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Rhipicephalus microplus, the “common cattle tick”, is the most important ectoparasite in livestock worldwide due to the economic and health losses it produces. This tick is a vector for pathogens of several tick-borne diseases. In Latin American countries, damages reach approximately USD 500 million annually due to tick infections, as well as tick-borne diseases. Currently, resistant populations for every chemical group of acaricides have been reported, posing a serious problem for tick control. This study aims to find new alternatives for controlling resistant ticks with compounds derived from small synthetic organic molecules and natural origins. Using BME26 embryonic cells, we performed phenotypic screening of 44 natural extracts from 10 Mexican plants used in traditional medicine, and 33 compounds selected from our chemical collection. We found 10 extracts and 13 compounds that inhibited cell growth by 50% at 50 µg/mL and 100 µM, respectively; the dose-response profile of two of them was characterized, and these compounds were assayed in vitro against different life stages of Rhipicephalus microplus. We also performed a target-directed screening of the activity of triosephosphate isomerase, using 86 compounds selected from our chemical collection. In this collection, we found the most potent and selective inhibitor of tick triosephosphate isomerase reported until now. Two other compounds had a potent acaricidal effect in vitro using adults and larvae when compared with other acaricides such as ivermectin and Amitraz. Those compounds were also selective to the ticks compared with the cytotoxicity in mammalian cells like macrophages or bovine spermatozoids. They also had a good toxicological profile, resulting in promising acaricidal compounds for tick control in cattle raising.

A key and unresolved question in aging research is how to quantify aging at the individual level that led to development of ”aging clocks”, machine learning algorhythms trained to predict individual age from high-dimensional molecular data under the the assumption that individual deviations of the predicted age from the chronological age contain information on the individual condition (often referred to as ”biological age”). A full validation of such clocks as biomarkers for clinical studies of ageing would require a comparison of their predictions with information on actual lifespan and long-term health. Such studies take decades in humans, but could be conducted in a much shorter time-frame in animal models. We developed a transcriptomic clock in the turquoise killifishNothobranchius furzeri. This species is the shortest-lived vertebrate that can be cultured in captivity and is an emerging model organism for genetic and experimental studies on aging. We developed a proprietary deep learning architecture that autonomously selects a customizable number of input genes to use for its predictions in order to reduce overfitting and increase interpretability, and adopts an adversarial learning framework to identify tissue-independent transcriptional patterns. We called this architecture the Selective Adversarial Deep Neural Network (SA-DNN) and trained it on a multi-tissue transcriptomic dataset ofN. furzeri. This SA-DNN predicted age of the test set with an accuracy of 1 day, i.e. less than 1% of the total species’ lifespan and detected genetic, pharmacological and environmental interventions that are known to influence lifespan in this species. Finally, a human transcriptomic multi-tissue clock that uses as input the orthologs of the genes selected by our SA-DNN inN. furzerireaches an average error of∼3 years rivalling epigenetic clocks. Our SA-DNN represents the prototype of a new class of aging clocks that provide biomarkers applicable to intervention studies in model organisms and humans.

A vast body of studies is available that describe age-dependent gene expression in relation to aging in a number of different model species. These data were obtained from animals kept in conditions with reduced environmental challenges, abundant food, and deprivation of natural sensory stimulation. Here, we compared wild- and captive aging in the short-lived turquoise killifish (Nothobranchius furzeri). These fish inhabit temporary ponds in the African savannah. When the ponds are flooded, eggs hatch synchronously, enabling a precise timing of their individual and population age. We collected the brains of wild fish of different ages and quantified the global age-dependent regulation of transcripts using RNAseq. A major difference between captive and wild populations is that wild populations had unlimited access to food and hence grew to larger sizes and reached asymptotic size more rapidly, enabling the analysis of age-dependent gene expression without the confounding effect of adult brain growth. We found that the majority of differentially expressed genes show the same direction of regulation in wild and captive populations. However, a number of genes were regulated in opposite direction. Genes downregulated in the wild and upregulated in captivity were enriched for terms related to neuronal communication. Genes upregulated in the wild and downregulated in captive conditions were enriched in terms related to DNA replication. Finally, the rate of age-dependent gene regulation was higher in wild animals, suggesting a phenomenon of accelerated aging.

This study contributes to the understanding of the child-environment relationship, based on the daily life lived in a lowland community in the interior of Amazonas, Brazil, which is distinguished by the seasonality of the flood and ebb of rivers. Among the 54 participants in the study, 18 were girls and 36 boys, with an average age of 10 years (SD: 2.5). From the content analysis of the data obtained in a semi-structured interview, three perceptual categories of everyday life emerged: the category named “singular”, manifested in 40.7% of the children, the daily life is permeated by activities and positive experiences. In the “habitual” category, daily life is described by 37% of children, as a place like any other place to live. In the “of diligence” category, identified in 22.2% of the children, experiences marked by the demands of a lowland environment stand out. The different perceptions of daily life are correlated with education and age range. O foco desse estudo é contribuir para a compreensão da relação criança-ambiente, a partir do cotidiano vivido em uma comunidade da várzea no interior do Amazonas, que se distingue pela sazonalidade da cheia e vazante dos rios. Participaram do estudo 54 crianças, sendo 18 meninas e 36 meninos, com média de idade de 10 anos (dp: 2,5). A partir da análise de conteúdo dos dados obtidos em entrevista semiestruturada emergiram três categorias perceptivas do cotidiano: a categoria nomeada “singular”, manifestada em 40,7% das crianças, percebe o cotidiano permeado por atividades e vivências positivas. Na categoria “habitual”, o cotidiano é descrito como um lugar como qualquer outro para se viver, foi constatada por 37% das crianças. Na categoria “de diligência”, identificada em 22,2% das falas, ressalta-se vivências marcadas pelas demandas próprias de um ambiente de várzea. As diferentes percepções do cotidiano estão correlacionadas com a escolaridade e faixa etária.

