FOXO family isoforms.

FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, and cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role of FOXOs in lifespan regulation in animal systems from hydra, C elegans, Drosophila, and mice. Together with the observation that FOXO3 is the second most replicated gene associated with extreme human longevity suggests that pharmacological targeting of FOXO proteins can be a promising approach to treat cancer and other age-related diseases and extend life and health span. However, due to the broad range of cellular functions of the FOXO family members FOXO1, 3, 4, and 6, isoform-specific targeting of FOXOs might lead to greater benefits and cause fewer side effects. Therefore, a deeper understanding of the common and specific features of these proteins as well as their redundant and specific functions in our cells represents the basis of specific targeting strategies. In this review, we provide an overview of the evolution, structure, function, and disease-relevance of each of the FOXO family members.

Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function.

Parkinson's disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the alpha-synuclein protein causing an autosomal-dominant form of PD. There are limited studies assessing pathogenic SNCA mutations in patient-derived isogenic cell models. Here we provide a functional assessment of dopaminergic neurons derived from a patient harbouring the p.A30P SNCA mutation. Using two clonal gene-corrected isogenic cell lines we identified image-based phenotypes showing impaired neuritic processes. The pathological neurons displayed impaired neuronal activity, reduced mitochondrial respiration, an energy deficit, vulnerability to rotenone, and transcriptional alterations in lipid metabolism. Our data describes for the first time the mutation-only effect of the p.A30P SNCA mutation on neuronal function, supporting the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease-modifying compound screenings and drug discovery strategies.

Diversity of leaf anatomy within a single leaflet and between leaflets of four Butia (Arecaceae, Arecoideae) species.

This paper is an investigation into how the anatomy changes within a leaflet and between the leaflets of a single leaf blade of Butia. Four species of Butia were studied: Butiaparaguayensis, B.eriospatha, B.yatay and B.odorata. Changes in the anatomical characters are important because some have been used in keys to help separate the species. Recently, anatomical mid-rib characters were used in a key to separate species of Butia. We found that characters, such as abaxially projected or rounded mid-rib fibrous ring or number and arrangement of accessory bundles, do change within a single leaflet or between the leaflets of a single leaf blade. Growing conditions and leaf developmental maturity are also important factors that influence leaflet anatomy and may cause one to be misled in an identification key based on anatomical characters. We re-emphasize the importance of always sampling from the same part of the leaf, to have a broader sampling, be attentive to the environmental condition and health of the plant from which you are sampling and to consider population differences.

Estimation of economic value for efficiency and animal health and welfare traits, teat and udder structure, in Canadian Angus cattle.

The Canadian Angus Association recently developed genetic evaluations for teat and udder structure, which impact efficiencies, and animal health and welfare. Genetic selection tools are most effective incorporated into economic selection indexes. An important factor in the development of economic indexes is the estimation of the economic value and discounted gene expression coefficients, and thereby the economic weight, of each trait. Traditional estimation methods, interrogation of previous studies quantifying the impact of the traits and bioeconomic modelling, were reinforced using producer surveys that employed pairwise ranking methods. Estimates of discounted genetic expression coefficients, economic value and economic weight for teat and udder score in Canadian Angus cattle were 0.31 per sire, $52.47, and $16.91 per score change on a per calf born basis, respectively, indicating that functional traits such as teat and udder structure have a significant impact on profitability and should be included in genetic selection programmes. Limitations in previous studies illustrate the need for longitudinal studies on traits that impact efficiencies and animal health and welfare.

Mitochondria interaction networks show altered topological patterns in Parkinson's disease.

Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation.

Generation of two iPS cell lines (HIHDNDi001-A and HIHDNDi001-B) from a Parkinson's disease patient carrying the heterozygous p.A30P mutation in SNCA.

