Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for ...cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell-specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell-mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.
Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) ...have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.
There is limited research on female football players, especially related to their physical and cognitive performance under different climactic conditions. We analyzed the impact of a hot ...environmental temperature on physical performance and anticipation in elite female football players during a fatigue‐inducing intermittent protocol. Elite female players (n = 21) performed the countermovement jump (CMJ) and responded to filmed sequences of offensive play under two distinct environmental temperatures (i.e., mild environment temperature‐ 20°C and 30% rh versus hot environment temperature‐ 38°C and 80% rh), interspersed by 1‐week interval. Linear mixed models were used. CMJ performance declined following the intermittent protocol on both temperature conditions (p < 0.05). Moreover, there were significant main effects for protocol on CMJ speed (m/s) (p = 0.001; ηp2 = 0.12), CMJ power (p = 0.002; ηp2 = 0.11), and CMJ Heightmax (p = 0.002; ηp2 = 0.12). After performing the intermittent protocol, exposure to a hot temperature caused a greater decline in anticipation accuracy (mild temperature = 64.41% vs. hot temperature = 53.44%; p < 0.001). Our study shows impaired performance in elite female football players following an intermittent protocol under hot compared with mild environmental conditions. We report decreased performance in both CMJ and anticipation performance under hotter conditions. The results reveal that exposure to hot temperatures had a negative effect on the accuracy of their anticipatory behaviors. We consider the implication of the work for research and training interventions.
Microvascular dysfunction is an early event in the pathogenesis of systemic sclerosis (SSc). The objective of this scoping review is to update the current information and the level of knowledge about ...the mechanisms of microvascular dysfunction in pre-SSc, very early diagnosis of SSc (VEDOSS) and early SSc.
A PubMed® database search allowed us to include original data from full-length articles in English in which the main topic was microvascular dysfunction in pre-SSC, VEDOSS or early SSc. Data was extracted using a customized form.
In the present review 437 articles were identified, and 42 studies included, reporting data from a total of 1069 patients with pre-SSc, VEDOSS or early-SSc. Distinct mechanisms of microvascular injury were identified comprising, angiogenesis and vasculogenesis, cell surface proteins and adhesion, molecules expression, cytokines profile, inflammatory and oxidation pathways, and skin perfusion determinants. Most of the studies were conducted in early SSc, with a reduced number in pre-disease stages, in which the prompt recognition of specific mechanisms and biomarkers may allow targeted treatment to prevent disease progression.
Although different molecular expression patterns and signaling pathways related to microvascular dysfunction in pre-SSc, VEDOSS, and early SSc were identified, additional prospective longitudinal studies and combined work with functional evaluation of peripheral skin perfusion are needed.
•Mechanisms underlying the microvascular dysfunction in early SSc and in pre-disease stages are distinct from later stages.•Those include angiogenesis, cell surface and adhesion molecules, cytokines, inflammatory and oxidation pathways.•Future prospective studies combining biochemical, immunologic and skin perfusion determinants are needed.
Climate change is a global phenomenon that affects biophysical systems and human well-being. The Paris Agreement of the United Nations Framework Convention on Climate Change entered into force in ...2016 with the objective of strengthening the global response to climate change by keeping global temperature rise this century well below 2 °C above pre-industrial levels and to pursue efforts to limit the temperature increase even further to 1.5 °C. The agreement requires all Parties to submit their “nationally determined contributions” (NDCs) and to strengthen these efforts in the years ahead. Reducing carbon emissions from deforestation and forest degradation is an important strategy for mitigating climate change, particularly in developing countries with large forests. Extensive tropical forest loss and degradation have increased awareness at the international level of the need to undertake large-scale ecological restoration, highlighting the need to identify cases in which restoration strategies can contribute to mitigation and adaptation. Here we consider Brazil as a case study to evaluate the benefits and challenges of implementing large-scale restoration programs in developing countries. The Brazilian NDC included the target of restoring and reforesting 12 million hectares of forests for multiple uses by 2030. Restoration of native vegetation is one of the foundations of sustainable rural development in Brazil and should consider multiple purposes, from biodiversity and ecosystem services conservation to social and economic development. However, ecological restoration still presents substantial challenges for tropical and mega-diverse countries, including the need to develop plans that are technically and financially feasible, as well as public policies and monitoring instruments that can assess effectiveness. The planning, execution, and monitoring of restoration efforts strongly depend on the context and the diagnosis of the area with respect to reference ecosystems (e.g., forests, savannas, grasslands, wetlands). In addition, poor integration of climate change policies at the national and subnational levels and with other sectorial policies constrains the large-scale implementation of restoration programs. The case of Brazil shows that slowing deforestation is possible; however, this analysis highlights the need for increased national commitment and international support for actions that require large-scale transformations of the forest sector regarding ecosystem restoration efforts. Scaling up the ambitions and actions of the Paris Agreement implies the need for a global framework that recognizes landscape restoration as a cost-effective nature-based solution and that supports countries in addressing their remaining needs, challenges, and barriers.
