Characterization of human gene products homologous to fission yeast multi-drug resistance determinants

Novel mechanisms involved in the resistance to cytotoxic agents have been recently described both in fission yeast and in mammalian cells. The work described in this thesis was focused on novel determinants of multi-drug resistance in mammalian cells and their possible mechanism of action. Human Pohl, a highly conserved subunit of the regulatory particle of the 26 S proteasome complex, has been shown to confer moderate resistance to chemotherapeutic drugs and ultraviolet light in mammalian cells by a P-gp-independent mechanism. The mechanism by which HA-Pohl causes drug resistance was investigated. Using constitutive and inducible expression of HA-tagged Pohl in mammalian cells, it was found that most overexpressed Pohl is not associated with the 26S proteasome complex. The cells expressing HA-Pohl exhibited elevated protein levels of the two AP-1 components, c-Jun and c-Fos, associated with an increased stabilisation of c-Jun possibly caused by an interaction between HA-Pohl and c-Jun. Furthermore, HA-Pohl overexpression led to an increase in AP-1 transcriptional and DNA binding activities. As c-Jun and c-Fos are both degraded by the ubiquitin/proteasome pathway, it is proposed that Pohl is able to negatively modulate the ubiquitin-dependent proteolysis of transcription factors with consequent alteration of cellular drug susceptibility. PWPl is member of the WD-40 repeat protein family and is the closest known human relative of the fission yeast pwpl+ multi-drug resistance gene. It is shown here that overexpression of human Pwpl in mammalian cells leads to multi-drug sensitivity possibly via positive modulation of the AP-1 DNA binding and transcriptional activity. Preliminary data obtained using an RNA anti-sense strategy, together with data obtained elsewhere, suggest that human Pwpl might have a role in the regulation of cell growth

FINES Bordering Practices and Natural Features in Livy

FINES. Bordering practices and natural features in Livy Antonio Montesanti, University of Exeter PhD in Classics and Ancient History May 2014 The fullest and most comprehensive unpacking of the term finis has yet to be achieved. Studies have narrowly focussed on the idea of border, boundary or frontier, without even entertaining the prospect of interpreting the study from the ancient point of view. This investigation considers the use of the word finis in Livy and attempts to recreate a conception of finis which mirrors as closely as possible that of a Roman of the Republic up to the very Early Empire. Besides the remarkably high usage of the term by Livy, the author’s work is also useful due to its chronological nature, which allows for broad investigation throughout the Republican Period, as well as shedding light on the Early Imperial concept of finis. The main aim of this dissertation is to provide a collective analysis of diverse cases, which together can help build a complete picture of the detectable features related to the term finis. As well as this, the analysis of the contexts – in which the term finis is used has also cast light on those features of finis – that have remained fixed despite the different historical contexts in which they appear. For example, throughout my study, two fundamental concepts will continue to pop up in front of the reader’s eyes: a) the inapplicability of modern conceptual categories to the idea of finis and b) finis – if translated as border, boundary or frontier – as a concept applicable not to a line, but to a spatial element. On the basis of Livy’s evidence – drawn from his work Ab Urbe Condita – this study attempts to present a reconstruction of the term through the identification of an entirely new concept. This study is conceived in terms of a crescendo, which begins with the basic definitions attached to finis and evolves, adding an increasing number of evidences until it reaches a climax, whereby the reader can see both those invariable features of finis in Livy’s account and the 4 Introduction: Research guidelines evolution of the term as fines are applied within different political contexts. Rome – a city that rose on a finis, the Tiber River – reinvented or remodelled the concept of finis, demonstrating behaviour antithetical to the notion of confining herself behind a ‘single line’. Once identified as a finis, the natural features helped the Romans to exert their imperium, which was itself an embodiment of the features contained within the concept of finis. The establishment of the fines provided an ‘imaginary’ subdivision of the territory subjected to the Roman imperium in a series of land strips. This is documented by Livy through Rome’s expansionist ‘finis-system’, from a single occupation of the Janiculum Hill to the scientific approach and setting of the treaty of Apamea. Although the lacunae in Ab Urbe Condita – from 168 B.C. onwards – do not permit a direct connection between the Late Republic and the Early Empire, some elements can be used to evidence an intimate relationship between Livy’s and Augustus’ thinking and terminology. To some extent, this common intent has made possible this attempted reconstruction of the ‘bordering practices’ used in the last 150 years of the Republic, as well as the possible evolution of such practices in the first 150 about years of the Empire

