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Abstract Aims Immune checkpoint inhibitors (ICIs) are antineoplastic drugs designed to activate the immune system's response against cancer cells. Evidence suggests that they may lead to immune‐related adverse events, particularly when combined (e.g., anti‐CTLA‐4 plus anti‐PD‐1), sometimes resulting in severe conditions such as myocarditis. We aimed to investigate whether a previously sustained cardiac injury, such as pathological remodelling due to hypertension, is a prerequisite for ICI therapy‐induced myocarditis. Methods We evaluated the cardiotoxicity of ICIs in a hypertension (HTN) mouse model (C57BL/6). Weekly doses were administered up to day 21 after the first administration. Our analysis encompassed the following parameters: (i) survival and cardiac pathological remodelling, (ii) cardiac function assessed using pressure‐volume (PV)‐loops, with brain natriuretic peptide (BNP) serving as a marker of haemodynamic dysfunction and (iii) cardiac inflammation (cytokine levels, infiltration, and cardiac antigen autoantibodies). Results After the first administration of ICI combined therapy, the treated HTN group showed a 30% increased mortality (P = 0.0002) and earlier signs of hypertrophy and pathological remodelling compared with the untreated HTN group. BNP (P = 0.01) and TNF‐α (3), characterised by T cell infiltration and increased cardiac antigen antibodies (86% showed a titre of 1:160). The control group treated with ICI was unaffected in any evaluated feature. Conclusions Our findings indicate that pre‐existing sustained cardiac damage is a necessary condition for ICI‐induced myocarditis.

Abstract: Assai (Euterpe oleracea Mart.) cultivars BRS-Pará (BRS-PA) and BRS-Pai d’Égua (BRS-PDE) were selected for cultivation in upland regions of the Amazon. Given these cultivars were developed from different progenitors, we postulated that they differ regarding water-deficit tolerance. To test this hypothesis, plants of both cultivars were evaluated under well-watered (control) and water-deficit conditions (pre-dawn leaf water potential of – 2.33 MPa). Relative to control, the water-deficit decreased net CO2 assimilation rate (A) and transpiration by 82% and 86% in both cultivars, while the stomatal conductance (gs) was reduced by 93% and 87% in stressed plants of BRS-PDE and BRS-PA. The water-deficit improved instantaneous water-use efficiency by 43% in both cultivars, while intrinsic water-use efficiency (A/gs) increased by 193% and 33% in BRS-PDE and BRS-PA. The water-deficit induced 44% increase in foliar proline and 27% decrease in soluble carbohydrates in both cultivars, while foliar sucrose decreased by 53% in BRS-PA and 16% in BRS-PDE in relation to control. The relative water content in stressed plants of both cultivars was decreased by 8.5% in relation to control. In conclusion, the more efficient stomatal opening control and higher A/gs in BRS-PDE indicate this cultivar better copes with drought than BRS-PA.

Abstract The H9c2 myoblast cell line, isolated from the left ventricular tissue of rat, is currently used in vitro as a mimetic for skeletal and cardiac muscle due to its biochemical, morphological, and electrical/hormonal signaling properties. During culture, H9c2 cells acquire a myotube phenotype, where a critical component is the inclusion of retinoic acid (RA). The results from some authors on H9c2 suggested that thousands of genes respond to RA stimuli, while others report hundreds of genes responding to RA over different cell types. In this article, using a more appropriate experimental design, we first confirm the H9c2 cardiac phenotype with and without RA and report transcriptomic and physiological changes regarding calcium handling, bioenergetics, and other biological concepts. Interestingly, of the 2360 genes showing a transcriptional change, 622 genes were statistically associated with the RA response. Of these genes, only 305 were RA-specific, and the rest also showed a culture-time component. Thus, the major expression changes (from 74 to 87%) were indeed due to culture conditions over time. Unexpectedly, only a few components of the retinol pathway in KEGG responded to RA. Our results show the role of RA in the H9c2 cultures impacting the interpretation using H9c2 as an in vitro model.

Human foreskin fibroblasts are directly reprogrammed into insulin-producing cells using 5 pancreatic transcription factors, without pluripotency induction.

