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Abstract The TIGIT+FOXP3+Treg subset (TIGIT+Tregs) exerts robust suppressive activity on cellular immunity and predisposes septic individuals to opportunistic infection. We hypothesized that TIGIT+Tregs could play an important role in intensifying the COVID-19 severity and hampering the defense against nosocomial infections during hospitalization. Herein we aimed to verify the association between the levels of the TIGIT+Tregs with the mechanical ventilation requirement, fatal outcome, and bacteremia during hospitalization. TIGIT+Tregs were immunophenotyped by flow cytometry from the peripheral blood of 72 unvaccinated hospitalized COVID-19 patients at admission from May 29th to August 6th, 2020. The patients were stratified during hospitalization according to their mechanical ventilation requirement and fatal outcome. COVID-19 resulted in a high prevalence of the TIGIT+Tregs at admission, which progressively increased in patients with mechanical ventilation needs and fatal outcomes. The prevalence of TIGIT+Tregs positively correlated with poor pulmonary function and higher plasma levels of LDH, HMGB1, FGL2, and TNF. The non-survivors presented higher plasma levels of IL-33, HMGB1, FGL2, IL-10, IL-6, and 5.54 times more bacteremia than survivors. Conclusions: The expansion of the TIGIT+Tregs in COVID-19 patients was associated with inflammation, lung dysfunction, bacteremia, and fatal outcome.

Summary: Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production in LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production.

Abstract Neutrophils rely predominantly on glycolytic metabolism for their biological functions, including reactive oxygen species (ROS) production. Although pyruvate kinase M2 (PKM2) is a glycolytic enzyme known to be involved in metabolic reprogramming and gene transcription in many immune cell types, its role in neutrophils remains poorly understood. Here, we report that PKM2 regulates ROS production and microbial killing by neutrophils. Zymosan-activated neutrophils showed increased cytoplasmic expression of PKM2. Pharmacological inhibition or genetic deficiency of PKM2 in neutrophils reduced ROS production and Staphylococcus aureus killing in vitro. In addition, this also resulted in phosphoenolpyruvate (PEP) accumulation and decreased dihydroxyacetone phosphate (DHAP) production, which is required for de novo synthesis of diacylglycerol (DAG) from glycolysis. In vivo, PKM2 deficiency in myeloid cells impaired the control of infection with Staphylococcus aureus. Our results fill the gap in the current knowledge of the importance of lower glycolysis for ROS production in neutrophils, highlighting the role of PKM2 in regulating the DHAP and DAG synthesis to promote ROS production in neutrophils.

Abstract Human activity has diminished forests in different terrestrial ecosystems. This is well illustrated in the Brazilian Atlantic Forest, which still hosts high levels of species richness and endemism, even with only 28% of its original extent remaining. The consequences of such forest loss in remaining populations can be investigated with several approaches, including the genomic perspective, which allows a broader understanding of how human disturbance influences the genetic variability in natural populations. In this context, our study investigated the genomic responses of Euterpe edulis Martius, an endangered palm tree, in forest remnants located in landscapes presenting different forest cover amount and composed by distinct bird assemblage that disperse its seeds. We sampled 22 areas of the Brazilian Atlantic Forest in four regions using SNP markers inserted into transcribed regions of the genome of E. edulis, distinguishing neutral loci from those putatively under natural selection (outlier). We demonstrate that populations show patterns of structure and genetic variability that differ between regions, as a possible reflection of deforestation and biogeographic histories. Deforested landscapes still maintain high neutral genetic diversity due to gene flow over short distances. Overall, we not only support previous evidence with microsatellite markers, but also show that deforestation can influence the genetic variability outlier, in the scenario of selective pressures imposed by these stressful environments. Based on our findings, we suggest that, to protect genetic diversity in the long term, it is necessary to reforest and enrich deforested areas, using seeds from populations in the same management target region.

Vertebrate frugivores play important ecological roles. Here, the authors analyse a global dataset on plants and birds and find that plant-frugivore networks are more dissimilar, yet structurally consistent, across ecoregion and biome boundaries.

Abstract Interspecific interactions are a major determinant of stability in ecological communities and are known to vary with biotic and abiotic conditions. Deforestation is the primary driver of the ongoing sixth mass extinction, yet its effect on species interactions remains largely unexplored. We investigate how deforestation affects species interactions using a complex systems model and a co‐occurrence dataset of 363 bird species, observed across 134 sites, from 5 regions across the Brazilian Atlantic Forest totalling 27,226 interactions. Both theoretical and empirical results show that interspecific interactions vary non‐monotonically with forest cover and are more positive than average in areas with higher forest cover, and to a lesser extent in highly deforested areas. Observed differences in interactions reflect both species turnover and changes in pairwise interactions. Our results point to changes in stability across the gradient of deforestation that may lead to varying community resilience to environmental perturbations. Key Interdisciplinary Aspects Species interactions are expected to vary due to the biological, chemical and physical changes caused by deforestation on their local environment. We use a mathematical complex systems approach, as well as ecological data, to show that species interactions are more positive in highly forested areas. We propose that the alteration of species interactions caused by deforestation will affect the stability of communities and their resilience to future perturbations (e.g. climate change).

