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The exposure of viticulture to climate change and extreme weather conditions makes the winemaking sector particularly vulnerable, being one of its major challenges in the current century. While grapevine is considered a highly tolerant crop to several abiotic stresses, Mediterranean areas are frequently affected by adverse environmental factors, namely water scarcity, heat and high irradiance, and are especially vulnerable to climate change. Due to the high socio-economic value of this sector in Europe, the study of adaptation strategies to mitigate the negative climate change impacts are of main importance for its sustainability and competitiveness. Adaptation strategies include all the set of actions and processes that can be performed in response to climate change. It is crucial to improve agronomic strategies to offset the loss of productivity and likely changes in production and fruit quality. It is important to look for new insights concerning response mechanisms to these stresses to advance with more effective and precise measures. These measures should be adjusted to local terroirs and regional climate change projections for the sustainable development of the winemaking sector. This review describes the direct climate change impacts (on phenology, physiology, yield and berry quality), risks, and uncertainties for Mediterranean viticulture, as well as a set of canopy, soil and water management practices that winegrowers can use to adapt their vines to warmer and drier conditions.

Hippocampal seizures mimicking mesial temporal lobe epilepsy (MTLE) cause a profound disruption of the adult neurogenic niche in mice. Seizures provoke neural stem cells to switch to a reactive phenotype (reactive-neural stem cells, React-NSCs)) characterized by multibranched hypertrophic morphology, massive activation to enter mitosis, symmetric division and final differentiation into reactive astrocytes. As a result, neurogenesis is chronically impaired. Here we, using a mouse model of MTLE, show that the epidermal growth factor receptor (EGFR) signalization pathway is key for the induction of React-NSCs and that its inhibition exerts a beneficial effect on the neurogenic niche. We show that during the initial days after the induction of seizures by a single intrahippocampal injection of kainic acid, a strong release of zinc and heparin-binding epidermal growth factor, both activators of the EGFR signalization pathway in neural stem cells, is produced. Administration of the EGFR inhibitor gefitinib, a chemotherapeutic in clinical phase IV, prevents the induction of React-NSCs and preserves neurogenesis.SignificanceIn mouse models of MTLE-HS, seizures cause a profound disruption of the hippocampal neurogenic niche and neurogenesis results chronically impaired, in agreement with what occurs in the human MTLE-HS hippocampus. Thus, the normal cognitive functions associated with neurogenesis are altered, but also the endogenous regenerative capacity that could compensate the high rate of neurons in the granule cell layer of the dentate gyrus. We provide here for the first time a molecular mechanism (the EGFR transduction pathway) regulating the induction of React-NSCs.

Background: Blood–brain barrier permeability (BBBp) is a key process involved in ischemic stroke pathophysiology. However, there is a lack of consensus on how BBBp evolves after the ischemia injury, and its clinical relevance at different timepoints post stroke. Aims: The main objective of this study is to assess BBBp evolution through stroke phases and its implications on patient outcomes. Methods: We screened PubMed/MEDLINE, Embase, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials up to 31 December 2021. We included research quantitatively using neuroimaging to assess BBBp in stroke patients. BBBp in the different phases was evaluated by a random-effect model based on the standardized mean difference (SMD) between the ipsilateral and contralateral sides of the brain. We performed a subgroup analysis on clinical outcome, reperfusion treatment, haemorrhagic transformation, and imaging method. Results: We identified 3761 studies, of which 22 (1592 patients and 1787 evaluations) were included in our study. Overall, 17 studies reported BBBp for the hyperacute phase, 8 for the acute, 5 for the subacute, and 2 for the chronic phase. All phases were associated with increased BBBp: 0.74 (0.48–0.99), 1.68 (0.94–2.42), 1.98 (0.96–3.00), and 1.00 (0.45–1.55), respectively. An increase in BBBp was associated with hemorrhagic transformation in the hyperacute phase and with improved functional outcomes in the late subacute phase. Conclusion: BBBp is persistently increased after stroke, peaking in the acute and subacute phases. The degree of BBBp influences patient outcomes depending on stroke phase. Our findings support the clinical relevance of BBBp dynamics in stroke care.