In tokamak and other fusion devices, magnetic control is the main tool that allows to regulate the plasma current, position and shape; it is in charge of actuating the desired plasma current waveform, steering the plasma position to a given set point and maintain the plasma shape close to a prescribed plasma equilibrium. This work describes the application of several physics concepts and computational tools in order to obtain a novel optimal controller for the plasma centroid position, which has been implemented and tested in the real-time plasma control system at the ISTTOK tokamak. A key point for the development of the new control system was the installation of a recently upgraded hardware, that numerically integrates in real-time the magnetic probes signals.

Leprosy is a chronic disease and also a global health issue, with a high number of new cases per year. Toll-like receptors can respond to mycobacterial molecules in the early stage of infection. As important components of the innate immune response, alterations in genes coding for these receptors may contribute to susceptibility/protection against diseases. In this context, we used a case-control study model (183 leprosy cases vs. 185 controls) to investigate whether leprosy patients and the control group, in southern Brazil, have different frequencies in TLR1 (TLR1 G>T; rs5743618), TLR2 (TLR2 T>C, rs1816702 and rs4696483), and TLR4 (TLR4 A>G, rs1927911) polymorphisms. Analysis of the TLR1 1805G>T polymorphism presented the G/G genotype more frequently in the control group. TLR2 T>C rs1816702 and TLR2 T>C rs4696483, the T/T and C/T genotype, respectively, were more frequent in the control group than in leprosy patients, suggesting protection from leprosy when the T allele is present (rs4696483). Haplotype analyses between TLR1 (rs5743618) and TLR2 (rs1816702 and rs4696483) polymorphisms suggest risk for the presence of the TCC haplotype and protection in the presence of the TCT haplotype. This study suggests that polymorphisms in TLR1 and TLR2 are factors that may contribute to development/resistance of leprosy.

Propósito – Apresentar uma proposta sistemática de regulamentar a dosimetria das penalidades e os valores de multas aplicadas por entidades reguladoras. Metodologia/abordagem/design – A técnica foi desenvolvida por meio de três abordagens teórico-metodológicas: a primeira se versa sobre o direito penal, na busca pela adequação do tradicional sistema trifásico à realidade dos reguladores; a segunda adentra no viés do direito administrativo sancionador; e a terceira se baseia na teoria econômica do direito, o qual visa o bem-estar social. Resultados – A técnica permitiu a sistematização das atividades regulatórias coercitivas e sancionatórias, bem como se apresentou como uma importante ferramenta para fundamentar a dosimetria das penas. Implicações práticas – O método foi testado, e se apresentou adequado para os serviços de transporte rodoviário interestadual semiurbano de passageiros, os quais estão sob responsabilidade da Agência Nacional de Transportes Terrestres (ANTT). Por sua vez, destaca-se que a técnica pode ser adaptada a qualquer matéria regulatória que contemple penalidades e/ou multas. Originalidade/relevância do texto – O trabalho é relevante para auxiliar os agentes públicos atuantes em agências reguladoras ou em áreas afins, quando da elaboração ou edição de normativos coercitivos e sancionadores.

A pesquisa aplicada em Geomorfologia envolve coleta e análise de dados e se insere no planejamento, manejo e decisão sobre ocupação, produção, recreação e conservação. Nesse sentido, o uso de geotecnologias no estudo da erosão tem crescido e é preciso conhecer sua capacidade de contribuição. Por isso, o objetivo deste artigo é apresentar potenciais metodológicos e analíticos que o uso de Laser Scanner Terrestre (LST) possui, combinado ao imageamento por VANT, para monitorar e diagnosticar a erosão por voçorocas. As técnicas foram utilizadas de maneira experimental, trazendo um debate das relações metodológicas possíveis, explicitando prós e contras de cada uma. Ambas oferecem variadas possibilidades analíticas. No presente trabalho, as características de cada equipamento revelaram resultados quantitativos, pelo uso do LST, e qualitativos, com o VANT. Nota-se a complementaridade entre as duas técnicas, contribuindo para os estudos sobre erosão linear. As imagens aéreas geradas pelo VANT permitiram verificar caminhos preferenciais e variação de acúmulo de material erodido, além de servir ao processamento de dados do LST. A partir da nuvem de pontos deste, foram calculados 2.240,34 m² de área da voçoroca, ou 0,22ha, e 20,34 m³ de volume de solo erodido. Pelos dados e cálculos obtidos, foi estimada uma taxa erosiva de 8,65 t·ha-1·ano para um período mínimo de atividade erosiva de 17 anos. O uso destas geotecnologias segue desafiador na Geomorfologia, principalmente na erosão por voçorocas. Sua tarefa é ampliar a compreensão dos processos, as variações de escala e desenvolver novas pesquisas, com maior detalhe e precisão, na busca por ações de controle mais eficazes.