Dermal fibroblasts from a patient carrying a heterozygous c.88G > C mutation in the SNCA gene that encodes alpha-synuclein were reprogrammed to pluripotency by retroviruses. This pathogenic mutation generates the p.A30P form of the alpha-synuclein protein leading to autosomal dominantly inherited Parkinson's disease (PD). Two clonal iPS cell lines were generated (A30P-3 and A30P-4) and characterised by validating the silencing of viral transgenes, the expression of endogenous pluripotency genes, directed differentiation into three germ layers in-vitro and a stable molecular genotype. These iPSC lines will serve as a valuable resource in determining the role of the p.A30P SNCA mutation in PD pathogenesis.

Visible-light reduced silver nanoparticles' toxicity in Allium cepa test system.

Silver nanoparticles (AgNPs) are widely used in consumer products due to their antibacterial property; however, their potential toxicity and release into the environment raises concern. Based on the limited understanding of AgNPs aggregation behavior, this study aimed to investigate the toxicity of uncoated (uc-AgNP) and coated with polyvinylpyrrolidone (PVP-AgNP), at low concentrations (0.5-100 ng/mL), under dark and visible-light exposure, using a plant test system. We exposed Allium cepa seeds to both types of AgNPs for 4-5 days to evaluate several toxicity endpoints. AgNPs did not cause acute toxicity (i.e., inhibition of seed germination and root development), but caused genotoxicity and biochemical alterations in oxidative stress parameters (lipid peroxidation) and activities of antioxidant enzymes (superoxide dismutase and catalase) in light and dark conditions. However, the light exposure decreased the rate of chromosomal aberration and micronuclei up to 5.60x in uc-AgNP and 2.01x in PVP-AgNP, and 2.69x in uc-AgNP and 3.70x in PVP-AgNP, respectively. Thus, light exposure reduced the overall genotoxicity of these AgNPs. In addition, mitotic index alterations and morphoanatomical changes in meristematic cells were observed only in the dark condition at the highest concentrations, demonstrating that light also reduces AgNPs cytotoxicity. The light-dependent aggregation of AgNPs may have reduced toxicity by reducing the uptake of these NPs by the cells. Our findings demonstrate that AgNPs can be genotoxic, cytotoxic and induce morphoanatomical and biochemical changes in A. cepa roots even at low concentrations, and that visible-light alters their aggregation state, and decreases their toxicity. We suggest that visible light can be an alternative treatment to remediate AgNP residues, minimizing their toxicity and environmental risks.

Double Blinded Randomized Trial of Subcutaneous Trigeminal Nerve Stimulation as Adjuvant Treatment for Major Unipolar Depressive Disorder.

BACKGROUND: More than 30% of major depressive disorder patients fail to respond to adequate trials of medications and psychotherapy. While modern neuromodulation approaches (ie, vagal nerve stimulation, deep brain stimulation) are yet to prove their efficacy for such cases in large randomized controlled trials, trigeminal nerve stimulation (TNS) has emerged as an alternative with promising effects on mood disorders. OBJECTIVE: To assess efficacy, safety, tolerability, and placebo effect duration of continuous subcutaneous TNS (sTNS) in treatment-resistant depression (TRD). METHODS: The TREND study is a single-center, double-blind, randomized, controlled, phase II clinical trial. Twenty unipolar TRD patients will receive V1 sTNS as adjuvant to medical therapy and randomized to active vs sham stimulation throughout a 24-wk period. An additional 24-wk open-label phase will follow. Data concerning efficacy, placebo response, relapse, and side effects related to surgery or electrical stimulation will be recorded. We will use the HDRS-17, BDI-SR, IDS_SR30, and UKU scales. EXPECTED OUTCOMES: The main outcome measure is improvement in depression scores using HAM-17 under continuous sTNS as adjuvant to antidepressants. Active stimulation is expected to significantly impact response and remission rates. Minor side effects are expected due to the surgical procedure and electrical stimulation. The open-label phase should further confirm efficacy and tolerability. DISCUSSION: This study protocol is designed to define efficacy of a novel adjuvant therapy for TRD. We must strive to develop safe, reproducible, predictable, and well-tolerated neuromodulation approaches for TRD patients impaired to manage their lives and contribute with society.