Field-grown grapevines are often exposed to multiple environmental stresses, which challenges wine-growers to develop sustainable measures to sustain vine growth, yield, and quality. Under field conditions this task is demanding, due to differences in the magnitudes of stresses and associated plant responses. In this study we explored the hypothesis that kaolin-particle film application improves grapevine photoprotection through the regulation of xanthophyll cycle genes, limiting the thermal dissipation of excess energy under harsh environmental conditions. Hence, we selected two grapevine varieties, Touriga-Nacional (TN) and Touriga-Franca (TF), grown in the Douro Demarcated Region, and evaluated changes in light dissipation mechanisms, xanthophyll cycle components, and the expression of xanthophyll cycle genes during the 2017 summer season. The results showed that, from veraison to ripening, kaolin triggered the up-regulation of violaxanthin de-epoxidase (VvVDE1) and zeaxanthin epoxidase (VvZEP1) genes, indicating optimised regulation of the xanthophyll cycle. Kaolin treatment also decreased chlorophyll (Chla, Chlb, Chl(a+b)) and carotenoid (Car) accumulation under increasing summer stress conditions in both varieties and lowered the non-photochemical quenching (NPQ) of grapevines on ripening, suggesting a long-term response to summer stress. In addition, kaolin-treated grapevines showed increased Chla/Chlb and lower Chl(a+b)/Car ratios, displaying some features of high light adapted leaves. Overall, this study suggests that kaolin application enabled grapevines to benefit from fluctuating periods of summer stress by managing chlorophyll and carotenoid content and limiting down-regulation of both photochemistry and photoinhibition processes. Under Mediterranean field conditions, kaolin application can be considered an efficient method of minimising summer stress impact on grapevines., This work was supported by National Funds by FCT - Portuguese Foundation for Science and Technology, under the project UIDB/04033/2020, the Clim4Vitis project – “Climate change impact mitigation for European viticulture: knowledge transfer for an integrated approach”, funded by the European Union's Horizon 2020 Research and Innovation programme, under grant agreement no. 810176, and by the project I&D&I AgriFood XXI, operation NORTE-01-0145-FEDER-000041, co-funded by the European Regional Development Fund (FEDER) through NORTE 2020 (Programa Operacional Regional do Norte, 2014/2020). Sara Bernardo acknowledges the financial support provided by the FCT-Portuguese Foundation for Science and Technology (PD/BD/128273/2017) under the Doctoral Programme “Agricultural Production Chains – from Fork to Farm”.

Polymerase theta (POLθ) is an error-prone DNA polymerase whose loss is synthetically lethal in cancer cells bearing breast cancer susceptibility proteins 1 and 2 (BRCA1/2) mutations. To investigate the basis of this genetic interaction, we utilized a small-molecule inhibitor targeting the POLθ polymerase domain. We found that POLθ processes single-stranded DNA (ssDNA) gaps that emerge in the absence of BRCA1, thus promoting unperturbed replication fork progression and survival of BRCA1 mutant cells. A genome-scale CRISPR-Cas9 knockout screen uncovered suppressors of the functional interaction between POLθ and BRCA1, including NBN, a component of the MRN complex, and cell-cycle regulators such as CDK6. While the MRN complex nucleolytically processes ssDNA gaps, CDK6 promotes cell-cycle progression, thereby exacerbating replication stress, a feature of BRCA1-deficient cells that lack POLθ activity. Thus, ssDNA gap formation, modulated by cell-cycle regulators and MRN complex activity, underlies the synthetic lethality between POLθ and BRCA1, an important insight for clinical trials with POLθ inhibitors.

Kaolin-particle film has been considered a low-cost technology to mitigate the adverse effects of high light and temperature, and drought in several crops. However, the underlying excess energy absorption and dissipation mechanisms, and related components associated with kaolin photoprotective effects in grapevines are poorly explored. This study aims to understand the interactions between kaolin foliar treatment and photosynthetic pigments accumulation, carotenoids metabolism, xanthophyll cycle regulation, and its putative role on the non-photochemical quenching (NPQ) processes in Touriga-Franca (TF) and Touriga-Nacional (TN) varieties. The experiments were conducted during the 2017 summer season in a commercial vineyard, and measurements were performed at pre-dawn and midday in each sampling date (EL35 – veraison; EL38 – full mature). Overall, TF variety showed higher accumulation of chlorophylls, xanthophylls, and de-epoxidation state (DPS) than TN. Kaolin treatment enhanced TN chlorophyll accumulation up to 114 % at EL35 (veraison) and 123 % at EL38 (full mature), highlighting its protective role on chlorophyll degradation, while no changes were found in TF, which might indicate a lower need for particle-film technology in this variety under the current environmental conditions. Individual carotenoids were mainly higher in the treated leaves of both varieties, as well as the xanthophyll cycle pigments zeaxanthin (Zx) and violaxanthin (Vx). Simultaneously, the DPS and NPQ values were lower in TN and TF treated leaves (1.92 – 2.36) compared to untreated vines (3.19 – 3.24), suggesting that there might be other components influencing NPQ levels beyond Zx, with an indirect role in long-lasting NPQ processes. In addition, in the TF kaolin-treated leaves, violaxanthin de-epoxidase (VvVDE1) and zeaxanthin epoxidase (VvZEP1) gene expression were respectively 3-fold and 4-fold upregulated at stage EL35, while VvZEP1 gene expression decreased at stage EL38 in TN kaolin-treated leaves, indicating an optimised regulation of the xanthophyll cycle. These findings suggest that kaolin treatment promoted a fine-tuning of grapevine summer stress responses under sustained summer stress factors, by managing xanthophyll cycle dynamics, and pigments accumulation., This work was supported by National Funds by FCT - Portuguese Foundation for Science and Technology, under the project UIDB/04033/2020, the Clim4Vitis project – "Climate change impact mitigation for European viticulture: knowledge transfer for an integrated approach", funded by European Union's Horizon 2020 research and innovation programme, under grant agreement no. 810176. Authors acknowledge Rui Flores from “Herdade do Esporão”, for the collaboration and efforts in making the vineyard facilities available for this study, as well as BASF collaboration, namely Paulo Matos. The technical assistance of Inmaculada Carbonell (IATA-CSIC) in pigment analysis is also gratefully acknowledged. Sara Bernardo acknowledges the financial support provided by the FCT-Portuguese Foundation for Science and Technology (PD/BD/ 128273/2017), under the Doctoral Programme "Agricultural Production Chains – from fork to farm", and Dinis L.-T. thanks the FCT and UTAD for the research contract (D.L. Law no. 57/2017).