A afirmação propalada na mídia de que as secas da Região Sudeste estão sendo causadas pelo desmatamento da Amazônia não tem base científica e não sobrevive a uma análise de dados climáticos. A estiagem pela qual o Sudeste passou em 2013 e 2014 - e que causou grandes transtornos sociais notadamente pela falta de água para consumo humano especialmente nas grandes cidades - é decorrente da variabilidade natural do clima e já ocorreu, até com intensidade maior, no passado, notadamente nas décadas de 1930 e 1960, quando o desmatamento da Amazônia era incipiente. A umidade para as chuvas do Sudeste não é produzida na Amazônia. Ela vem do Atlântico Tropical, apenas passa sobre a Amazônia e interage com a floresta. A partir de uma caixa virtual inscrita entre 0º e 12,5ºS, 45ºW e 75ºW, calculou-se a divergência do fluxo de umidade no período 1999 a 2014 utilizando o conjunto de dados de Reanálises disponíveis no ESRL/PDS/ NOAA. Os resultados indicam que os anos de 2013 e 2014 apresentaram os maiores valores de fluxo de umidade média anual exportado para região Sul/Sudeste, 2014[3,45x108 kg/s] e 2013[3,08x108 kg/s] respectivamente, durante o período estudado. Este estudo, portanto, demonstra que não houve falta de umidade atmosférica sobre o Sudeste. E, ainda, as análises dos campos de velocidade vertical Ômega e ROLE observados no verão austral mostram a permanência de um sistema de alta pressão atmosférica sobre a Região que produziu intensa estabilidade atmosférica particularmente em 2014. Apesar do forte aquecimento continental nessa estação do ano, esse sistema de alta pressão foi o responsável pela seca severa, pois inibiu a formação de nuvens e o desenvolvimento de nuvens de tempestades e, simultaneamente, bloqueou a entrada dos sistemas frontais vindos do sul do Continente Sul-Americano, que é um mecanismo fundamental na produção do total pluviométrico regional durante o verão austral. Conclui-se que a estiagem na Região Sudeste nos anos de 2013-2014 não foi provocada pela falta de umidade atmosférica e sim pela falta de um mecanismo dinâmico capaz de converter em chuva a umidade proveniente do Atlântico Tropical.

The growing number of users of these passenger terminals indicates that the quality of services should be improved through the expansion of their capacity or by process rationalization. This article aims to contribute to the improvement of the vehicle access process at Uberlândia’s airport using the Discrete Event Simulation and Queue Theory. During the analysis, three scenarios that can improve the subsystem were identified, two of which were more advantageous: one for the short-term and another for the medium term, through the establishment of an access route.

Interstate bus services in Brazil can occur between nearby or distant municipalities. In the former situation the bus service should be classified as ‘semi-urban’; it is delegated by Federal concession that requires a bidding process and must be provided by urban buses. In the latter situation the bus service should be classified as ‘road’; it is directly authorized by the public authority and must be provided by coaches. Brazilian law distinguishes between ‘nearby’ and ‘distant’ cities when the service occurs with ‘urban’ or ‘regional’ characteristics, but does not specify parameters for that distinction. This paper presents a multi-criteria method used to better classify and regulate those bus transport services. The method was applied to categorize 11 interstate markets of which 4 were considered to be ‘semi-urban’. In conclusion, the study served as a basis to support a government decision.