Genetic and economic benefits of selection based on performance recording and genotyping in lower tiers of multi-tiered sheep breeding schemes.

BACKGROUND: Performance recording and genotyping in the multiplier tier of multi-tiered sheep breeding schemes could potentially reduce the difference in the average genetic merit between nucleus and commercial flocks, and create additional economic benefits for the breeding structure. METHODS: The genetic change in a multiple-trait breeding objective was predicted for various selection strategies that included performance recording, parentage testing and genomic selection. A deterministic simulation model was used to predict selection differentials and the flow of genetic superiority through the different tiers. Cumulative discounted economic benefits were calculated based on trait gains achieved in each of the tiers and considering the extra revenue and associated costs of applying recording, genotyping and selection practices in the multiplier tier of the breeding scheme. RESULTS: Performance recording combined with genomic or parentage information in the multiplier tier reduced the genetic lag between the nucleus and commercial flock by 2 to 3 years. The overall economic benefits of improved performance in the commercial tier offset the costs of recording the multiplier. However, it took more than 18 years before the cumulative net present value of benefits offset the costs at current test prices. Strategies in which recorded multiplier ewes were selected as replacements for the nucleus flock did modestly increase profitability when compared to a closed nucleus structure. Applying genomic selection is the most beneficial strategy if testing costs can be reduced or by genotyping only a proportion of the selection candidates. When the cost of genotyping was reduced, scenarios that combine performance recording with genomic selection were more profitable and reached breakeven point about 10 years earlier. CONCLUSIONS: Economic benefits can be generated in multiplier flocks by implementing performance recording in conjunction with either DNA pedigree recording or genomic technology. These recording practices reduce the long genetic lag between the nucleus and commercial flocks in multi-tiered breeding programs. Under current genotyping costs, the time to breakeven was found to be generally very long, although this varied between strategies. Strategies using either genomic selection or DNA pedigree verification were found to be economically viable provided the price paid for the tests is lower than current prices, in the long-term.

Butia capitata (Mart.) Becc. lamina anatomy as a tool for taxonomic distinction from B. odorata (Barb. Rodr.) Noblick comb. nov (Arecaceae).

The distinction between Butia capitata and B. odorata is based only on a few morphological characteristics, therefore there is a need for additional studies for supporting the separation of the species. As lamina anatomy characteristics are relevant in circumscribing Arecaceae taxa, this work aimed to describe B. capitata lamina anatomy and compare it with B. odorata. Samples from the middle portion of the pinnae were collected and processed in accordance with standard plant anatomy techniques. The epidermis is uniseriate and composed of a thick cuticle and epicuticular waxes into like hooked filaments. The subsidiary cells that arch over the guard cells are located at the hypodermis. The mesophyll is isobilateral and compact. The vascular bundles are collateral with a sclerenchymatic sheath extension that reaches the hypodermis. The stegmata cells have spherical and druse-like silica bodies. The midrib faces the adaxial surface with a thick fibrous layer surrounding the vascular bundles adjacent to the chlorenchyma. The stratified expansion tissue is on the abaxial surface, within the boundary between the mesophyll and midrib. Raphides are only found in B. capitata. Small bundles of the midrib fully surround the fibrous cylinder only in B. odorata. These characteristics are diagnostic and useful for supporting the proposed separation.

Phenotypic plasticity of Neonotonia wightii and Pueraria phaseoloides grown under different light intensities.