Electric solar wind sail applications overview

We analyse the potential of the electric solar wind sail for solar system space missions. Applications studied include fly-by missions to terrestrial planets (Venus, Mars and Phobos, Mercury) and asteroids, missions based on non-Keplerian orbits (orbits that can be maintained only by applying continuous propulsive force), one-way boosting to outer solar system, off-Lagrange point space weather forecasting and low-cost impactor probes for added science value to other missions. We also discuss the generic idea of data clippers (returning large volumes of high resolution scientific data from distant targets packed in memory chips) and possible exploitation of asteroid resources. Possible orbits were estimated by orbit calculations assuming circular and coplanar orbits for planets. Some particular challenge areas requiring further research work and related to some more ambitious mission scenarios are also identified and discussed.Comment: 18 pages, 3 figures, accepted for publication in ESTCube-1 special issue of Proceedings of the Estonian Academy of Science

Usefulness of movement time in the assessment of Parkinson’s disease

Abstract Reaction time (RT) and movement time (MT) are reported to be delayed in Parkinson's disease (PD), but their clinical utility and relationship with clinical findings is still uncertain. We investigated RT and MT in 22 PD patients at baseline conditions and following acute oral trials of levodopa and biperiden, an anticholinergic drug. At baseline conditions, RT and MT of PD patients were abnormally delayed compared with those of 16 normal control subjects. Both RT and MT were longer in more severely affected patients compared with the mild PD patients; in the mild PD patients with asymmetrical signs both responses were longer on the more affected side. Bradykinesia was the clinical symptom that best correlated with the objective measurements, with a stronger correlation for MT than for RT. The oral administration of levodopa significantly improved both the responses, whereas biperiden was ineffective. The magnitude of RT and MT improvement after levodopa differed; MT improvement was related to PD severity, whereas RT improvement was not. These results suggest that MT, rather than RT, is an objective, simple, and reliable tool to evaluate bradykinesia and its levodopa-induced modifications in PD