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No. of bitstreams: 4 ATA DEFESA.pdf: 633557 bytes, checksum: 9a3653d1ea37a1413322990ba2b28fed (MD5) CartaEncaminhamentoTCC-TESE-DISSERTA????O.pdf: 166733 bytes, checksum: 0bd118d4500e29a32eecb3682181428a (MD5) Tese_Elisa Ferrari Justulin Zacarias.pdf: 4689154 bytes, checksum: 5e4919ffbac0fbbce5a942bbe44a8c4f (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2021-12-15 FAPEAM - Funda????o de Amparo ?? Pesquisa do Estado do Amazonas Place identity is a revealing aspect of the way a person interacts with the environment. It is built from the person-environment relationship and encompasses a complex network woven by cognitive and affective aspects, behavioral skills, experiences, cultural aspects, interpersonal relationships and the temporal dimension. The more significant place identity, the more people become in favor of adopting practices of environmental protection and care. Thus, the study of the place identity contributes to the proposition of interventions that optimize more sustainable person-environment relationships from childhood. As it is a new concept, there is a lot to be researched, in particular how all this is being built over the years. The general objective of this study was to understand the implications of the child-environment relationship in the constitution of place identity in the S??o Francisco Community, Careiro da V??rzea-AM. Therefore, the specific objectives were: a) To characterize the daily life of the child from the relationship with the riverside environment of the floodplain; b) Identify the social use of spaces by children; c) Verify aspects of place identity in the conduct of environmental care in the place. This understanding was the basis for the elaboration of a place identity model based on the theoretical and empirical research present in this study. Therefore, exploratory research with a multimethod approach was carried out. The first stage of the research consisted of applying the technique of free association of words on the places frequented in the community. The second stage of the research consisted in the application of the technique of directed drawing and interview. The semi-structured interview protocol was designed with open and closed questions about aspects that characterize the way of living in the community and ecological practices. The data made it possible to get to know places of greater affinity (school, home and church), places of lesser affinity boring (none) and places of lesser affinity dangerous (river/lake, paths and bush); the categories of daily perception were classified into habitual, singular and diligence. The analysis of the collected data revealed the need to propose a new model of place identity, it consists of five dimensions intertwined with each other ??? environmental, interpersonal, cultural, personal and temporal. From this model, it appears that the children's place identity is strengthened in the interpersonal, personal, cultural dimensions, but the environmental dimension can be stimulated. The insertion of devices and services that are more present and typical of other places can give the community more strength for positive evaluation. Children are able to perceive the place where they live, establish objective and subjective bonds, recognize the peculiarities of the place and how they relate to it in the various dimensions that forge the place identity. However, this construction must be maintained for the care of oneself, others and the place itself. A identidade de lugar (IdL) ?? um aspecto revelador do modo como a pessoa interage com o ambiente. ?? constru??da a partir da rela????o pessoa-ambiente e abarca uma complexa rede tecida por aspectos cognitivos, afetivos, aptid??es comportamentais, experi??ncias, aspectos culturais, rela????es interpessoais e a dimens??o temporal. Quanto mais significativa a IdL, mais as pessoas se tornam favor??veis a ado????o de pr??ticas de prote????o e cuidado ambiental. Assim, o estudo da IdL contribui na proposi????o de interven????es que otimizem rela????es pessoa-ambiente mais sustent??veis desde a inf??ncia. Por ser um conceito novo, h?? muito a ser pesquisado, em particular como tudo isso vai sendo constru??do ao longo dos anos. Assim, o objetivo geral deste estudo foi compreender as implica????es da rela????o crian??a-ambiente na constitui????o da identidade de lugar na Comunidade S??o Francisco, Careiro da V??rzea- AM. Para tanto, os objetivos espec??ficos foram: a) Caracterizar o cotidiano da crian??a a partir da rela????o com o ambiente ribeirinho da v??rzea; b) Identificar o uso social dos espa??os pelas crian??as e c) a Verificar aspectos da identidade de lugar na conduta de cuidado ambiental do lugar. Tal compreens??o fundamentou a elabora????o de um modelo de IdL a partir da pesquisa te??rica e emp??rica presente neste estudo. Para tanto foi realizado uma pesquisa explorat??ria com abordagem multim??todos. A primeira fase da pesquisa consistiu na aplica????o da t??cnica de associa????o livre de palavras sobre os lugares frequentados na comunidade. A segunda etapa da pesquisa, consistiu na aplica????o da t??cnica do desenho dirigido e entrevista. O protocolo da entrevista semiestruturada foi elaborado com quest??es abertas e fechadas sobre aspectos que caracterizam o modo de viver na comunidade e sobre as pr??ticas ecol??gicas. Os dados possibilitaram conhecer lugares de maior afinidade (escola, casa e igreja), lugares de menor afinidade chato (nenhum) e lugares de menor afinidade perigosos (rio/lago, caminhos e mato); as categorias de percep????o do cotidiano foram classificadas em habitual, singular e de dilig??ncia. A an??lise dos dados coletados revelou a necessidade de proposi????o de um novo modelo de IdL, ?? constitu??do por cinco dimens??es entrela??adas entre si ??? ambiental, interpessoal, cultural, pessoal e temporal. A partir desse modelo, verifica-se que a IdL das crian??as est?? fortalecida nas dimens??es interpessoal, pessoal, cultural, por??m a dimens??o ambiental pode ser estimulada. A inser????o de aparatos e servi??os que est??o mais presentes e s??o pr??prios de outros lugares pode conferir ?? comunidade mais for??a de avalia????o positiva. As crian??as conseguem perceber o lugar onde vivem, estabelecem v??nculos objetivos e subjetivos, reconhecem as peculiaridades do lugar e como se relacionam com ele nas diversas dimens??es que v??o forjando a IdL. No entanto, essa constru????o deve ser mantida tanto para o cuidado de si, dos outros e do pr??prio lugar. Nenhuma N??o

The first purpose of this study was to verify the association between Instability Severity Index Score (ISIS) and Recurrent Shoulder Dislocation (RSD) after a first episode treated conservatively. The second aim is to identify the risk factors associated with RSD after a primary acute shoulder anterior dislocation treated conservatively. A total of 111 patients with first traumatic anterior shoulder dislocation treated at a single trauma centre between January 2014 and March 2016 were enrolled. The main predictive variables of risk factors and the ISIS score were calculated. Among the 85 patients included, 26 cases of RSD were observed (30.6%). Considering the whole population, no significant association between ISIS and RSD were reported. Regarding other risk factors, high-risk working activities and rotator cuff injury had a significantly higher RSD risk. Sex, dominant limb, familiar history, hyperlaxity, contact or overhead sports, competitive sport, post-reduction physiokinesitherapy, return to sports activity time, Hill-Sachs lesion, bony Bankart lesion and great tuberosity fracture did not seem to influence the risk of RSD. No correlation between ISIS score and RSD in patients treated conservatively after a first episode of shoulder dislocation were reported. The only risk factors with a significant association to RSD were high-risk working activities and rotator cuff injury.