Effects of global climate change on inland artisanal fisheries have received little attention from scientists. We investigated fisheries of the Lower Amazon in Brazil using a wavelet analysis of a ...13‐year data series of fishery catches, environmental variables, and climatic indices, to determine how these variables affected catches of different species. The catch per unit of effort (CPUE) of gillnet and line fisheries increased over time. Relative humidity, latent heat, and sea surface temperatures influenced productivity of both fisheries. El Niño had a negative and immediate effect on gillnet CPUE, while its effect on line fishing was positive, with an eight month lag. Our findings indicate that fishery productivity was modulated by climate events, which influenced ecosystems and modified habitats and ecological niches, andthereby impacted fishery productivity.
Resumo
Os possíveis efeitos dos câmbios climáticos globais nas pescarias artesanais de águas interiores são pouco investigados. Estudaram‐se aqui as pescarias de peixes da região do Baixo Amazonas, Brasil. Usou‐se a análise de wavelet com séries de 13 anos de dados de desembarques pesqueiro, variáveis ambientais e índices climáticos, buscando responder como essas variáveis interferem no resultado das pescarias de diferentes espécies. A CPUE das pescarias com redes de emalhe e com linhas apresentaram tendência temporal positiva. A umidade, calor latente e temperatura da superfície do mar influenciaram a produtividade das pescarias com ambas as artes de pesca. El Niño mostrou efeito negativo e imediato sobre a CPUE das redes de emalhe, enquanto nas linhas o efeito foi positivo com defasagem de oito meses. Isto sugere que o resultado das pescarias é modulado por eventos climáticos, que influenciam no ecossistema e modificam o habitat e os nichos ecológicos o que, por sua vez, impacta na produtividade pesqueira.
•3D fracture loci of uncoupled ductile fracture models were calibrated for 2024-T351 aluminum alloy and DP600 steel.•The type and number of calibration tests has a marginal influence in the fracture ...locus and predictive ability of the models.•Quite different shapes of the fracture locus are observed for between both materials.•The models present different levels of prediction accuracy in the high range of stress triaxiality, for both materials.•It is difficult to select the most appropriate model based only on the objective function value.
The prediction of ductile failure is crucial for the progress of metal forming industries. Therefore, uncoupled fracture models have been proposed and continuously extended, trying to improve their forecasting abilities. However, without an assessment analysis of their predictive ability, it is difficult to establish the most suitable model, for describing the onset of failure under a wide range of loading conditions. Actually, a fair comparison of models’ predictive ability requires the use of an extensive experimental database and a similar calibration procedure. In this context, seven uncoupled fracture models are chosen and revisited to study the effect of the type and number of tests used for calibration on their predictive ability. Experimental datasets available in literature were considered for 2024-T351 aluminium alloy and for DP600 steel. For each material, the experimental dataset was split in two subsets. The first one includes tests that were carried out under plane stress conditions that were used in the calibration procedure. For the aluminium alloy, different groups of 6 tests, covering distinct stress states, were elicited from the experimental subset and applied in the calibration of the seven models. The remaining tests were used to assess the predictive ability and their sensibility regarding the group used in models’ calibration. Different trends of the fracture loci are observed, depending on the selected models and the tests used in their calibration. However, the analysis of the results indicates that a set of at least 6 experimental tests is appropriate to calibrate fracture models, providing that they enable covering a wide range for the stress triaxiality and Lode parameter. Finally, the conclusions provide some recommendations for the improvement of the calibration procedure.