This work presents the “Realistic Dynamics Of Simulated Operations” (DROpS), the name given to the dynamics using the “dropper” device as an object of teaching and learning. The objective is to present alternatives for professors teaching content related to simulation of discrete events to graduate students in production engineering. The aim is to enable students to develop skills related to data collection, modeling, statistical analysis, and interpretation of results. This dynamic has been developed and applied to the students by placing them in a situation analogous to a real industry, where various concepts related to computer simulation were discussed, allowing the students to put these concepts into practice in an interactive manner, thus facilitating learning

OBJECTIVE: compare blood loss in 40 patients underwent to unilateral total knee replacement with the release of ischemia before and after skin closure and compressive dressing. METHODS: in a prospective randomized study, in 40 patients underwent to total knee replacement, dividing then into two groups: group A in which the ischemia was released before skin closure, allowing bleeding control and group B where the ischemia was released after skin suture and pressure dressing. We compared the results of laboratory tests of serum hemoglobin before surgery and 48 hours postoperatively, the blood volume contained in vacuum suction drain and the transfusions that was necessary. RESULTS: As a result, the post operative serum hemoglobin levels had a mean decrease of 3.57 g/dL in group A and 4.24 g/dL in group B with an average of 0.67g/dL difference between them, statistically insignificant.The observed mean drainage, in the vacuum drain, were 705 mL in group A and 700 mL in group B. The 5ml difference between medians was considered statistically insignificant. The number of patients who received transfusions was four patients in both groups and all received two units of red blood cells. CONCLUSION: the post operative serum hemoglobin levels, as well as the need of blood transfusion, in the patient underwent to total knee replacement, where the ischemia was released before wound closure, has no statistical effect in comparison with patients where the sutures and bandages were done after the ischemia release. Level of Evidence IB - Individual randomized controlled trial with narrow confidence interval. OBJETIVO: Avaliar comparativamente a perda sanguínea em pacientes submetidos à artroplastia total do joelho, com liberação da isquemia antes e após suturas e curativo compressivo. MÉTODOS: Fez-se um estudo prospectivo randomizado em 40 pacientes submetidos à artroplastia total do joelho divididos em dois grupos. No primeiro grupo a isquemia foi liberada antes do fechamento da ferida operatória, o que permitiu o controle do sangramento. No segundo a isquemia foi liberada após suturas e curativo compressivo. Foram comparados os resultados dos níveis de hemoglobina sérica antes da cirurgia e em 48 horas do pós-operatório, o volume sanguíneo contido no dreno de sucção a vácuo nesse período e a quantidade de transfusões de sangue que foram necessárias. RESULTADOS: Os níveis de hemoglobina pós-operatória tiveram uma diminuição média de 3,57g∕dL no grupo A e de 4,24g∕dL no grupo B, consideradas estatisticamente insignificantes (p = 0,23). Quatro pacientes nos dois grupos receberam duas unidades de concentrado de hemácias, sendo a diferença entre as médias drenado foram considerados estatisticamente insignificantes, para os grupos estudados. CONCLUSÃO: A concentração de hemoglobina sérica pós-operatória, bem como a necessidade de hemoderivados, nos pacientes submetidos à artroplastia total do joelho, na qual a liberação da isquemia foi deflagrada antes do fechamento da ferida operatória, não tem significância estatística quando comparada com a dos pacientes em que essa liberação foi feita após suturas e cultivado. Nivel de evidencia IB - Ensaio clínico controlado e rendomizado com intervalo de confiança estreito.

O objetivo deste trabalho foi avaliar a capacidade de plantas jovens de mogno-africano (Khaya ivorensis) em recuperar seu status hídrico e trocas gasosas após período de deficit hídrico. Plantas com aproximadamente 315 dias, irrigadas (controle) e não irrigadas, foram avaliadas aos 14 dias da suspensão da irrigação e após um, três e sete dias da retomada da irrigação (reidratação). No dia 14, o potencial hídrico foliar de antemanhã (Ψam) das plantas estressadas foi reduzido a -2,66 MPa. Com a restrição hídrica, foram observadas reduções significativas no conteúdo relativo de água na antemanhã (redução de 32%), na taxa de assimilação líquida de CO2 (90%), na condutância estomática (95%), na transpiração (93%) e na razão entre concentração intercelular e ambiental de CO2 (37%). Durante a reidratação, o status hídrico das plantas estressadas foi restabelecido após três dias. As trocas gasosas também se restabeleceram, mas de forma mais lenta que o status hídrico. Sob deficit hídrico, a concentração de prolina aumentou e a de carboidratos solúveis totais diminuiu. Plantas jovens de mogno-africano são tolerantes ao deficit hídrico moderado.The objective of this work was to evaluate the capacity of young plants of African mahogany (Khaya ivorensis) to recover their water status and gas exchange after water deficit. Plants with approximately 315 days, irrigated (control) and non-irrigated, were evaluated after water was withheld for 14 days, and after one, three, and seven days of irrigation resumption (rehydration). On day 14, the predawn leaf water potential (Ψam) of stressed plants was reduced to -2.66 MPa. With water deficit, significant decreases were observed in predawn relative water content (32% reduction), in net assimilation rate of CO2 (90%), in stomatal conductance (95%), in transpiration (93%), and in intercellular to ambient ratio of CO2 concentration (37%). During rehydration, the water status of stressed plants was recovered after three days. Gas exchange was also recovered, but in a slower rate than water status. Under water deficit, proline concentration increased and total soluble carbohydrate concentration decreased. Young African mahogany plants are tolerant to moderate water deficit.

