMI (OB patients supplemented with only folic acid (OB-F): 30.2 \ub1 0.7; OB-SIN: 32.7 \ub1 1.1 kg/m2). Women age was similar in all groups (NW: 36.7 \ub1 0.6; OB-F: 37.6 \ub1 1.7; OB-SIN: 35.9 \ub1 1.1 years). Among OB women, antioxidant capacity was significantly higher in OB-SIN than in OB-F. mtDNA levels showed an opposite trend, being decreased in OB-SIN and increased in OB-F compared to NW, though not reaching statistical significance. mtDNA levels were significantly and inversely correlated with the number of total oocytes and metaphase II (mature) oocytes. Pregnancy rate was similar in NW (36.8%) and OB-SIN (33.3%) women, while it was lower in OB-F patients (11.1%). CONCLUSION We analyzed molecular markers in granulosa cells and follicular fluid as indicators of oocytes oxidative state. Our results suggest that supplementation with a compound of ALA -a natural antioxidant, cofactor in the mt respiratory chain- and MYO -an insulin-sensitizer- might increase antioxidant defenses and reduce oxidative stress in the obese ovarian environment, possibly contributing at restoring physiological conditions. This might improve IVF pregnancy rates in obese infertile women. Further studies are needed to clarify the synergic action of ALA, MYO and FA on the oocyte oxidative environment. Supported by Laborest Sp

Placental ERRγ-CYP19 expressions and circulating 17-Beta Estradiol in IUGR pregnancies

Introduction: Sex steroids are regulating factors for intrauterine growth. 17- f Estradiol (E2) is particularly critical to a physiological pregnancy, as increased maternal E2 was correlated to lower birth weight. The placenta itself is a primary source of estrogens, synthetized from cholesterol precursors. Cytochrome P450 aromatase (encoded by CYP19 gene) is a rate-limiting enzyme for E2 biosynthesis. CYP19 transcription is supported by Estrogen Related-Receptor Gamma (ERR\u3b3), thus having an indirect role in placental steroidogenesis. Here we investigated maternal E2 levels and placental CYP19 and ERR expressions in pregnancies with intrauterine growth restriction (IUGR). Methods: Singleton pregnancies were studied. E2 was measured in maternal plasma by electrochemiluminescence in 16 term controls and 11 IUGR (classified by umbilical artery doppler Pulsatility Index) at elective cesarean section, and also in 13 controls during pregnancy at a gestational age comparable to IUGR. CYP19 and ERR\u3b3 expressions were analyzed in placental tissue. Maternal/fetal characteristics, placental and molecular data were compared among study groups and tested for correlations. Results: Maternal E2 plasma concentrations were significantly decreased in IUGR compared to controls at delivery. When analyzing normal pregnancies at the same IUGR gestational age, E2 levels were not different to IUGR. However, E2 levels at delivery positively correlated with placental efficiency. Placental CYP19 was significantly higher in IUGR placental tissue versus controls, with levels specifically increased in female IUGR placentas. ERR\u3b3 expression was not different among groups. Discussion: We report a positive correlation between 17- f Estradiol levels and placental efficiency, that might indicate a disrupted steroidogenesis in IUGR pregnancies. Moreover, we showed alterations of CYP19 in IUGR placentas, possibly indicating a compensatory effect to the adverse IUGR intrauterine environment, also depending on fetal sex. Further studies are needed to deeper investigate IUGR alterations in the complex interaction among molecules involved in placental steroidogenesis

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.Acknowledgements: This work was supported by grants from the International Society for Neurochemistry (ISN) and Alexander von Humboldt Foundation (to M.C.D.); Agencia Nacional de Promoción Científica y Tecnológica (PBIT/09 2013, PICT-2015-0285 and PICT-2016-4647 to L.M.; PICT-2014-1537 to M.C.D.); GENMED Labex and JPND PERADES grant; and JPND EADB grant (German Federal Ministry of Education and Research, BMBF: 01ED1619A)

Sugar and abscisic acid signaling orthologs are activated at the onset of ripening in grape