Time is relative in large-vessel occlusion acute ischemic stroke (LVO-AIS). We aimed to evaluate the rate of inter-hospital ASPECTS decay in patients transferred from a primary (PSC) to a comprehensive stroke center (CSC); and to identify patients that should repeat computed tomography (CT) before thrombectomy.This was a retrospective cohort study of consecutive anterior circulation LVO-AIS transferred patients. The rate of ASPECTS decay was defined as (PSC-ASPECTS - CSC-ASPECTS)/hours elapsed between scans. Single-phase CT angiography (CTA) at the PSC was used to classify the collateral score. We compared patients with futile versus useful CT scan re-evaluation.We included 663 patients, of whom 245 (37.0%) repeated CT at a CSC. The median rate of ASPECTS decay was 0.4/h (0.0-0.9). Patients excluded from thrombectomy after a CT scan repeat (n=64) had a median ASPECTS decay rate of 1.18/h (0.83-1.61). Patients with absent collateral circulation had a median rate of 1.51(0.65-2.19). The collateral score was an independent predictor of the ASPECTS decay rate (aβ = -0.35; 95%CI -0.45 - -0.19, p0.001). Age (aOR: 1.04 95% CI 1.02-1.07, p0.001), NIHSS (aOR: 1.11 95% CI 1.06-1.15, p0.001), PSC ASPECTS (aOR: 0.74 95% CI 0.60-0.91, p=0.006) and the CTA collateral score (aOR: 0.14 95% CI 0.08-0.22, p0.001) were independent predictors of the usefulness of a CT scan repeat.The rate of ASPECTS decay can be predicted by the CTA collateral score, helping in the selection of patients that would benefit from repeating a CT assessment on arrival at the CSC.

O Design e engenharia são áreas fundamentais do processo de desenvolvimento de produto, que tem vindo a evoluir cada vez mais para uma área multidisciplinar e de equipa. A presente dissertação resume as atividades desenvolvidas ao longo do estágio curricular na Brasão De La Espada. O estágio permitiu a integração na equipa de desenvolvimento de produto da empresa, proporcionando o desenvolvimento de projetos e tarefas aplicados a um contexto real de indústria, contemplando essencialmente a fase de projeto de detalhe. Paralelamente a estas atividades, foi desenvolvido um projeto autoproposto que surgiu de uma oportunidade de intervenção encontrada no decorrer do estágio. O objetivo do projeto visa promover a cultura local portuguesa, através de um produto que corresponda aos valores e padrões de qualidade da empresa. Neste contexto surge a reinterpretação da cadeira portuguesa, uma referência icónica do design português do século XX. O desafio do projeto passou pela adaptação do processo construtivo a novos materiais: madeira maciça e vime. Pretende-se assim que esta reinterpretação da cadeira possa valorizar o nosso território pela promoção do simbolismo do mobiliário português, assim como posicionar o produto num novo segmento de mercado. Design and engineering are fundamental areas of the product development process, which has been evolving more and more into a multidisciplinary and team area. This dissertation summarizes the activities developed during the curricular internship at Brasão De La Espada. The internship allowed integration in the company’s product development team, providing the development of projects and tasks applied to a real industry context, essentially contemplating the detailed design phase. Alongside these activities, a self-proposed project was developed that emerged from an intervention opportunity found during the internship. The aim of the project is to promote local Portuguese culture, through a product that matches the company’s values and quality standards. In this context, the reinterpretation of the Portuguese chair emerges, an iconic reference in 20th-century Portuguese design. The project’s challenge involved adapting the construction process to new materials: solid wood and wicker. It is intended that this reinterpretation of the chair can enhance our territory by promoting the symbolism of Portuguese furniture, as well as positioning the product in a new market segment. Mestrado em Engenharia e Design de Produto

POLθ promotes repair of DNA double-strand breaks (DSBs) resulting from collapsed forks in homologous recombination (HR) defective tumors. Inactivation of POLθ results in synthetic lethality with the loss of HR genes BRCA1/2, which induces under-replicated DNA accumulation. However, it is unclear whether POLθ-dependent DNA replication prevents HR-deficiency-associated lethality. Here, we isolated Xenopus laevis POLθ and showed that it processes stalled Okazaki fragments, directly visualized by electron microscopy, thereby suppressing ssDNA gaps accumulating on lagging strands in the absence of RAD51 and preventing fork reversal. Inhibition of POLθ DNA polymerase activity leaves fork gaps unprotected, enabling their cleavage by the MRE11-NBS1-CtIP endonuclease, which produces broken forks with asymmetric single-ended DSBs, hampering BRCA2-defective cell survival. These results reveal a POLθ-dependent genome protection function preventing stalled forks rupture and highlight possible resistance mechanisms to POLθ inhibitors.