Neste artigo apresenta-se o estado da arte da literatura acadêmica acerca da pesquisa empírica denominada identidade de lugar. Fez-se um levantamento de estudos publicados nas seguintes bases de dados: Periódicos CAPES, Scientific Electronic Library Online (SciELO) e ScienceDirect, com a utilização dos descritores: identidade de lugar e place identity. Foram selecionadas 67 publicações que atendem aos critérios de inclusão. Os dados foram submetidos à análise descritiva, análise de correspondência e análise da estrutura de similaridade ou análise dos menores espaços e análise de conteúdo, o que possibilitou uma visão geral acerca das fontes selecionadas. Os temas que sintetizam a análise temática das fontes são: análise teórica e operacionalização do conceito; conceitos confluentes; implicações da identidade de lugar; operacionalização da identidade de lugar e variáveis que promovem implicações na identidade de lugar.

Pyroxenites constitute the major form of heterogeneity in the upper mantle. Their occurrence in supra-subduction zone settings is mostly testified by veins and layers in refractory ophiolitic peridotites, where they represent a crucial witness of melt migration in the forearc/subarc environment [1,2]. The New Caledonia ophiolite hosts one of the largest forearc mantle section worldwide, providing a unique perspective into upper mantle processes. The sequence is dominated by ultra-depleted harzburgites [3], locally overlain by mafic-ultramafic cumulates [4,5,6]. The harzburgites are highly refractory residues that register a multi-phase evolution, including fluid-assisted melting in a forearc environment and contamination by fluid- and melt inputs triggered by Eocene subduction [1]. Pyroxenitic rocks intruding the harzburgites are only known in the Bogota peninsula shear zone, which records HT deformation along a paleotransform fault [7]. In this contribution, we report a comprehensive petrological and geochemical characterization on a new set of pyroxenites from this locality. The pyroxenites (~5-15 cm-thick) generally cut the peridotite foliation at variable angles, but concordant, locally boudinaged, layers also occur. Pyroxenite textures range from cumulitic to porphyroclastic or granoblastic-polygonal. The studied samples mostly consist of amphibole-bearing (5-44 vol.%) websterites, with variable amounts of orthopyroxene (27-67 vol.%) and almost constant clinopyroxene contents (~ 25-29 vol.%). Minor olivine-bearing orthopyroxenites are also present. Accessory phases include high-Ca (An= 82-86 mol%) plagioclase, Cr-rich spinel (Cr# = 50-61), sulfides and, occasionally, apatite. Pyroxenes displays high Mg# (Mg# Opx= 91-92; Mg# Cpx= 84-93), coupled with low Al2O3 contents (0.97-1.92 wt% and 1-2.42 wt% for orthopyroxene and clinopyroxene, respectively). Amphibole is high Mg# edenite. Application of conventional pyroxene thermometry yield equilibration temperatures ranging between 930-1040°C, comparable to the enclosing harzburgites (~ 950°C), whereas amphibole-plagioclase geothermometer provides lower temperatures (~ 800°C). Bulk rock composition of the websterites show variable Mg# (82-91) and REE concentrations ranging between 1 to 10 times chondritic values. They are characterized by flat to LREE-depleted (LaN/SmN 0.28-0.92) patterns, coupled to weak MREE-HREE fractionation (GdN/YbN = 1.73-1.92) and Eu negative anomalies. By contrast, orthopyroxenites display notably lower concentrations (0.1≤REE≤1 chondrite abundances). As a whole, clinopyroxene REE patterns of the websterites mirror bulk rocks at higher absolute values. Putative melts in equilibrium with clinopyroxene indicate strongly enriched compositions (up to 300 times chondritic values) coupled to variable LREE-HREE fractionation (LaN/LuN = 3-19) and flat to fractionated HREE (GdN/LuN 1-2). Such enriched liquids, which show some analogies with pre-obduction adakite-like dikes [8], have never been recorded in the MTZ cumulitic sequence of the New Caledonia ophiolite and shed new light on the magmatic activity in the early stage of subduction. [1] Varfalvy, Canad Mineral, 1997, 35 (2), 543-570.[2] Berly et al., J. Petrol., 2006, 47(8), 1531-1555.[3] Secchiari et al., Geosc. Front., 2020, 11(1), 37–55. [4]. [4] Marchesi et al., Chem. Geol., 2009, 266, 171-186.[5] Pirard et al., J. Petrol., 2013, 54, 1759–1792.[6] Secchiari et al., Contrib. Mineral. Petrol., 2018, 173(8), 66.[7] Chatzaras et al., Geology, 2020, 48 (6): 569–573.[8] Cluzel et al., Terra Nova, 2006, 6, 395–402.