The onset of ripening involves changes in sugar metabolism, softening, and color development. Most understanding of this process arises from work in climacteric fruits where the control of ripening is predominately by ethylene. However, many fruits such as grape are nonclimacteric, where the onset of ripening results from the integration of multiple hormone signals including sugars and abscisic acid (ABA). In this study, we identified ten orthologous gene families in Vitis vinifera containing components of sugar and ABA-signaling pathways elucidated in model systems, including PP2C protein phosphatases, and WRKY and homeobox transcription factors. Gene expression was characterized in control- and deficit-irrigated, field-grown Cabernet Sauvignon. Sixty-seven orthologous genes were identified, and 38 of these were expressed in berries. Of the genes expressed in berries, 68% were differentially expressed across development and/or in response to water deficit. Orthologs of several families were induced at the onset of ripening, and induced earlier and to higher levels in response to water deficit; patterns of expression that correlate with sugar and ABA accumulation during ripening. Similar to field-grown berries, ripening phenomena were induced in immature berries when cultured with sucrose and ABA, as evidenced by changes in color, softening, and gene expression. Finally, exogenous sucrose and ABA regulated key orthologs in culture, similar to their regulation in the field. This study identifies novel candidates in the control of nonclimacteric fruit ripening and demonstrates that grape orthologs of key sugar and ABA-signaling components are regulated by sugar and ABA in fleshy fruit

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

NFXL2 modifies cuticle properties in Arabidopsis

Loss of the Arabidopsis NFX1-LIKE2 (NFXL2) gene (At5g05660) results in elevated ABA levels, elevated hydrogen peroxide levels, reduced stomatal aperture, and enhanced drought stress tolerance. Introduction of the NFXL2–78 isoform into the nfxl2–1 mutant is largely sufficient for complementation of the phenotype. We show here that cuticular properties are altered in the nfxl2–1 mutant. The NFXL2–78 protein binds to the SHINE1 (SHN1), SHN2, SHN3, and BODYGUARD1 (BDG1) promoters and mediates weaker expression of these genes. The SHN AP2 domain transcription factors influence cuticle properties. Stronger SHN1, SHN2, and SHN3 expression in the nfxl2–1 mutant may cause altered cuticle properties including reduced stomatal density, and partly explain the enhanced drought stress tolerance. The BDG1 protein also controls cuticle development and is essential for osmotic stress regulation of ABA biosynthesis. Stronger BDG1 expression in nfxl2–1 plants may allow elevated ABA accumulation under drought stress. We conclude that the NFXL2–78 protein is part of a regulatory network that integrates the biosynthesis and action of ABA, ROS, and cuticle components

Effects of α-lipoic acid and myo-inositol supplementation on the oocyte environment of infertile obese women : a preliminary study

Obesity is becoming pandemic and is associated with impaired reproductive potential. Oxidative stress, low-grade chronic inflammation and mitochondrial dysfunctions, which characterize obesity, strongly affect oocyte environment and function. Supplementation with antioxidant and anti-inflammatory compounds has been suggested to improve fertility. Here we evaluated the effect of \u3b1-lipoic acid and myo-inositol supplementation on the oocyte environment of infertile obese women. Nineteen normal-weight and twenty-three obese women, infertile for non-ovarian reasons, were recruited. For two months before ovarian stimulation, all women received 400\u3bcg/die folic acid, whereas 15 obese were additionally supplemented with 800mg \u3b1-lipoic acid, 2g myo-inositol/die. Antioxidant capacity was measured in follicular fluid by enzymatic assay; mitochondrial DNA (mtDNA) content and mRNA levels of two respiratory chain subunits were analyzed in granulosa cells by Real-time PCR. Pregnancy rate was similar between normal-weight and treated obese, and lower in untreated obese patients. Supplemented women showed significantly higher antioxidant levels in follicular fluid compared to the two groups taking only folic acid. Conversely, granulosa cells mtDNA content was decreased in treated and higher in untreated obese patients compared to normal-weight women, suggesting mtDNA increases to compensate for oxidative-stress damages. Reduced expression of respiratory subunits in untreated obese may confirm mitochondria impairment. Interestingly, mtDNA levels inversely correlated to both total and metaphase II oocyte number. In this preliminary study, combined supplementation of \u3b1-lipoic acid and myo-inositol in infertile obese women was associated with amelioration in the oxidative status of the oocyte environment, possibly contributing to a higher pregnancy rate