Plants have the ability to undergo morphophysiological changes based on availability of light. The present study evaluated biomass accumulation, leaf morphoanatomy and physiology of Neonotonia wightii and Pueraria phaseoloides grown in full sunlight, as well as in 30% and 50% shade. Two assays were performed, one for each species, using a randomized block design with 10 replicates. A higher accumulation of fresh mass in the shoot of the plants was observed for both species under cultivation in 50% shade, while no differences were detected between the full sunlight and 30% shade. N. wightii and P. phaseoloides showed increase in area and reduction in thickness leaf when cultivated in 50% shade. There were no changes in photosynthetic rate, stomatal conductance, water use efficiency and evapotranspiration of P. phaseoloides plants because growth environment. However, the shade treatments caused alterations in physiological parameters of N. wightii. In both species, structural changes in the mesophyll occurred depending on the availability of light; however, the amount of leaf blade tissue remained unaltered. Despite the influence of light intensity variation on the morphophysiological plasticity of N. wightii and P. phaseoloides, no effects on biomass accumulation were observed in response to light.

Physical Stress Echocardiography: Prediction of Mortality and Cardiac Events in Patients with Exercise Test showing Ischemia / Ecoestresse Físico: Predição de Mortalidade e Eventos Cardíacos em Pacientes com Ergometria Isquêmica

Background: Studies have demonstrated the diagnostic accuracy and prognostic value of physical stress echocardiography in coronary artery disease. However, the prediction of mortality and major cardiac events in patients with exercise test positive for myocardial ischemia is limited. Objective: To evaluate the effectiveness of physical stress echocardiography in the prediction of mortality and major cardiac events in patients with exercise test positive for myocardial ischemia. Methods: This is a retrospective cohort in which 866 consecutive patients with exercise test positive for myocardial ischemia, and who underwent physical stress echocardiography were studied. Patients were divided into two groups: with physical stress echocardiography negative (G1) or positive (G2) for myocardial ischemia. The endpoints analyzed were all-cause mortality and major cardiac events, defined as cardiac death and non-fatal acute myocardial infarction. Results: G2 comprised 205 patients (23.7%). During the mean 85.6 ± 15.0-month follow-up, there were 26 deaths, of which six were cardiac deaths, and 25 non-fatal myocardial infarction cases. The independent predictors of mortality were: age, diabetes mellitus, and positive physical stress echocardiography (hazard ratio: 2.69; 95% confidence interval: 1.20 - 6.01; p = 0.016). The independent predictors of major cardiac events were: age, previous coronary artery disease, positive physical stress echocardiography (hazard ratio: 2.75; 95% confidence interval: 1.15 - 6.53; p = 0.022) and absence of a 10% increase in ejection fraction. All-cause mortality and the incidence of major cardiac events were significantly higher in G2 (p < 0. 001 and p = 0.001, respectively). Conclusion: Physical stress echocardiography provides additional prognostic information in patients with exercise test positive for myocardial ischemia. .

Fundamento: Estudos têm demonstrado a acurácia diagnóstica e o valor prognóstico da ecocardiografia com estresse físico na doença arterial coronária, mas a predição de mortalidade e de eventos cardíacos maiores, em pacientes com teste ergométrico positivo para isquemia miocárdica, é limitada. Objetivo: Avaliar a predição de mortalidade e de eventos cardíacos maiores pela ecocardiografia com estresse físico em pacientes com teste ergométrico positivo para isquemia miocárdica. Métodos: Trata-se de uma coorte retrospectiva em que foram estudados 866 pacientes consecutivos, com teste ergométrico positivo para isquemia miocárdica, submetidos à ecocardiografia com estresse físico. Os pacientes foram divididos em dois grupos: ecocardiografia com estresse físico negativa (G1) ou positiva (G2) para isquemia miocárdica. Os desfechos avaliados foram mortalidade por qualquer causa e eventos cardíacos maiores, definidos como óbito cardíaco e infarto agudo do miocárdio não fatal. Resultados: O G2 constituiu-se de 205 (23,7%) pacientes. Durante o seguimento médio de 85,6 ± 15,0 meses, ocorreram 26 óbitos, sendo seis por causa cardíaca, e 25 casos de infarto agudo do miocárdio não fatais. Os preditores independentes de mortalidade foram idade, diabetes melito e a ecocardiografia com estresse físico + (hazard ratio: 2,69; intervalo de confiança de 95%: 1,20 - 6,01; p = 0,016), com os seguintes eventos cardíacos maiores: idade, doença arterial coronária prévia, ecocardiografia com estresse físico + (hazard ratio: 2,75; intervalo de confiança de 95%: 1,15 - 6,53; p = 0,022) e ausência do incremento de 10% na fração de ejeção. A mortalidade por qualquer causa e os eventos cardíacos maiores foram ...