The New Caledonia ophiolite hosts one of most complete sections of a nascent arc, representing an excellent natural laboratory for investigating the origin and the evolution of subduction systems. The sequence, originated during the onset of the Eocene subduction [1, 2], is composed of ultra-depleted forearc harzburgites [3] overlain by a dunite-dominated transition zone (500m thick), in turn overtopped by mafic-ultramafic cumulate lenses. The ultramafic rocks of the transition zone (mainly dunites and wehrlites) most likely resulted from melt-peridotite reactions involving primitive arc tholeiites and boninitic magmas [2]. By contrast, dunite-pyroxenite and gabbronorite cumulates derive from H2O-poor depleted melts transitional between boninites and arc-tholeiites [2, 4].In this contribution, we report the first occurrence of amphibole-bearing ultramafic lithologies in the New Caledonia arc sequence. Our study deals with a petrological and geochemical characterisation of a 2.5km x 5km composite, roughly snowball-shaped, intrusive body, consisting of pyroxenite, dunite, wehrlite, hornblendite and associated mafic-ultramafic, locally sheared, dikes from the Plum area (Massif du Sud). The pyroxenite component, which forms the core of the intrusion, consists of coarse-grained websterites, mainly composed of weakly oriented orthopyroxene (~ 30-75 vol.%) and clinopyroxene (~ 20-40 vol.%), with variable amounts of edenitic amphibole (~ 2-30 vol.%). The amphibole generally occurs as poikilitic crystals or develops as coronas on pyroxenes. Highly calcic plagioclase (An= 83-96 mol %) is scarce in the pyroxenite body (~ 2 vol. %), but more abundant in the associated dikes (~ 10-50 vol.%). Clinopyroxene shows variable Mg# (0.82-0.92) and low Al2O3 (0.99-2.00 wt%). Likewise, amphibole yields high Mg# (0.712-0.865). Estimated equilibrium temperatures based on conventional pyroxene thermometry range between 870-970°C, whereas amphibole-plagioclase pairs provide slightly lower values (800-910 °C).Whole rocks have moderately high Mg# (71-82) and REE concentrations one to five times chondritic values. The websterites of the main body show LREE-depleted (LaN/NdN = 0.5-0.8), weakly concave downward patterns, with flat HREE segments (LuN/TmN = 1.1-1.3). The mafic-ultramafic dikes display similar patterns, bearing depleted to flat LREE segments (LaN/NdN = 0.6-1) and positive Eu anomalies. For all the investigated lithologies, extended trace element diagrams indicate enrichments for FME (i.e. Rb, Ba, U) and Th, coupled to Zr-Hf depletion. Strong Sr positive spikes are only observed for the crosscutting dikes, while the pyroxenite body yields Sr negative anomalies.Geochemical modelling shows that the putative liquids in equilibrium with the websterites have intermediate Mg# (57–63) and incompatible trace element patterns sharing remarkable similarities with the New Caledonia CE-boninites [5]. However, they significantly differ from the equilibrium melts reported for the other intrusive rocks of the sequence [1, 4], suggesting greater compositional variability for the liquids ascending into the Moho transition zone and lower crust. Our results support the notion that petrological and geochemical heterogeneity of magmatic products may be distinctive features of subduction infancy. References[1] Marchesi et al., Chem. Geol., 2009, 266, 171-186.[2] Pirard et al., J. Petrol., 2013, 54, 1759–1792.[3] Secchiari et al., Geosc. Front., 2020, 11(1), 37–55.[4] Secchiari et al., Contrib. Mineral. Petrol., 2018, 173(8), 66.[5] Cluzel et al., Lithos, 2016, 260, 429–442.

Atg6Beclin 1 mediates autophagy and endosomal trafficking. We investigated how Atg6 influences replication stress. Combining genetic, genomic, metabolomic, and proteomic approaches, we found that the Vps34-Vps15-Atg6Beclin 1-Vps38UVRAG-phosphatydilinositol-3 phosphate (PtdIns(3)P) axis sensitizes cells to replication stress by favoring the degradation of plasma membrane amino acid (AA) transporters via endosomal trafficking and ESCRT proteins, while the PtdIns(3)P phosphatases Ymr1 and Inp53 promote survival to replication stress by reversing this process. An impaired AA uptake triggers activation of Gcn2, which attenuates protein synthesis by phosphorylating eIF2α. Mec1Atr-Rad53Chk1/Chk2 activation during replication stress further hinders translation efficiency by counteracting eIF2α dephosphorylation through Glc7PP1. AA shortage-induced hyperphosphorylation of eIF2α inhibits the synthesis of 65 stress response proteins, thus resulting in cell sensitization to replication stress, while TORC1 promotes cell survival. Our findings reveal an integrated network mediated by endosomal trafficking, translational control pathways, and checkpoint kinases linking AA availability to the response to replication stress.

Mediante un análisis comparado de la violencia homicida en el periodo posacuerdo en Colombia y El Salvador, se busca argumentar si es razonable sostener la hipótesis de la “salvadorización” de Colombia tras la firma del Acuerdo de Paz entre el Gobierno y LAS FARC-EP. El análisis cuestiona el discurso de la salvadorización sostenido por sectores políticos opositores al Acuerdo, planteando que, tanto la guerra como la paz en ambos países presentan diferencias sustanciales, por lo que no es posible hacer una analogía entre el comportamiento de la violencia posacuerdo salvadoreña y colombiana, lo que evidencia el carácter artificioso de dicho discurso. Asimismo, se analiza la transformación de la violencia en Colombia tras la firma del Acuerdo de Paz, caracterizada por el reacomodo de los grupos armados ilegales en los antiguos territorios de la guerrilla, hecho que refuerza las diferencias con el país centroamericano. Through a comparative analysis of violence in the post-accord period in Colombia and El Salvador, it is sought to argue whether it is reasonable to support the hypothesis of salvadorization of Colombia after signing the Peace Accord between the Government and theFARC-EP. The analysis questions the discourse of salvadorization, promoted by political sectors opposing the Agreement, stating that war and peace in both countries present significant differences, so it is not possible to make an analogy between the behavior of post-accord violence, evidencing the contrived nature of this discourse. In addition, the transformation of the violence in Colombia after signing the Peace Accord is analyzed, which is characterized by the geographical rearrangement of illegal armed groups in the former guerrilla territories.

Resumo: A ideia do comportamento sustentável emerge diante de um cenário de crise ambiental como uma possível solução em busca da reversão desse quadro. Entretanto há dificuldades em efetivar esse novo modo de pensar e agir, uma vez que o comportamento humano é alimentado por uma matriz complexa de filtros. Por essa razão, compreender a relação pessoa-ambiente pode fornecer instrumentos para superar esse impasse. Abstract: The idea of sustainable behavior, emerges in in a context of environmental crisis as a possible solution looking for a reversal of this crisis. However, there are profound difficulties in changing this new way of thinking and acting, since a complex array of filters powers human behavior towards the environment. For this reason, understanding the person-environment relationship can provide tools to overcome this impasse. Résumé: L'idée d'un comportement durable émerge avant un scénario de crise environnementale comme une solution possible recherchant le contraire de ses crises. Quoi qu'il en soit, ils ont des difficultés profondes en changeant cette nouvelle façon de penser et agir, depuis que le complexe ensemble de ses filtres puissants une fois que le comportement humain s' adapte á l'environnement. Pour cette raison, comprenant la relation personne-environnement, peut fournir des instrumentos pour vaincre cette impasse. Resumen: La idea de conducta sustentable surge ante un escenario de crisis ambiental como una posible salida en la búsqueda de una solución a esta situación. Sin embargo, existen dificultades en la realización de esta nueva forma de pensar y actuar, ya que el comportamiento humano es impulsado por un complejo conjunto de filtros. Por esta razón, la comprensión de la relación persona-ambiente puede proporcionar herramientas para superar esta problemática.