Research ArticleReceived: 22 December 2020 Revised: 6 April 2021 Accepted article published: 5 July 2021 Published online in Wiley Online Library:(wileyonlinelibrary.com) DOI 10.1002/jsfa.11413Uncovering the effects of kaolin on balancingberry phytohormones and quality attributesof Vitis vinifera grown in warm-temperateclimate regionsSara Bernardo,aLia-Tânia Dinis,aNelson Machado,bAna Barros,aMarta Pitarch-Bielsa,cAureliano C Malheiro,aAurelio Gómez-Cadenascand José Moutinho-Pereir aa*AbstractBACKGROUND: The application of kaolin particle lm is considered a short-term strategy against several environmental stres-ses in areas with a Mediterranean-like climate. However, it is known that temperature uctuations and water availability overthe season can jeopardize kaolin efciency in many Mediterranean crops. Hence, this study aims to evaluate the effects of kao-lin foliar application on berry phytohormones, antioxidant defence, and oenological parameters at veraison and harvest stagesof Touriga-Franca (TF) and Touriga-Nacional (TN) grapevines in two growing seasons (2017 and 2018). The 2017 growing sea-son was considered the driest (−147.1 dryness index) and the warmest (2705 °C growing degree days) of the study.RESULTS: In 2017, TF kaolin-treated berries showed lower salicylic acid (−26.6% compared with unsprayed vines) and abscisicacid (ABA) (−10.5%) accumulation at veraison, whereas salicylic acid increased up to 28.8% at harvest. In a less hot season, TNand TF kaolin-treated grapevines showed a twofold in ABA content and a threefold increase in the indole-3-acetic acid contentat veraison and lower ABA levels (83.8%) compared with unsprayed vines at harvest. Treated berries showed a decreased sugarcontent, without compromising malic and tartaric acid levels, and reactive oxygen species accumulation throughout berryripening.CONCLUSION: The results suggest kaolin exerts a delaying effect in triggering ripening-related processes under severe summerstress conditions. Treated berries responded with improved antioxidant defence and phytohormone balance, showing signif-icant interactions between kaolin treatment, variety, and developmental stage in both assessed years.

The water content in an agricultural crop is of crucial importance and can either be estimated through proximal or remote sensing techniques, allowing better irrigation scheduling and avoiding extreme water stress periods. However, the current climate change context is increasing the use of eco-friendly practices to reconcile water management and thermal protection from sunburn. These approaches aim to mitigate summer stress factors (high temperature, high radiation, and water shortage) and improve the plants’ thermal efficiency. In this study, data from unmanned aerial vehicles (UAVs) were used to monitor the efficiency of foliar kaolin application (5%) in a commercial vineyard. Thermal infrared imagery (TIR) was used to compare the canopy temperature of grapevines with and without kaolin and to compute crop water stress and stomatal conductance indices. The gas exchange parameters of single leaves were also analysed to ascertain the physiological performance of vines and validate the UAV-based TIR data. Generally, plants sprayed with kaolin presented a lower temperature compared to untreated plants. Moreover, UAV-based data also showed a lower water stress index and higher stomatal conductance, which relate to eco-physiological measurements carried out in the field. Thus, the suitability of UAV-based TIR data proved to be a good approach to monitor entire vineyards in regions affected by periods of heatwaves, as is the case of the analysed study area.

Background: The dependence is defined by the commitment of the person’s individual capacity for selfcare and its evaluation determines the implementation of a suitable and feasible therapeutic plan. Objective: The aim of this study was the validation of the Care Dependency Scale for Rehabilitation (CDS-R), which makes it possible to evaluate, besides physical aspects, the psycho-social aspects, in particular the adjustment of the person to sickness situation. Methodology: The translation and cultural adjustment of the CDS-R to the Portuguese language were carried out according to the guidelines of Beaton, Bombardier, Guillemin, and Ferraz (2000), in 2015. The CDS-R validation for the Portuguese language was carried out according to the guidelines of Vilelas (2009) and conception of Pestana and Gageiro (2005). Results: The CDS-R is a valid and reliable instrument, with the total Cronbach alpha value obtained of 0.971, which allows nurses specialist in rehabilitation to evaluate the degree of independence and autonomy of the person in health transition processes. Conclusion: From the values obtained, it is considered that the CDS-R is validated for the Portuguese population