Sementes de Schizolobium amazonicum apresentam dormência física a qual pode ser quebrada por diferentes métodos de escarificação. Nesta pesquisa, os efeitos da escarificação das sementes em lixa e água quente sob os aspectos fisiológicos relacionados à germinação das sementes e à qualidade das plântulas obtidas foram avaliados. Sementes de S. amazonicum foram escarificadas pela (i) imersão em água a 100°C/ 2 min e pela (ii) fricção das sementes em lixa. Sementes não escarificadas foram utilizadas como testemunha. As seguintes variáveis foram avaliadas: viabilidade dos tecidos (por meio do teste de tetrazólio), taxa de germinação, índice de velocidade de germinação (IVG), taxa de embebição das sementes, depleção do endosperma e emergência, uniformidade e acúmulo de biomassa das plântulas resultantes. As sementes oriundas de ambos os tratamentos foram igualmente coradas pelo tetrazólio. A escarificação em lixa resultou em maior germinação, maior IVG, rápida embebição e depleção do endosperma em comparação às sementes escarificadas em água a 100°C/2 min. A emergência de plântulas e o índice de emergência foram maiores em sementes escarificadas em lixa, cujas plântulas apresentaram-se mais uniformes e com maior acúmulo de biomassa que aquelas obtidas após escarificação em água a 100°C/2 min. Do exposto, a escarificação de sementes de paricá em lixa é mais eficiente na promoção da germinação e produção de plântulas uniformes.

O objetivo deste trabalho foi avaliar o crescimento e a produção de fitomassa de três variedades de milho submetidas a diferentes manejos da capoeira, em sistema de corte e trituração, em Marapanim, nordeste do Pará, no período da seca. Utilizou-se o delineamento experimental de blocos ao acaso, com 18 tratamentos e quatro repetições. As parcelas foram constituídas por três manejos da capoeira: natural, enriquecida com ingá (Inga edulis) e tachi-branco (Sclerolobium paniculatum) e enriquecida com ingá e tachi-branco com adubação fosfatada. Foram introduzidas três variedades de milho (BRS Sol da Manhã, BRS 4154 Saracura e BR 106), distribuídas em subparcelas com ou sem adubação complementar (NPK). Foram avaliadas as variáveis: altura da planta, diâmetro do caule, número de folhas, massa de matéria úmida e seca e estande. Os manejos com capoeira enriquecida e capoeira enriquecida com adubação fosfatada influenciaram positivamente a altura das plantas, o diâmetro do colmo e a produção de fitomassa; a adubação complementar potencializou o efeito dos manejos para estas variáveis.

Human aging is associated with loss of function and regenerative capacity. Human bone marrow derived mesenchymal stromal cells (hMSCs) are involved in tissue regeneration, evidenced by their capacity to differentiate into several lineages and therefore are considered the golden standard for cell-based regeneration therapy. Tissue maintenance and regeneration is dependent on stem cells and declines with age and aging is thought to influence therapeutic efficacy, therefore, more insight in the process of aging of hMSCs is of high interest. We, therefore, hypothesized that hMSCs might reflect signs of aging. In order to find markers for donor age, early passage hMSCs were isolated from bone marrow of 61 donors, with ages varying from 17-84, and clinical parameters, in vitro characteristics and microarray analysis were assessed. Although clinical parameters and in vitro performance did not yield reliable markers for aging since large donor variations were present, genome-wide microarray analysis resulted in a considerable list of genes correlating with human age. By comparing the transcriptional profile of aging in human with the one from rat, we discovered follistatin as a common marker for aging in both species. The gene signature presented here could be a useful tool for drug testing to rejuvenate hMSCs or for the selection of more potent, hMSCs for cell-based therapy.