Physical Stress Echocardiography: Prediction of Mortality and Cardiac Events in Patients with Exercise Test showing Ischemia.

Background: Studies have demonstrated the diagnostic accuracy and prognostic value of physical stress echocardiography in coronary artery disease. However, the prediction of mortality and major cardiac events in patients with exercise test positive for myocardial ischemia is limited. Objective: To evaluate the effectiveness of physical stress echocardiography in the prediction of mortality and major cardiac events in patients with exercise test positive for myocardial ischemia. Methods: This is a retrospective cohort in which 866 consecutive patients with exercise test positive for myocardial ischemia, and who underwent physical stress echocardiography were studied. Patients were divided into two groups: with physical stress echocardiography negative (G1) or positive (G2) for myocardial ischemia. The endpoints analyzed were all-cause mortality and major cardiac events, defined as cardiac death and non-fatal acute myocardial infarction. Results: G2 comprised 205 patients (23.7%). During the mean 85.6 ± 15.0-month follow-up, there were 26 deaths, of which six were cardiac deaths, and 25 non-fatal myocardial infarction cases. The independent predictors of mortality were: age, diabetes mellitus, and positive physical stress echocardiography (hazard ratio: 2.69; 95% confidence interval: 1.20 - 6.01; p = 0.016). The independent predictors of major cardiac events were: age, previous coronary artery disease, positive physical stress echocardiography (hazard ratio: 2.75; 95% confidence interval: 1.15 - 6.53; p = 0.022) and absence of a 10% increase in ejection fraction. All-cause mortality and the incidence of major cardiac events were significantly higher in G2 (p < 0. 001 and p = 0.001, respectively). Conclusion: Physical stress echocardiography provides additional prognostic information in patients with exercise test positive for myocardial ischemia.Fundamento: Estudos têm demonstrado a acurácia diagnóstica e o valor prognóstico da ecocardiografia com estresse físico na doença arterial coronária, mas a predição de mortalidade e de eventos cardíacos maiores, em pacientes com teste ergométrico positivo para isquemia miocárdica, é limitada. Objetivo: Avaliar a predição de mortalidade e de eventos cardíacos maiores pela ecocardiografia com estresse físico em pacientes com teste ergométrico positivo para isquemia miocárdica. Métodos: Trata-se de uma coorte retrospectiva em que foram estudados 866 pacientes consecutivos, com teste ergométrico positivo para isquemia miocárdica, submetidos à ecocardiografia com estresse físico. Os pacientes foram divididos em dois grupos: ecocardiografia com estresse físico negativa (G1) ou positiva (G2) para isquemia miocárdica. Os desfechos avaliados foram mortalidade por qualquer causa e eventos cardíacos maiores, definidos como óbito cardíaco e infarto agudo do miocárdio não fatal. Resultados: O G2 constituiu-se de 205 (23,7%) pacientes. Durante o seguimento médio de 85,6 ± 15,0 meses, ocorreram 26 óbitos, sendo seis por causa cardíaca, e 25 casos de infarto agudo do miocárdio não fatais. Os preditores independentes de mortalidade foram idade, diabetes melito e a ecocardiografia com estresse físico + (hazard ratio: 2,69; intervalo de confiança de 95%: 1,20 - 6,01; p = 0,016), com os seguintes eventos cardíacos maiores: idade, doença arterial coronária prévia, ecocardiografia com estresse físico + (hazard ratio: 2,75; intervalo de confiança de 95%: 1,15 - 6,53; p = 0,022) e ausência do incremento de 10% na fração de ejeção. A mortalidade por qualquer causa e os eventos cardíacos maiores foram significativamente superiores no G2 (p < 0, 001 e p = 0,001, respectivamente). Conclusão: A ecocardiografia com estresse físico oferece informações prognósticas adicionais em pacientes com teste ergométrico positivo para isquemia miocárdica.