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The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53CHK1/CHK2 controls histone degradation to assist DNA repair. However, Rad53 deficiency causes histone-dependent growth defects in the absence of DNA damage, pointing out unknown physiological functions of the Rad53-histone axis. Here we show that histone dosage control by Rad53 ensures metabolic homeostasis. Under physiological conditions, Rad53 regulates histone levels through inhibitory phosphorylation of the transcription factor Spt21NPAT on Ser276. Rad53-Spt21 mutants display severe glucose dependence, caused by excess histones through two separable mechanisms: dampening of acetyl-coenzyme A-dependent carbon metabolism through histone hyper-acetylation, and Sirtuin-mediated silencing of starvation-induced subtelomeric domains. We further demonstrate that repression of subtelomere silencing by physiological Tel1ATM and Rpd3HDAC activities coveys tolerance to glucose restriction. Our findings identify DDR mutations, histone imbalances and aberrant subtelomeric chromatin as interconnected causes of glucose dependence, implying that DDR kinases coordinate metabolism and epigenetic changes., The relationship between DNA damage response (DDR) and regulation of the tolerance to glucose restriction is currently unclear. Here the authors reveal that maintaining a physiological level of histones by Rad53-Spt21 is necessary for glucose tolerance via multiple parallel pathways, including derepression of subtelomeric genes and acetyl-coA regulation by histone acetylation.

Over the years, there has been growing interest in using Machine Learning techniques for biomedical data processing. When tackling these tasks, one needs to bear in mind that biomedical data depends on a variety of characteristics, such as demographic aspects (age, gender, etc) or the acquisition technology, which might be unrelated with the target of the analysis. In supervised tasks, failing to match the ground truth targets with respect to such characteristics, called confounders, may lead to very misleading estimates of the predictive performance. Many strategies have been proposed to handle confounders, ranging from data selection, to normalization techniques, up to the use of training algorithm for learning with imbalanced data. However, all these solutions require the confounders to be known a priori. To this aim, we introduce a novel index that is able to measure the confounding effect of a data attribute in a bias-agnostic way. This index can be used to quantitatively compare the confounding effects of different variables and to inform correction methods such as normalization procedures or ad-hoc-prepared learning algorithms. The effectiveness of this index is validated on both simulated data and real-world neuroimaging data., Comment: This is the accepted manuscript. The edited version is freely available until 23/03/2020 at the following link: https://authors.elsevier.com/a/1aVYZ3KEGa9GJo

Purpose The lack of inter-method agreement can produce inconsistent results in neuroimaging studies. We evaluated the intra-method repeatability and the inter-method reproducibility of two widely-used automatic segmentation methods for brain MRI: the FreeSurfer (FS) and the Statistical Parametric Mapping (SPM) software packages. Methods We segmented the gray matter (GM), the white matter (WM) and subcortical structures in test-retest MRI data of healthy volunteers from Kirby-21 and OASIS datasets. We used Pearson’s correlation (r), Bland-Altman plot and Dice index to study intra-method repeatability and inter-method reproducibility. In order to test whether different processing methods affect the results of a neuroimaging-based group study, we carried out a statistical comparison between male and female volume measures. Results A high correlation was found between test-retest volume measures for both SPM (r in the 0.98–0.99 range) and FS (r in the 0.95–0.99 range). A non-null bias between test-retest FS volumes was detected for GM and WM in the OASIS dataset. The inter-method reproducibility analysis measured volume correlation values in the 0.72–0.98 range and the overlap between the segmented structures assessed by the Dice index was in the 0.76–0.83 range. SPM systematically provided significantly greater GM volumes and lower WM and subcortical volumes with respect to FS. In the male vs. female brain volume comparisons, inconsistencies arose for the OASIS dataset, where the gender-related differences appear subtler with respect to the Kirby dataset. Conclusions The inter-method reproducibility should be evaluated before interpreting the results of neuroimaging studies.

Resumo: O trabalho foi realizado para discutir a conservação e manejo da fauna silvestre amazônica a partir da relação entre humano e não humano como respostas a defaunação na época do Antropoceno. Na Amazônia, essas práticas transformam o modo como as populações humanas se relacionam com as espécies pirarucu, quelônios e jacarés. Abstract: The work was carried out to discuss the conservation and management of Amazonian wild fauna from the relationship between human and nonhuman as responses to defaunation in the Anthropocene era. In the Amazon these practices transform the way human populations relate to pirarucu, chelonians and alligators. Résumé: Le travail a été mené pour discuter de la conservation et de la gestion de la faune sauvage amazonienne à partir de la relation entre les humains et les non-humains en tant que réponses à la défaillance à l’ère de l’anthropocène. En Amazonie, ces pratiques transforment la façon dont les populations humaines se rapportent aux pirarucu, aux chéloniens et aux alligators. Resumen: El trabajo fue realizado para discutir la conservación y manejo de la fauna silvestre amazónica a partir de la relación entre humano y no humano como respuestas a la defaunación en la época del Antropoceno. En la Amazonia estas prácticas transforman el modo en que las poblaciones humanas se relacionan con las especies pirarucu, quelonios y caimanes.