Human mesenchymal stromal cells are regarded as the golden standard for cell-based therapies. They present multilineage differentiation potential and trophic and immunosuppressive abilities, making them the best candidate for clinical applications. Several molecules have been described to increase bone formation and were mainly discovered by candidate approaches towards known signaling pathways controlling osteogenesis. However, their bone forming potential is still limited, making the search for novel molecules a necessity. High-throughput screening (HTS) not only allows the screening of a large number of diverse chemical compounds, but also allows the discovery of unexpected signaling pathways and molecular mechanisms for a certain application, even without the prior knowledge of the full molecular pathway. Typically HTS is performed in cell lines, however, in this manuscript we have performed a phenotypical screen on more clinically relevant human mesenchymal stromal cells, as a proof of principle that HTS can be performed in those cells and can be used to find small molecules that impact stem cell fate. From a library of pharmacologically active small molecules, we were able to identify novel compounds with increased osteogenic activity. These compounds allowed achieving levels of bone-specific alkaline phosphatase higher than any other combination previously known. By combining biochemical techniques, we were able to demonstrate that a medium to high-throughput phenotypic assay can be performed in academic research laboratories allowing the discovery of novel molecules able to enhance stem cell differentiation.

Perceptual training enhances the ability to anticipate crucial information for decision‐making, for example, a soccer goalkeeper predicting penalty kick direction. However, it remains unclear whether perceptual practice alone (implicit method) is sufficient for optimal decision‐making improvement, or whether emphasising pertinent details during practice (explicit method) could yield better results. This study compared implicit and explicit methods of learning ball direction prediction during soccer penalties, involving both goalkeepers and non‐soccer players (novices). Participants engaged in a single training session, either through the explicit method (watching videos highlighting relevant information) or implicit method (watching regular videos). Specialised software was used to display penalty kick videos, mimicking the goalkeeper's viewpoint up to 200 ms before ball contact, and measuring reaction time and response choice. Both implicit and explicit training led to consistent performance gains for goalkeepers and novices alike, notably enhancing ball direction prediction accuracy. Reaction time was unaffected by training. This suggests that both explicit and implicit training methods exhibit similar effectiveness, applicable to soccer goalkeepers and novices. [ABSTRACT FROM AUTHOR]

AbstractPerformance of sport-related ballistic motor skills, like ball hitting in golf and baseball, requires wide movements to produce highly fast and spatially accurate movements. In this study, we assessed the effect of movement amplitude on directional accuracy in a ballistic hitting task. Participants performed the task of moving a manual handle over a flat surface to hit with high speed a moveable disc, aiming to propel it towards a frontal target. Five movement amplitudes were compared, ranging from 11.5 cm to 27.5 cm in steps of 4 cm. Kinematic analysis evaluated motions of the handle, disc, and arm joints. Results showed that greater movement amplitudes led to longer acceleration phases, with delayed peak velocities at the handle, shoulder and elbow, leading to higher contact and peak linear velocities of the handle, and higher angular velocities at the shoulder and elbow. Manipulation of movement amplitude led to no evidence for effects on either disc directional accuracy or variability. Results also revealed no evidence for differences in variability of contact velocity, peak velocity and time of peak velocity across movement amplitudes in the shoulder, elbow, and wrist. Our results indicated that greater movement amplitudes in hitting a spatial target lead to increased contact velocity while not affecting directional accuracy or movement variability. [ABSTRACT FROM AUTHOR]

The study aimed to analyze the use of complementary and integrative health practices (CIHPs) during labor and birth in a freestanding birth center. A total of 28 different CIHPs were applied with or used by laboring women. The most adopted CIHPs were mind-body practices (99.9%) and natural products (35.5%), mostly used by primiparous women (P <.05). Adopting CIHPs can increase care quality, increase positive experiences during childbirth, and promote evidence-based choices. [ABSTRACT FROM AUTHOR]