Stroke represents the second leading cause of mortality and morbidity worldwide. Ischemic strokes are the most prevalent type of stroke, and they are characterized by a series of pathological events prompted by an arterial occlusion that leads to a heterogeneous pathophysiological response through different hemodynamic phases, namely the hyperacute, acute, subacute, and chronic phases. Stroke treatment is highly reliant on recanalization therapies, which are limited to only a subset of patients due to their narrow therapeutic window; hence, there is a huge need for new stroke treatments. Nonetheless, the vast majority of promising treatments are not effective in the clinical setting due to their inability to cross the blood-brain barrier and reach the brain. In this context, nanotechnology-based approaches such as nanoparticle drug delivery emerge as the most promising option. In this review, we will discuss the current status of nanotechnology in the setting of stroke, focusing on the diverse available nanoparticle approaches targeted to the different pathological and physiological repair mechanisms involved in each of the stroke phases. info:eu-repo/semantics/publishedVersion

At a local scale, kaolin particle-film technology is considered a short-term adaptation strategy to mitigate the adverse effects of global warming on viticulture. This study aims to evaluate kaolin application effects on photochemistry and related defence responses of Touriga Franca (TF) and Touriga Nacional (TN) grapevines planted at two Portuguese winegrowing regions (Douro and Alentejo) over two summer seasons (2017 and 2018). For this purpose, chlorophyll a fluorescence transient analysis, leaf temperature, foliar metabolites, and the expression of genes related to heat stress (VvHSP70) and stress tolerance (VvWRKY18) were analysed. Kaolin application had an inhibitory effect on VvHSP70 expression, reinforcing its protective role against heat stress. However, VvWRKY18 gene expression and foliar metabolites accumulation revealed lower gene expression in TN-treated leaves and higher in TF at Alentejo, while lipid peroxidation levels decreased in both treated varieties and regions. The positive kaolin effect on the performance index parameter (PIABS) increased at ripening, mainly in TN, suggesting that stress responses can differ among varieties, depending on the initial acclimation to kaolin treatment. Moreover, changes on chlorophyll fluorescence transient analysis were more pronounced at the Douro site in 2017, indicating higher stress severity and impacts at this site, which boosted kaolin efficiency in alleviating summer stress. Under applied contexts, kaolin application can be considered a promising practice to minimise summer stress impacts in grapevines grown in Mediterranean-like climate regions.

IntroductionIschaemic stroke is the most prevalent type of stroke and is characterised by a myriad of pathological events triggered by a vascular arterial occlusion. Disruption of the blood-brain barrier (BBB) is a key pathological event that may lead to fatal outcomes. However, it seems to follow a multiphasic pattern that has been associated with distinct biological substrates and possibly contrasting outcomes. Addressing the BBB permeability (BBBP) along the different phases of stroke through imaging techniques could lead to a better understanding of the disease, improved patient selection for specific treatments and development of new therapeutic modalities and delivery methods. This systematic review will aim to comprehensively summarise the existing evidence regarding the evolution of the BBBP values during the different phases of an acute ischaemic stroke and correlate this event with the clinical outcome of the patient.Methods and analysisWe will conduct a computerised search on Medline, EMBASE, Cochrane Central Register of Controlled Trials, Scopus and Web of Science. In addition, grey literature and ClinicalTrials.gov will be scanned. We will include randomised controlled trials, cohort, cross-sectional and case-controlled studies on humans that quantitatively assess the BBBP in stroke. Retrieved studies will be independently reviewed by two authors and any discrepancies will be resolved by consensus or with a third reviewer. Reviewers will extract the data and assess the risk of bias of the selected studies. If possible, data will be combined in a quantitative meta-analysis following the guidelines provided by Cochrane Handbook for Systematic Reviews of Interventions. We will assess cumulative evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach.Ethics and disseminationEthical approval is not needed. All data used for this work are publicly available. The result obtained from this work will be published in a peer-reviewed journal and disseminated in relevant conferences.PROSPERO registration numberCRD42019147314.

Kaolin protective effect was assessed in a white grapevine cultivar &lsquo, Cerceal&rsquo, in &lsquo, Alentejo&rsquo, Region (southeast Portugal) where plants face extreme conditions during the summer season. We addressed the hypothesis that kaolin effects lead to several changes in leaves, fruits, and wine characteristics on the primary and secondary metabolism. Results showed that kaolin reduces leaf temperature which provokes an improvement in physiological parameters such as net photosynthesis and water use efficiency. This protection interferes with berry color, leaving them more yellowish, and an increase in phenolic compounds were observed in all fruit tissues (skin, seed, and pulp). Additionally, both berry and wine characteristics were strongly affected, with an increase of tartaric and malic acid and consequently high total acidity, while the sugar concentration decreased 8.9% in berries provoking a low wine alcohol level. Results also showed that kaolin induces high potassium, magnesium, and iron, and low copper and aluminum concentrations. Moreover, the control wine showed higher content of esters related with hostile notes whereas wine from kaolin treated vines presented higher content of esters associated with fruity notes. Overall, the results strengthen the promising nature of kaolin application as a summer stress mitigation strategy protecting grapevine plants and improving fruit quality and creating more balanced wines.

EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFR(T790M) and EGFR(C797S). It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in EGFR(T790M) and EGFR(C797S) tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3–dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor–resistant tumors, with EGFR(T790M) and EGFR(C797S) mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib or osimertinib, respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib-treated patients after disease progression.