The mTOR inhibitor everolimus is effective against advanced pancreatic neuroendocrine tumors (pNETs). However, it can cause metabolic adverse events, such as hyperglycemia, hypertriglyceridemia and hypercholesterolemia. In this work we aimed at evaluating the impact of systemic and tumor lipid metabolism on everolimus efficacy. We carried out a monocentric, retrospective study to correlate plasma triglyceride and cholesterol levels with the progression free survival (PFS) of advanced pNET patients treated with everolimus. In formalin fixed, paraffin embedded (FFPE) tumor specimens, we also assessed by mRNA quantification and immunohistochemistry the expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), two enzymes crucially involved in fatty acid biosynthesis, and we analyzed their impact on PFS. We evaluated 58 consecutive pNET patients who started everolimus between December 2006 and January 2015. Patients with higher plasma triglycerides during the first 3 months of treatment had an increased risk of disease progression (aHR 3.08, 95% CIs 1.15-8.21; p = 0.025). In 23 FFPE tumor specimens amenable for IHC evaluations, we found a positive correlation between ACC1 and FASN at both mRNA (r = 0.87, p = 0.00045) and protein (r = 0.68, p = 0.0004) level. Patients with higher ACC1 protein expression in metastatic lesions had significantly lower PFS when compared to patients with lower ACC1 levels (5.5 vs. 36 months; aHR 4.49, 95% CIs 1.08-18.72; p = 0.039). In conclusion, systemic and tumor lipid metabolism are associated with the PFS of everolimus-treated patients with advanced pNETs; based on these findings, dietary and pharmacological interventions targeting lipid metabolism could improve everolimus efficacy in this patient population.

Rationale & Objective Although primary atypical hemolytic uremic syndrome (aHUS) is associated with abnormalities in complement genes and antibodies to complement factor H, the role of complement in secondary aHUS remains debatable. We evaluated the usefulness of an ex vivo test to: (1) detect complement activation within the endothelium in primary and secondary aHUS, (2) differentiate active disease from remission, (3) monitor the effectiveness of eculizumab therapy, and (4) identify relapses during eculizumab dosage tapering and after discontinuation of treatment. Study Design Case series. Setting & Participants 121 patients with primary aHUS and 28 with secondary aHUS. Serum samples were collected during acute episodes, following remission, and during eculizumab treatment and were assessed using a serum-induced ex vivo C5b-9 endothelial deposition test. Results Serum-induced C5b-9 deposition on cultured microvascular endothelium was quantified by calculating the endothelial area covered by C5b-9 staining; values were expressed as percentage of C5b-9 deposits induced by a serum pool from healthy controls. Testing with adenosine diphosphate–activated endothelium demonstrated elevated C5b-9 deposits for all untreated patients with aHUS independent of disease activity, while testing with unstimulated endothelium demonstrated deposits only in active disease. Similar findings were observed in secondary aHUS. Serum-induced C5b-9 deposits on activated and unstimulated endothelium normalized during eculizumab treatment. 96% (22/23) of patients receiving eculizumab at extended 3- or 4-week dosing intervals demonstrated normal C5b-9 deposits on activated endothelium, despite most patients having CH50Eq (serum complement activity) > 20 UEq/mL, indicating that adequate complement control was achieved even with incomplete blockade of circulating C5. During eculizumab dosage tapering or after treatment discontinuation, all patients experiencing relapses versus only 6% (1/17) of those in stable remission had elevated C5b-9 deposits on unstimulated endothelium. Limitations The C5b-9 endothelial deposition test can be performed in only specialized laboratories. Findings on eculizumab dosage tapering need to be confirmed with longitudinal monitoring of C5b-9 deposition. Conclusions The C5b-9 endothelial deposition assay may represent an advance in our ability to monitor aHUS activity and individualize therapy.

Submitted by Divis??o de Documenta????o/BC Biblioteca Central (ddbc@ufam.edu.br) on 2018-03-06T15:51:21Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Disserta????o_Elisa F. J. Zacarias.pdf: 3279300 bytes, checksum: 069d3b4f63177b321766e47085c3f968 (MD5) Approved for entry into archive by Divis??o de Documenta????o/BC Biblioteca Central (ddbc@ufam.edu.br) on 2018-03-06T15:51:34Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Disserta????o_Elisa F. J. Zacarias.pdf: 3279300 bytes, checksum: 069d3b4f63177b321766e47085c3f968 (MD5) Made available in DSpace on 2018-03-06T15:51:34Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Disserta????o_Elisa F. J. Zacarias.pdf: 3279300 bytes, checksum: 069d3b4f63177b321766e47085c3f968 (MD5) Previous issue date: 2018-01-26 CAPES - Coordena????o de Aperfei??oamento de Pessoal de N??vel Superior The present study aimed to understand the behavior that establishes Connectedness to Nature among fathers and mothers residing in Manaus-AM, and the implications for the experiences that they provided for their children. The construct Connectedness to Nature (CN) can be defined as the emotional attachment of people to nature, which is manifested in the adoption of attitudes that reveal environmental care and concern. Thus, in this research, it was imperative to apprehend the meaning of nature, since it is the result of a historical construction. Additionally, the research tries to understand what characterizes the lived experiences in nature of the parents and children, and identify the behaviors that define their relationship with nature. This is a descriptive exploratory study with a multi-method approach. The instruments used were semi-structured interview, free word association and social scale. Fifty-eight people (33 fathers and 25 mothers), residents of Manaus and with children up to 11 years of age, participated in this study. The data generated by the interviews was submitted to Content Analysis, after categorization was made using Descriptive Analysis; the free word association technique was subjected to Similarity Structure Analysis (SSA). Finally, the social scales were worked out from the Exploratory Factor Analysis (EFA) and Simple Descriptive Analysis (SDA). All quantitative analysis was performed using the SPSS (Social Package for Social Sciences) program. The results revealed that when referring to nature the participants do so in both an objective (geophysical aspects and elements present in it) and subjective (social, symbolic and affective aspects) way. For most parents accessing nature as a space for their children???s leisure is not their preferred choice. There is a slight expectation that, in the future, it will be possible to make use of this space, but this desire is shared by only a few parents. For these urban famillies leisure activities are primarily carried out in enclosed, public or domestic, spaces. This is the both the current situation, and the desired ideal situation. The results highlight this disparity and suggest that parents are not trying to overcome it. It was found that the majority of parents have a high level of CN (or Connectedness to Nature). However, this is not manifested as more time spent in contact with nature or in actions of environmental care. There is an incongruity between feeling connected to nature and being actually present in it. Some factors that contribute to this gap were listed by the participants - such as such as safety and security issues and the lack of leisure time. The data shows that there is a long way to go, before the connection with nature, in fact, results in actions that express care for the natural environment and in experiences in nature. To achieve this, family and social support must be more effective. O presente estudo teve como quest??o norteadora compreender o comportamento de Conex??o com a Natureza em pais/m??es residentes em Manaus-AM e suas implica????es nas experi??ncias proporcionadas aos seus filhos(as). O construto conex??o com a natureza pode ser definido como a liga????o emocional das pessoas com a natureza, o que se manifesta na ado????o de atitudes que revelam o cuidado e a preocupa????o ambiental. Assim, nessa pesquisa, foi imprescind??vel apreender o significado de natureza, pois essa ?? resultado de uma constru????o hist??rica. Al??m disso, foi caracterizado as experi??ncias vivenciadas entre pais e filhos(as) no ambiente natural e identificado os comportamentos que marcam a rela????o com a natureza. Trata-se de uma pesquisa descrita-explorat??ria com abordagem multim??todos. Os instrumentos empregados foram entrevista semiestruturada, associa????o livre de palavras e escala social. Participaram deste estudo 58 pessoas (33 pais e 25 m??es), moradores de Manaus e com filhos at?? 11 anos de idade. Os dados gerados pela entrevista foram submetidos a An??lise de Conte??do, ap??s categoriza????o foi feita a An??lise Descritiva; a t??cnica da associa????o livre de palavras foi submetida a An??lise de Estrutura de Similaridade (SSA- Similarity Structure Analysis) finalmente, as escalas sociais foram trabalhadas a partir da An??lise Fatorial Explorat??ria e An??lise Descritiva Simples. Todas as an??lises quantitativas foram trabalhadas usando o programa SPSS (Social Package for Social Sciences). Os resultados revelaram que os participantes ao se referirem ?? natureza o fazem tanto sob a dimens??o objetiva (aspectos geof??sicos e elementos presentes nela) quanto subjetiva (aspectos sociais, simb??licos e afetivos). A natureza como espa??o de possibilidade de lazer aos filhos ainda ??, para a maioria dos pais, um lugar de baixa prefer??ncia para levar seus filhos. H?? uma leve expectativa de, no futuro, poder fazer uso desse espa??o, mas esse desejo ?? compartilhado por poucos pais. O lazer que predomina nessas fam??lias urbanas ?? o uso de espa??os fechados seja p??blico ou dom??stico, tanto atual quanto desejado numa condi????o ideal. Esses resultados indicam esse afastamento atual e sinaliza que pouco investimento esses pais parecem querer fazer para suprir esse d??ficit. Constatou-se, no entanto, que a maioria dos pais possui um elevado ??ndice de Conex??o com a Natureza, por??m isso n??o se manifesta em mais tempo em contato com a natureza ou em a????es de cuidado ambiental. Observa-se uma incongru??ncia entre o sentir-se conectado a natureza e estar nela efetivamente inserido. Alguns fatores que contribuem para essa lacuna foram elencados pelos participantes ??? como a inseguran??a e a disponibilidade de tempo. Os dados evidenciam que h?? um longo caminho a ser percorrido, para que a conex??o com a natureza, de fato, se materialize em a????es que expressem o cuidado com o ambiente natural e em experi??ncias na natureza. Nesse percurso, fam??lia e poder p??blico devem estar presentes.