Avaliação do ciclo de vida de embalagens de entrega de comida no Brasil

Em 2020, devido a crise sanitária, os restaurantes e a população se viram obrigados a desistir do atendimento presencial e se voltar para o delivery de alimentos. Esse mercado, que já estava em plena expansão, atingiu novos patamares com uma evolução de 27% no ano. Entretanto, esse crescimento se traduz no aumento do consumo de embalagens de uso único, sendo estas, usualmente de material plástico. Os plásticos convencionais são produzidos a partir de matérias-primas provenientes do petróleo, um recurso natural não renovável. No contexto atual de preocupação crescente com os impactos ambientais gerados, os biopolímeros são cada vez mais uma opção de substituição dos plásticos. Estes materiais são produzidos a partir de biomassa, uma matéria-prima renovável e, quando descartados em condições que favorecem o seu processo de decomposição, integram-se mais rapidamente à natureza do que os plásticos convencionais. No que se refere a estudos científicos de embalagens, uma das alternativas mais recentes no setor são os biopolímeros fabricados a partir do bagaço da canade- açúcar, espécie vegetal largamente cultivada e explorada em todo o Brasil. Com a introdução de novos produtos no mercado, torna-se relevante uma análise comparativa dos ciclos de vida, de maneira a evidenciar os impactos ambientais gerados em cada cadeia, possibilitando a escolha de um produto mais sustentável. Este estudo se propõe a realizar uma análise comparativa dos ciclos de vida de embalagens de delivery produzidas a partir de dois materiais distintos: o plástico polipropileno e o biopolímero de bagaço de cana-de-açúcar. Para realização da modelagem, foram utilizados o software OpenLCA e a base de dados Ecoinvent 2019. Inicialmente, foi definido como unidade funcional uma embalagem no formato de uma caixa de proporções 4 x 12 x 8 cm, o que corresponde a 15,8g de PP e 14,1g de biopolímero de bagaço. Em seguida, foram mapeados os fluxogramas de cada produto para auxiliar a etapa seguinte, de adaptação dos processos equivalentes da base utilizada. A modelagem levou em consideração uma produção totalmente nacional e com matriz energética 100% brasileira. Devido a esta premissa, os fluxos de locomoção e transporte foram considerados irrelevantes, pois seriam similares para ambos os produtos. Além disso, o processo de reciclagem de polipropileno não foi incluído no estudo, uma vez que o material reciclado ainda não é autorizado para contato com alimentos e, portanto, não seria reinserido na cadeia. O cenário brasileiro de descarte de resíduos sólidos foi retratado para ambos os materiais. Entretanto, um terceiro cenário foi analisado, considerando a política de descarte de resíduos orgânicos observada na Austrália com altas taxas em compostagem (58%). Finalmente, os resultados encontrados evidenciaram a embalagem de bagaço como material mais sustentável em 11 dos 12 impactos ambientais analisados, sendo a exceção apenas o consumo de água (19% superior para embalagens de bagaço). Todavia, os aspectos referentes a mudanças climáticas chamam atenção: a embalagem de bagaço, no cenário brasileiro de descarte, onde há priorização de aterros sanitários, apresenta uma pegada próxima a do PP, sendo apenas 7% inferior. Por outro lado, quando o cenário de descarte é alterado para o australiano, onde há priorização da compostagem, a embalagem de bagaço apresenta larga vantagem, sendo esta 44% inferior ao impacto gerado pelo PP. Portanto, evidencia-se a importância de políticas públicas adequadas para os resíduos orgânicos e a conscientização da população para suporte dessas políticas através de triagens do lixo domiciliar produzido

Health indicators in Brazil and Spain: strategies for health promoting universities

Aims: The study aims to identify and compare health indicators collected by national research in Spain and in Brazil that can generate action strategies for health promoting universities. Methods: This is an epidemiological, descriptive, cross-sectional study that uses the database of the Secretariat of Health Surveillance of the Brazilian Ministry of Health and the database of the National Statistics Institute of Spain. Based on the National Health Promotion Policy, the analyzer axis prioritizes defined themes; percentage of physical exercise, daily smokers, sedentary lifestyle, obesity and self-perception of health status were evaluated. The data were collected from 2014 to 2020. Results: In Brazil, physical exercise is the highest percentage indicator, whereas in Spain, sedentary lifestyle is the highest. Regarding the age group, Brazil presented the lowest prevalence of daily smokers in the age group from 18 to 24, with little increase in older age groups; in Spain, older age groups presented the highest rates of sedentary lifestyle and obesity. In 2020, 4.5% of Brazilians reported a negative self-perception of health and in Spain 6.6%. Conclusion: The indicators ‘physical exercise’, ‘daily smokers’ and ‘sedentary lifestyle’ presented better results in Brazil than in Spain. Brazil presents a better perspective on health when compared with Spain, as the results showed that older ages present higher rates of sedentary lifestyle and obesity. Our study results also show that Brazilians report better self-perception in health, which can be interpreted by health promotion strategies.This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES [001]

Impaired Flow-Mediated Dilation and Risk of Restenosis in Patients Undergoing Coronary Stent Implantation