Modeling of human exposure to benzene in urban environments.

Urban areas characterized by high spatial and temporal variability in air pollution levels require implementation of comprehensive approaches to address exposure of individuals. The main objective of this study was to implement a quantitative assessment of individual exposure to benzene in urban environments. For this purpose, ExPOSITION model based on a global positioning system (GPS) tracking approach was applied to estimate individual exposure in different microenvironments. The current investigation provides an application example and validation of the modeling approach against personal and biological exposure measurements collected during the measurements campaign. The probabilistic approach using the Johnson system of distributions was implemented to characterize variability of indoor concentrations. The results obtained for daily average individual exposure to benzene corresponded to mean levels of 1.6 and 0.8-2.7 µg/m(3) in terms of 5th-95th percentiles. Validation of the model results against several personal exposure samples collected for the selected individuals revealed a Pearson's correlation coefficient of .66. This modeling approach explicitly addressed the temporal and spatial variability in the exposure and established a source-receptor relationship.

Diagnostic and prognostic characteristics of phytotoxicity caused by fluoride on Spondias dulcis Forst. F. (Anacardiaceae).

The goal of this study was to determine the symptoms and microscopic damage caused by fluoride on Spondias dulcis, a fluoride-sensitive species. The plants were exposed to simulated fog with fluoride (0, 5, 10, 15 and 20 mg L(-1)) for 20 min daily during four consecutive days. Samples from leaflets without any apparent fluoride injury were collected to microscopic analysis. The percentage of necrosed leaf area was measured, and the level of pollutant in the dry matter from the basal and apical portions of the plant was determined. The necroses began 24 h after the first simulation mainly from the base of the leaflets. A higher level of necrosis was observed at the apical portion of the plants, a region of higher fluoride accumulation. The damage on the surface of the leaflets was characterized as plasmolysis, erosion of the epicuticular waxes and epidermal rupture. Structurally, the noticeable accumulation of granules and droplets green stained by toluidine blue in the spongy parenchima and the boundaries of ending veinlets was observed. The limb thickness reduction occurred due to plasmolysis in the mesophyll, showing an apparent correlation with the damage observed on the surface. The parameters observed in the laboratory are promising for field biomonitoring studies.

Isquemia miocárdica na síndrome cardíaca X investigada com ecocardiografia sob estresse físico / Myocardial ischemia in cardiac syndrome X evaluated by exercise echocardiography

Objetivo: Avaliar o significado da evidência da isquemia miocárdica e a ocorrência de eventos cardiovasculares na Síndrome Cardíca X (SCX), comparando com doença coronária obstrutiva inicial (DAC <- 50 por cento). Métodos: Estudo observacional de coorte, em, amostra de 605 pacientes (população fonte de 5.137 indivíduos), com ecocardiografia sob estresse físico (EEF) positiva para isquemia miocárdica, os quais foram submetidos à cineangiocoronariografia, e divididos, posteriormente, em 2 grupos: G1 (SCX, n=64) e G2 (DAC<- 50 por cento, n=84). Os pacientes foram comparados quanto às características clínicas, parâmetros ergométricos e ecocardiográficos, e seguidos po +- 43,8 meses (mínimo de 12 meses e máximo de 85 meses), quanto ao surgimento de ngina típica, infarto agudo do miocárdico...