In the latest decades, global warming impacts become an emergent issue, and short-term techniques such as kaolin have been proposed to mitigate summer stress effects on Mediterranean viticulture. Nevertheless, the impact of this technology on grape berry composition, particularly on different fractions of whole berry (skin, pulp, and seed) is not yet studied, being these data crucial to the expansion of waste and by-product industry. Thus, the purpose of the present study was to fulfill the identified gap of knowledge by investigating how a pre-veraison kaolin (5% w/v) exogenous application may impact secondary metabolites and antioxidant capacity (ABTS + and DPPH methods) at veraison and maturation, in whole berries and their fractions (skin, pulp, and seed), from seven red varieties (‘Touriga Franca’, ‘Touriga Nacional’, ‘Tinta Francisca’, ‘Vinhao’, ‘Grenache’, ‘Borracal’, and ‘Cornifesto’) under Mediterranean conditions conjugated with global warming. Afterwards, biometric, color and oenological parameters (soluble solids, pH, acidity, and soluble protein) were also quantified in whole berries. Our findings indicate that kaolin increased the berry size (up to 62.2 %) which reduced the skin-to-pulp weight ratio and consequently the anthocyanins contents (reaching − 41.7 %). Additionally, particle film reduced leaf temperature (until – 11.78 %) avoiding thermal stress which seems to decrease the production of proteins in grape berries treated (up to – 27.01 %), indicating a potential reduction of heat shock proteins production. Our results enlighten that it was crucial to analyze the several fractions of grape berries separately, because output resulting from the whole berry might lead to an inaccurate conclusion. In this vein, although often no changes were reported in the whole berry, when analyzing their specific fractions, we found that kaolin enhanced the production of secondary metabolites and antioxidant capacity in the seed (reaching 49,40 and 48.29 %, respectively), leading to a positive influence on berry quality which might be favorable to industrial by-products expansion. The findings also support that kaolin can represent a resilience strategy aiming to improve berry quality under the changing climatic scenario.

Extreme conditions, such as drought, high temperature, and solar irradiance intensity, are major factors limiting growth and productivity of grapevines. In a field experiment, kaolin particle film application on grapevine leaves was examined during two different summer conditions (in 2012 and 2013) with the aim to evaluate benefits of this practice against stressful conditions hindering photochemical processes. We used chlorophyll a fluorescence to investigate attached leaves. Two months after the application, during the hottest midday, the kaolin-treated plants showed by the JIP test significantly higher quantum yield of PSII photochemistry, flux ratios, maximum trapped excitation flux of PSI, absorption flux, electron transport flux, maximum trapped energy flux per cross section, and performance index than plants under control conditions in the warmer year. On the contrary, the treated plants showed a lower initial slope of relative variable fluorescence and a decrease in the absorption and electron transport per cross section. The JIP test showed higher efficiency of PSII in the plants treated with kaolin mainly in 2013 (higher temperature and drought). Our results supported the hypothesis that the accumulation of active PSII reaction centres was associated with decreased susceptibility to photoinhibition in the kaolin-treated plants and with more efficient photochemical quenching. Grapevines in the Douro Region seems to profit from the kaolin application.

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.jplph.2018.02.004., Water scarcity is associated with extreme temperatures and high irradiance, and significantly and increasingly affects grapevine yield and quality. In this context, the foliar application of kaolin, a chemically inert mineral that greatly reflects ultraviolet and infrared radiations, as well as, in part, photosynthetically active radiation, has recently been shown to decrease photoinhibition in mature leaves. Here, the influence of this particle film on grapevine leaf metabolome and carbohydrate metabolism was evaluated. Molecular mechanisms underlying photoassimilate synthesis, metabolism and transport capacity were assessed by targeted transcriptional analyses and enzymatic activity assays. Kaolin application increased sucrose concentration in leaves and sucrose transport/phloem loading capacity, as suggested by the stimulation of the transcription of sucrose transporters VvSUC12 and VvSUC27 in these source organs. While the biosynthesis of sucrose increased, as evidenced by higher sucrose content and sucrose phosphate synthase (SPS) activity in leaves, the concentration of transitory starch before the dark period remained unaltered, despite a higher total amylolytic activity in the leaves of kaolin-treated plants. Metabolomic analysis by GC-TOF-MS showed that the application of kaolin enhanced the amounts of simple sugars, including fructose, maltose, xylulose, xylose, sophorose, ribose and erythrose; sugars-phosphate, like mannose-6-Pi, hexose-6-Pi, glucose-6-Pi, glucose-1-Pi, glycerol--Pi and fructose-6-Pi; polyols, like xylitol, maltitol, lactitol, glycerol, galactinol and erythritol; organic acids and amino acids., The work was supported by European Union Funds (FEDER/ COMPETE-Operational Competitiveness Programme – INNOVINE – ref. 311775, Enoexcel – Norte – 07-0124-FEDER-000032, and INTERACT – NORTE-01- 0145-FEDER-000017 – Linha VitalityWine – ON 0013), and by Portuguese national funds (FCT-Portuguese Foundation for Science and Technology) under the project UID/AGR/04033/2013. Artur Conde was supported by INTERACT – NORTE-01- 0145-FEDER-000017 – Linha VitalityWine – ON 0013 (BPD/UTAD/INTERACT/VW/218/ 2016). Richard Breia was supported by FCT under the fellowship PD/ BD/113616/2015., info:eu-repo/semantics/publishedVersion