Background— Impaired endothelial function is a key event in the atherosclerosis process and predicts future cardiovascular events in subjects with and without coronary artery disease (CAD). We performed the first prospective study evaluating whether early measurement of brachial artery endothelium-dependent dilation (flow-mediated dilation [FMD]) after coronary stenting could predict occurrence of in-stent-restenosis. Methods and Results— The study population included 136 patients with single-vessel CAD undergoing percutaneous coronary intervention (PCI) with stenting and at least 6 months of follow-up. All patients underwent ultrasound detection of brachial artery reactivity 30 days after PCI; FMD was investigated before and after 5 minutes of occlusion of the brachial artery, and nitroglycerin-mediated dilation was investigated before and after administration of sublingual nitrates. Clinical in-stent restenosis was demonstrated in 20 patients (15%), whereas 116 patients (85%) remained free of signs or symptoms of recurrent ischemia. FMD was significantly impaired in patients with restenosis versus those without restenosis (percent diameter variation 4.6±5.8% versus 9.5±6.6%, P =0.002); moreover, 4% of patients with FMD ≥7% (median value) developed in-stent restenosis versus 28% of those with FMD <7% ( P =0.0001). On multivariate analysis, FMD was the strongest predictor of restenosis (OR 4.5, 95% CI 2.4 to 12.0); conversely, nitroglycerin-mediated dilation did not independently predict the risk of restenosis (OR 2.4, 95% CI 0.8 to 6.3). Conclusions— This is the first prospective study indicating that impaired FMD independently predicts occurrence of in-stent restenosis in patients undergoing PCI. Early evaluation of endothelial function after stenting may represent a useful screening tool to stratify patients according to future risk of restenosis

O PROGRAMA DE SAÚDE DA FAMÍLIA SOB OLHAR DA EQUIPE MULTIDISCIPLINAR

Esse trabalho tem como objetivo retratar a preocupação dos profissionais que atuam em PSF sobre o impacto de suas estratégias no processo de trabalho. A metodologia utilizada foi a pesquisa exploratória descritiva onde se utilizou como instrumento de coleta de dados um questionário semi-estruturado o qual foi respondido por 40 profissionais que atuam em PSF, em diversas Unidades Básicas de Saúde (UBS) da região metropolitana de Curitiba, no mês de junho de 2003. Após análise e discussão dos dados pudemos observar que os profissionais de saúde relatam que o PSF possui pontos positivos, negativos e significado de atuar no PSF. Dentre os pontos positivos citam: relacionamento estabelecido, conhecendo o território, qualidade do atendimento, satisfação, resultados apresentados em relação a prevenção e promoção da saúde e interação. Como pontos negativos referem: a falta de recursos, excesso de funções, baixa qualificação profissional, falta de entrosamento da equipe, falta de consciência e conhecimento do programa por parte da população, insatisfação da população, riscos enfrentados, aspectos políticos e sistema de referência. Estas categorias nos levaram à categoria central: O PSF SOB OLHAR DA EQUIPE MULTIDISCIPLINAR. Concluímos que o PSF é uma estratégia capaz de melhorar a qualidade de vida da população, mas que para isso aconteça, há necessidade de melhor gerenciamento de políticas locais, aumento de recursos financeiros e humanos, além de melhor capacitação profissional