Tumor cells may adapt to metabolic challenges by alternating between glycolysis and oxidative phosphorylation (OXPHOS). To target this metabolic plasticity, we combined intermittent fasting, a clinically feasible approach to reduce glucose availability, with the OXPHOS inhibitor metformin. In mice exposed to 24-h feeding/fasting cycles, metformin impaired tumor growth only when administered during fasting-induced hypoglycemia. Synergistic anti-neoplastic effects of the metformin/hypoglycemia combination were mediated by glycogen synthase kinase 3β (GSK3β) activation downstream of PP2A, leading to a decline in the pro-survival protein MCL-1, and cell death. Mechanistically, specific activation of the PP2A-GSK3β axis was the sum of metformin-induced inhibition of CIP2A, a PP2A suppressor, and of upregulation of the PP2A regulatory subunit B56δ by low glucose, leading to an active PP2A-B56δ complex with high affinity toward GSK3β. ispartof: CANCER CELL vol:35 issue:5 pages:798-+ ispartof: location:United States status: published

This study investigated the effects of high hydrostatic pressure (HHP) and ultraviolet radiation (UV-C), individually and combined, on the physical, chemical and bacterial parameters of Nile tilapia (Oreochromis niloticus) fillets stored at 4 °C for 14 days. Tilapia fillets were divided into four groups: control (untreated samples), UV-C, HHP, and UV-C combined with HHP (UV-C+HHP); UV-C was applied at dose of 0.103 ± 0.002 J/cm2, and HHP at a pressure of 220 MPa for 10 min at 25 °C. All samples were analyzed for total aerobic mesophilic count (TAMC), total aerobic psychrotrophic count (TAPC), Enterobacteriaceae count, pH, lipid oxidation, total volatile basic nitrogen (TVB-N), ammonia (NH3), and biogenic amines. Although UV-C accelerated (P ≤ 0.05) the formation of cadaverine, both UV-C and HHP, alone or together, retarded bacterial growth and delayed the increase (P ≤ 0.05) in pH, TVB-N, NH3 and biogenic amines during refrigerated storage, extending the shelf life of refrigerated tilapia fillets at least 2.5 times considering the TAMC counts. Lipid oxidation was unaffected (P > 0.05) by UV-C radiation, and decreased (P ≤ 0.05) by HHP and UV-C+HHP. HHP alone or combined with UV-C showed higher potential benefits for tilapia fillets preservation considering the positive influence on cadaverine levels and lipid oxidation.