International audience; Foreseen climate change points to shifts in agricultural production patterns worldwide, which may impact ecosystems directly, as well as the economic and cultural contexts of the wine industry. Moreover, the combined effects of environmental threats (light, temperature, and water relations) at different scales are expected to impair natural grapevine mechanisms, decreasing yield and the quality of grapes. Hence, the interaction between several factors, such as climate, terroir features, grapevine stress responses, site-specific spatial-temporal variability, and the management practices applied, which represents and effective challenge for sustainable Mediterranean viticulture, allowed researchers to develop adaptive strategies to cope with environmental stresses. Here, we review the effects of abiotic stresses on Mediterranean-like climate viticulture and the impacts of summer stress on grapevine growth, yield, and quality potential, as well as the subsequent plant responses and the available adaptation strategies for winegrowers and researchers. Our main findings are as follows: (1) environmental stresses can trigger dynamic responses in grapevines, comprising photosynthesis, phenology, hormonal balance, berry composition, and the antioxidant machinery; (2) field research methodologies, laboratory techniques, and precision viticulture are essential tools to evaluate grapevine performance and the potential quality for wine production; and (3) advances in the existing adaptation strategies are vital to maintain sustainability and regional wine identity in a changing climate. Also, these topics suggest that rational and focused management of grapevines may enlighten grapevine summer stress responses and improve the resilience of agro-ecosystems under harsh conditions. Despite the challenge of developing different strategic responses, winegrowers should clearly define their objectives, so applied research can provide rational technical support for the decision making process towards sustainable viticulture.

The exogenous kaolin application in grapevine has shown a great potential as summer stress mitigation strategy because it positively impacts fruit quality as a result of many molecular and biochemical changes. In the present study we wanted to address the hypothesis that the observed improved antioxidant capacity could also result from a more efficient enzymatic antioxidant system response. For that purpose, the enzymatic activity of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APx), glutathione reductase (GR) and glutathione peroxidase (GPx) were measured in kaolin treated plants, and correlated to some biomarkers of oxidative status, including hydrogen peroxide (H2O2), total thiobarbituric acid reactive substances (TBARS) and proline. Also, to assess if kaolin particle film could mediate epigenetic modifications, the levels of DNA methylation (5-methylcytosine) were assessed in leaf tissues through a stereological analysis. Results showed that the activity of the ascorbate-glutathione cycle key enzymes was boosted in kaolin treated plants, which translated into a less oxidative damage in leaf and berry tissues (lower H2O2 levels and lipid peroxidation). Results also showed that the methylation of DNA, which seems to be stimulated by the harsh environmental conditions, was decreased in leaves from kaolin treated plants., “Fundação Maria Rosa” to our team. The postdoctoral fellowships awarded to L.-T. Dinis (SFRH/BPD/84676/2012), A. Luzio (BPD/ INTERACT/VITALITYWINE/184/2016) and G. Pinto (SFRH/BPD/ 101669/2014; CESAM (UID/AMB/50017 − POCI-01-0145-FEDER007638)) are appreciated. We would also like to thank “Quinta do Vallado” for the collaboration and efforts in making the vineyard’s facilities available for the research and particularly to engineers António Pinto and Daniel Gomes and BASF for collaboration., info:eu-repo/semantics/publishedVersion

Tese de mestrado, Psicologia (Secção de Psicologia Clínica e da Saúde, Núcleo de Psicoterapia Cognitiva-Comportamental e Integrativa), Universidade de Lisboa, Faculdade de Psicologia, 2017 Submitted by Biblioteca FPIE-ULisboa (bibliorul@fpie.ulisboa.pt) on 2018-06-06T08:42:07Z No. of bitstreams: 1 ulfpie053011_tm.pdf: 805538 bytes, checksum: 7c909071b2e93dcca57a24025a1a999e (MD5) Made available in DSpace on 2018-06-06T08:42:35Z (GMT). No. of bitstreams: 1 ulfpie053011_tm.pdf: 805538 bytes, checksum: 7c909071b2e93dcca57a24025a1a999e (MD5) Previous issue date: 2017