PROPORÇÃO DE BACTÉRIAS MULTIRRESISTENTES DE UM HOSPITAL PÚBLICO SUL-BRASILEIRO

Introdução: O conhecimento da epidemiologia de bactérias em instituições hospitalares é de fundamental importância para guiar o tratamento empírico das infecções relacionadas aos cuidados de saúde. Objetivos: Analisar o perfil de sensibilidade das culturas realizadas em diferentes sítios dos principais patógenos multirresistentes no Hospital de Clínicas-UFPR, Curitiba, Brasil. Metodologia: Os dados foram analisados a partir da planilha de culturas do Serviço de Controle de Infecção Hospitalar (SCIH) do Hospital de Clínicas. Resultados: Foram analisadas 2312 amostras. Das 304 amostras de S. aureus, MRSA representou 18,4%. Dos isolados de Enterococcus sp, 48,1% eram VRE, em sua maioria representado pelo E. faecium. Porém a proporção de VRE em hemoculturas foi de 9,5%. De 731 amostras de Enterobactérias, 41% eram resistentes ao cefepima. Klebsiella pneumoniae foi a que apresentou maior proporção de cepas resistentes ao cefepima (65,9%) entre as Enterobactérias. As amostras de Acinetobacter baumannii apresentaram altas taxas de resistência à ampicilina-sulbactam (89,2%) e aos carbapenêmicos (90,3%). Dos antimicrobianos avaliados, o que apresentou melhor cobertura para os isolados de Pseudomonas aeruginosa foi a ceftazidima (79,2%). Conclusão: A proporção de MRSA foi menor do que a de outros hospitais brasileiros. A alta prevalência de Enterobactérias e de gram negativos não fermentadores de glicose resistentes confirmam a tendência nacional e latino-americana, com proporções maiores que a de hospitais norte americanos e europeus.Introduction: It is important to know the local prevalence of multidrug resistance bacterias in hospital environment in order to adequate empirical choice of antimicrobial therapy. Objectives: Describe antimicrobial activity to more frequent isolates from different sites of cultures in a tertiary hospital (Hospital de Clinicas – UFPR, Curitiba, Brazil). Methods: Information was analyzed from the culture data, provided by Service of Infection Control (SCIH) at Hospital de Clínicas. Results: A total of 2312 samples were analyzed. Of the 304 samples of S. aureus, MRSA accounted for 18.4%. Of Enterococcus sp, 48.1% were VRE, mostly represented by E. faecium. In contrast, the proportion of VRE in blood cultures was only 9.5%. Of the 731 cultures of Enterobacteriaceae, 41% were resistant to cefepima. Klebsiella pneumoniae showed the highest proportion of strains resistant to cefepime (65.9%) among the Enterobacteriaceae. Samples of Acinetobacter baumannii showed high levels of resistance to ampicillin-sulbactam (89.2%) and carbapenems (90.3%). Ceftazidime showed the better coverage (79,2%) between the antibiotic analyzed for isolates of Pseudomonas aeruginosa (79.2%). Conclusions: The proportion of MRSA was lower than that of other Brazilian hospitals. The high prevalence of resistant Enterobacteriaceae and gram-negative non-fermenting glucose confirm the national and Latin America trend, with the largest proportions than North American and European hospitals.

Disrupting Trajectories Leading to Domestic Violence

Research into male-on-female domestic violence traditionally focuses on its after-effects, with an emphasis on how victims can keep themselves safe or on the men who have been criminally charged in such incidents. This approach puts the responsibility on the victim to try and protect herself while offering support to the perpetrator only after the violence has occurred to prevent recidivism. This policy brief takes a different approach to understanding points of intervention that might prevent domestic violence from occurring in the first place. Using a robust 10-year dataset supplied by Calgary Police Service, the authors explored a trajectory of criminal behaviour and police interactions prior to an eventual charge for a criminal act involving domestic violence in 2019. While preliminary, the data analysis reported in this brief finds a distinct trajectory of increased criminal behaviour among male perpetrators leading up to a charge in 2019. In fact, the data shows a rising number of police interventions related to complaints involving possible acts of domestic violence during that 10-year period. Very few men in this sample were unknown to police prior to the charge in 2019. Domestic violence frequently makes headlines, and when femicide is committed, it is often accompanied by announcements of public vigils to be held for the victimized woman along with demands for an end to intimate partner violence. But rarely is the question raised, why do men continue to be the major perpetrators of this terrible violent act? And if there is always a passion and commitment to provide support to victims, where is the same passion and commitment to developing policies and strategies to work with men at risk of perpetrating violence and before they commit the offence of domestic violence? The approach of examining male perpetration trajectories analyzed in this policy brief, can help inform legislation, policies, and programs that can not only stop male violence before it starts, but subsequently reduce the suffering of women and their families