O processo de acelerada expansão urbana observado no Brasil a partir de meados do século XX, sem planejamento adequado, resultou em ocupação de áreas de risco de inundações urbanas por parte da população de baixa renda, gerando prejuízos sociais. Além disso, potencializou-se o risco de inundações por meio da impermeabilização do território, supressão da mata ciliar e retificação e canalização dos córregos. Com vistas à redução no risco de inundações em áreas urbanas, faz-se necessário, além da adoção de medidas mitigadoras nos locais assolados pelo problema, um disciplinamento adequado do uso e da ocupação do solo nas áreas ainda não urbanizadas da bacia, abordando a questão da drenagem. No entanto, o planejamento territorial urbano não é atribuição do sistema gestor de recursos hídricos, mas do município como um todo, de modo que há vários setores da gestão municipal que devem ser envolvidos nesse processo. Em meio a diferentes prioridades, a questão da drenagem urbana não tem sido satisfatoriamente abordada. Nesse contexto decisório a respeito do planejamento, é fundamental, portanto, que haja uma metodologia que possa conciliar os julgamentos divergentes e, por vezes, conflitantes acerca da alternativa mais adequada de uso e ocupação do solo. Os sistemas de suporte à decisão multicriteriais permitem contornar este problema, além de possibilitarem trabalhar com critérios incomensuráveis, de modo que se configuram como uma opção promissora para o planejamento territorial urbano. O objetivo deste trabalho foi justamente aplicar três métodos diferentes de análises multicriteriais ao planejamento de uso e ocupação do solo de uma bacia hidrográfica ainda em urbanização (rio Mineirinho, em São Carlos - SP) para escolher uma alternativa de uso e ocupação do solo dentre três possíveis. A primeira consistia em um futuro provável com base no histórico de urbanização da bacia e no Plano Diretor Municipal; a segunda, idem, com o acréscimo de um reservatório proposto no Plano Diretor de Drenagem Urbana de São Carlos; e a última propunha medidas de adequação da ocupação urbana ao sistema natural de drenagem. Dever-se-iam considerar os julgamentos de diferentes atores sociais e buscar a redução no risco de inundações urbanas. Um dos métodos utilizados, o Processo Analítico Hierárquico foi considerado menos adequado ao problema proposto que os outros dois (fuzzy-TOPSIS e fuzzy-ELECTRE). E apesar da dificuldade encontrada em realizar uma reunião com um conjunto de seis diferentes atores sociais para debater seus pontos de vista acerca de critérios de escolha e alternativas de uso e ocupação do solo na bacia, foi possível verificar as preferências do conjunto. Em geral, deseja-se alguma intervenção estrutural significativa para mitigar o problema das inundações, como o reservatório proposto no Plano Diretor de Drenagem Urbana de São Carlos. Embora os participantes da pesquisa tenham mostrado interesse pela proteção ambiental, não preferiram, em comparação às demais, a alternativa de uso e ocupação do solo que favorecia a adequação da ocupação urbana ao sistema natural de drenagem. The process of accelerated urban expansion observed in Brazil from the second half of the 20th century on, without adequate planning, resulted in the occupation of areas with risk of flooding by the population of lower income, what caused social loss. Besides, waterproofing of the territory, suppression of the riparian forest, and straightening and channeling of rivers increased the risk of flooding. In order to reduce this risk in urban areas, in addition to adopting mitigating measures on the spots affected by the problem, it is necessary to discipline the use and occupation of the soil where it has not yet been urbanized, taking into consideration the drainage matter. However, urban territory planning is not only attributed to the managers of the water systems, but to the city as a whole. This way, there are various sectors of the municipal management that should be involved in this process. Among different priorities, the matter of urban drainage has not been satisfactorily discussed. Thus it is fundamental to find a method to conciliate divergent judgements about the most adequate alternative for the use and occupation of the soil. The multicriteria decision support systems are able to do this and to work with incommensurable criteria, and therefore they are a promising option to apply in the context of urban territory planning. The main objective of this work was precisely using three different methods of multicriteria analysis in the planning of the soil use and occupation of the Mineirinho watershed (São Carlos - SP), which is still in the midst of an urbanization process, in order to choose one of the three possible alternatives of soil use and occupation. The first one consisted on a probable future, based on the watershed urbanization history and the Municipal Directive Plan; the second one, idem, with the addition of a reservoir proposed in the Urban Drainage Directive Plan of São Carlos; and the last one presented measures to adequate the occupation of the basin to the natural drainage system. The judgement of different social actors and the reduction of the urban flooding risk should be taken into account. One of the used methods - the Analytic Hierarchy Process (AHP) - was considered less suitable to the proposed problem than the other two (fuzzy-TOPSIS and fuzzy-ELECTRE). And although there was some difficulties to hold a meeting with a group of six different social actors who would debate their points of view concerning the choice criteria and the alternatives of soil use and occupation, it was possible to verify the preferences of the group. In general, they want a significant structural intervention to mitigate the urban flood problem, like the reservoir proposed in the Urban Drainage Directive Plan of São Carlos. In spite of the fact that the social actors showed interest for the environmental protection, they did not prefer, when comparing to the other alternatives, the one that most favored the adequacy of the urban occupation to the natural drainage system.

The aim of our study is a retrospective analysis of the 2 most common surgical treatments of symptomatic juvenile flat foot: different arthroereisis techniques. Exosinotarsal arthroereisis with metallic screw and endosinotarsal with bioabsorbable devices were compared. In total, 402 feet were examined for a median follow-up of 130 months. Only symptomatic (plantar or calcaneus pain), flexible, and idiopathic flat feet were included in our study. Congenital (fibrous/bone tarsal coalitions), neurologic, and posttraumatic flat feet were excluded. During clinical examination, the feet were categorized according to the Viladot classification, which took into consideration the plantar impression: only grades 3 and 4 were included (complete medial longitudinal arch collapse). Evaluation was determined by taking into consideration 3 parameters: clinical evaluation, pain, and variation of the radiologic angles. No statistical differences were found between the 2 techniques; the choice can be determined mostly by the surgeon's preference.

As currently performed, on line hemodiafiltration reduces, but does not normalize, the micro-inflammation of uremic patients. Recent technological advances make it possible to further reduce the inflammation connected to the dialysis treatment. Short bacterial DNA fragments are pro-inflammatory and can be detected in the dialysis fluids. However, their determination is not currently within normal controls of the quality of the dialysate. The scenario may change once the analysis of these fragments yields reliable, inexpensive, quick and easy to evaluate the results. At variance with standard bicarbonate dialysate, Citrate dialysate induces far less inflammation both for the well-known anti-inflammatory effect of such buffer and also because it is completely acetate free, e.g. a definitely pro-inflammatory buffer. However, the extensive use of citrate dialysate in chronic dialysis is prevented because of concerns about its potential calcium lowering effect. In our view, high convective exchange on line hemodiafiltration performed with dialysate, whose sterility and a-pirogenicity is guaranteed by increasingly sophisticated controls and with citrate buffer whose safety is certified, can serve as the gold standard of dialysis treatments in future.