Thin stamped bipolar plates (BPPs) are viewed as promising alternatives to traditional graphite BPPs in proton exchange membrane fuel cells. Metallic BPPs provide good thermal/electrical conductivity ...and exhibit high mechanical strength, to support the loads within the stack. However, BPPs manufactured by stamping processes are prone to defects. In this study, the effect of the tool’s geometry on the thin sheet formability is investigated through finite element simulation. Despite the broad variety of flow field designs, most of BPPs comprise two representative zones. Hence, in order to reduce the computational cost, the finite element analysis is restricted to these two zones, where the deformation induced by the stamping tools is investigated. The channel/rib width, the punch/die fillet radii, and the channel depth are the parameters studied. The analysis is conducted for a stainless steel SS304 with a thickness of 0.15 mm. The results show that the maximum value of thinning occurs always in the U-bend channel section, specifically in the fillet radius of the die closest to the axis of revolution.
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•Neutrophils are an immunological and diffuse source of neurotransmitters.•Neutrophils regulate sensory neuron functions and vice-versa.•Neutrophils play a crucial role in ...inflammatory disorders in the central nervous system.
Neutrophils are peripheral immune cells that represent the first recruited innate immune defense against infections and tissue injury. However, these cells can also induce overzealous responses and cause tissue damage. Although the role of neutrophils activating the immune system is well established, only recently their critical implications in neuro-immune interactions are becoming more relevant. Here, we review several aspects of neutrophils in the bidirectional regulation between the nervous and immune systems. First, the role of neutrophils as a diffuse source of acetylcholine and catecholamines is controversial as well as the effects of these neurotransmitters in neutrophil’s functions. Second, neutrophils contribute for the activation and sensitization of sensory neurons, and thereby, in events of nociception and pain. In addition, nociceptor activation promotes an axon reflex triggering a local release of neural mediators and provoking neutrophil activation. Third, the recruitment of neutrophils in inflammatory responses in the nervous system suggests these immune cells as innovative targets in the treatment of central infectious, neurological and neurodegenerative disorders. Multidisciplinary studies involving immunologists and neuroscientists are required to define the role of the neurons-neutrophils communication in the pathophysiology of infectious, inflammatory, and neurological disorders.
Asthma and COPD are leading causes of disability-adjusted life-years worldwide representing a huge burden on the health system and among patients. One of the reasons for the lack of disease control ...is poor inhalation technique, with impact on quality of life and symptom control.
To assess the effectiveness of a community pharmacist-led educational intervention on asthma and COPD patients’ inhalation technique.
The INspira study is a 6-month pilot cluster randomized controlled trial, conducted in community pharmacies of Portugal, enrolling adults aged 18 years or older, with a self-reported diagnosis of asthma or COPD and on inhaled therapy. Pharmacies were randomly allocated to Intervention or Control group. Intervention focused mainly on inhalation technique education via demonstration and repetition. Primary outcome was the proportion of patients scoring 100% in at least one inhaler.
From January to November 2019, 48 pharmacies recruited 201 asthma and COPD patients, of which 132 completed the 6-month follow-up. At the end of follow-up, the odds of intervention group patients score 100% compared to the control group were 5.63 (95% CI, 2.21; 14.35) in all inhalers in use and 6.77 (95% CI, 2.52; 18.20) considering at least one inhaler. Intervention group patients reported having a significantly lower number of scheduled appointments compared with the control group (OR = 0.17; 95% CI, 0.037; 0.79; p = 0.0135). No other significant differences were found between groups.
This pilot study suggested that pharmacist interventions can improve patients’ inhalation technique, with possible positive impact in healthcare resource use.
•Inadequate inhaler technique is a driver of poor disease control on asthma and COPD patients.•Less than 1 in every 4 patients correctly use their inhalers.•Pharmacist-led educational intervention significantly improves patient's inhalation technique.
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