Heat waves, high light intensities and water deficit are becoming important threats in many important viticultural areas worldwide, so the implementation of efficient and cost-effective mitigation strategies is crucial for the production of premium wines while maintaining productivity. In this context, the foliar application of kaolin, a chemically inert mineral with excellent reflective properties, is being developed and experimented as a strategy to reduce the impact of heat and drought in Douro vineyards (Northern Portugal), already revealing promising results. In the present study we investigated if an improved antioxidant capacity is part of the beneficial effects of kaolin, by studying changes in the enzymatic and nonenzymatic antioxidant system in leaves and berries (cv Touriga Nacional). Results showed that mature grape berries contained higher amounts of total phenols (40%), flavonoids (24%), anthocyanins (32%) and vitamin C (12%) than fruits from control vines, and important changes were also measured in leaves. In parallel, kaolin application improved the antioxidant capacity in berries, which was correlated with the observed increased content in secondary metabolites. Kaolin application also regulated secondary metabolism at the transcriptional level through the increase in the transcript abundance of genes encoding phenylalanine ammonia lyase and chalcone synthase., The study was undertaken under the PTDC/AGR-ALI/110877/2009 financed by 'Fundacao para a Ciencia e a Tecnologia' (FCT, Portugal), by Project ENOEXEL-NORTE-070124-FEDER-000032, financed by the North Portugal Regional Operational Programme (ON.2-0 Novo Norte) under the National Strategic Reference Framework (QREN), through FEDER, as well as by PIDDAC through FCT/MEC and by the European Project INNOVINE (ref. 311775). The postdoctoral fellowship (SFRH/BPD/84676/2012) awarded to the first author is appreciated. This work was also supported by the networking activities within the European project INNOVINE [ref. 311775] and the European COST Action [FA1106 "QualityFruit"]. We would also like to thank "Quinta Do Vallado" for the collaboration and efforts in making the vineyard's facilities available for the research and particularly to Engineer Antonio Pinto., info:eu-repo/semantics/publishedVersion

Tese de mestrado, Psicologia (Secção de Psicologia Clínica e da Saúde - Núcleo de Psicologia Clínica Dinâmica), Universidade de Lisboa, Faculdade de Psicologia, 2014 Submitted by Biblioteca FPIE-ULisboa (bibliorul@fpie.ulisboa.pt) on 2014-12-15T14:22:41Z No. of bitstreams: 1 ulfpie046662_tm.pdf: 801916 bytes, checksum: dcb69e78eedf6a6a39d08ee5ab9b5fc5 (MD5) Made available in DSpace on 2014-12-15T14:23:04Z (GMT). No. of bitstreams: 1 ulfpie046662_tm.pdf: 801916 bytes, checksum: dcb69e78eedf6a6a39d08ee5ab9b5fc5 (MD5) Previous issue date: 2014

Financial markets have been characterized by boom and bust cycles since the 1980s, while the responsibility for managing retirement wealth has increasingly shifted onto individual households at the same time. Policy makers and experts have expressed concern over rising risk exposure among older householders, who appear to be increasingly exposed to the growing financial risks just as they near retirement. We consider household data from the Federal Reserve's Survey of Consumer Finances from 1989 to 2010 to analyze the correlation between age and risk exposure. We test whether older householders' risk exposure has indeed grown over time, whether it has increased more than that of younger householders, whether changes in the demographic composition of older householders have contributed to older households' rising risk exposure, and the degree to which increases in risk exposure can be traced to a growing concentration of household assets held in stocks and housing and to rising householder indebtedness. Our results indicate that risk exposure has grown more for older householders than for younger ones, that demographic changes among older householders have contributed to additional increases in older householders' risk exposure, and that the growth of older householders' risk exposure is driven more by rising risky asset concentration and less by greater indebtedness.

In Mediterranean-like climate areas, field-grown grapevines are typically exposed to severe environmental conditions during the summer season, which can negatively impact the sustainability of viticulture. Despite the short-term mitigation strategies available nowadays to cope with climate change, little is known regarding their effectiveness in different demarcated winegrowing regions with differing climate features. Hence, we applied a kaolin suspension (5 %) to Touriga-Franca (TF) and Touriga-Nacional (TN) grapevine varieties located in two Portuguese demarcated regions (Alentejo and Douro) with different mesoclimates to study its effect on the physiological performance, hormonal balance and ABA-related grapevine leaf gene expression during the 2017 and 2018 growing seasons. Data show that 2017 was warmer than 2018 due to the occurrence of two heatwaves in both locations, highlighting the protective effect of kaolin application under severe environmental conditions. In the first study year, at midday, kaolin enhanced water use efficiency (23 % in Douro and 13 % in Alentejo), carbon assimilation rates (PN; 72 % in Douro and 25 % in Alentejo), and the soluble sugar content of grapevine leaves, while decreasing the accumulation of plant growth regulators (ABA, IAA, and SA) during the ripening stage. The results show an up-regulation of ABA biosynthesis-related genes (VvNCED) in TF treated vines from the Douro vineyard mainly in 2017, suggesting an increased stress response under severe summer conditions. Additionally, kaolin triggered the expression of ABA-responsive genes (VvHVA22a and VvSnRK2.6) mainly in TF, indicating different varietal responses to kaolin application under fluctuating periods of summer stress.

Mutational signatures are the outcomes of mutagenic processes that occur prior to, and during, tumorigenesis as a result of DNA damage, DNA repair, and DNA replication. In this issue of Cell Systems, Wojtowicz et al. introduce a new computational model aimed at deconstructing the mutational processes that shape cancer genomes.

The blood-brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1-3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery. info:eu-repo/semantics/publishedVersion