Summary: Invariant natural killer T (iNKT) cells are a distinct population of lymphocytes characterized by their reactivity to glycolipids presented by CD1d. iNKT cells are found throughout the body, and little is known about their tissue-specific metabolic regulation. Here, we show that splenic and hepatic iNKT cells are metabolically comparable and rely on glycolytic metabolism to support their activation. Deletion of the pyruvate kinase M2 (Pkm2) gene in splenic and hepatic iNKT cells impairs their response to specific stimulation and their ability to mitigate acute liver injury. In contrast, adipose tissue (AT) iNKT cells exhibit a distinctive immunometabolic profile, with AMP-activated protein kinase (AMPK) being necessary for their function. AMPK deficiency impairs AT-iNKT physiology, blocking their capacity to maintain AT homeostasis and their ability to regulate AT inflammation during obesity. Our work deepens our understanding on the tissue-specific immunometabolic regulation of iNKT cells, which directly impacts the course of liver injury and obesity-induced inflammation.

Biodiversity is already experiencing the effects of climate change through range expansion, retraction, or relocation, potentializing negative effects of other threats. Future projections already indicate richness reduction and composition modifications of bird communities due to global warming, which may disrupt the provision of key ecological services to ecosystem maintenance. Here, we systematically review the effect of morphological, ecological, and geographical traits on the amount of future suitable area for birds worldwide. Specifically, we tested whether body mass, diet, habitat type, movement pattern, range size, and biogeographic realm affect birds' suitable area. Our search returned 75 studies that modeled the effects of climate change on 1,991 bird species. Our analyses included 1,661 species belonging to 128 families, representing 83% of the total, for which we were able to acquire all the six traits. The proportion of birds' suitable area was affected by range size, body mass, habitat type, and biogeographic realm, while diet and movement pattern showed lower relative importance and were not included in our final model. Contrary to expectations, the proportion of birds' suitable area was negatively related to range size, which may be explained by higher climatic stability predicted in certain areas that harbor species with restricted distribution. In contrast, we observed that birds presenting higher body mass will show an increase of the proportion of suitable area in the future. This is expected due to the high exposure of smaller birds to environmental changes and their difficulty to keep thermoregulation. Our results also indicated a low proportion of suitable area to forest-dependent birds, which is in accordance with their higher vulnerability due to specific requirements for reproduction and feeding. Finally, the proportion of suitable area was low for birds from Oceania, which is expected since the region encompasses small islands isolated from continents, preventing their species from reaching new suitable areas. Our study highlights that different traits should be considered when assessing extinction risk of species based on future projections, helping to improve bird conservation, especially the most vulnerable to climate change.

Production of nitric oxide (NO) has been demonstrated in several malignancies, however its role remains not fully understood, specifically in relation to the metabolic and functional implications that it may have on immune cells participating in tumorigenesis. Here, we show that inducible NO synthase (iNOS) is expressed in cancers of the colon and the prostate, mainly by tumour cells, and NO generation is evidenced by widespread nitrotyrosine (NT) staining in tumour tissue. Furthermore, presence of NT is observed in the majority of tumour-associated macrophages (TAMs), despite low iNOS expression by these cells, suggesting that NO from the tumour microenvironment affects TAMs. Indeed, using a co-culture model, we demonstrate that NO produced by colon and prostate cancer cells is sufficient to induce NT formation in neighbouring macrophages. Moreover, exposure to exogenous NO promotes mitochondria-dependent and -independent changes in macrophages, which orientate their polarity towards an enhanced pro-inflammatory phenotype, whilst decreasing antigen-presenting function and wound healing capacity. Abrogating endogenous NO generation in murine macrophages, on the other hand, decreases their pro-inflammatory phenotype. These results suggest that the presence of NO in cancer may regulate TAM metabolism and function, favouring the persistence of inflammation, impairing healing and subverting adaptive immunity responses.

Este trabalho apresenta a caracterização geotécnica e mecânica de um solo arenoso fino laterítico (SAFL) e seu desempenho no campo como camada de sublastro em pavimento ferroviário. O SAFL é consagrado em pavimento rodoviário no Brasil, sua utilização em pavimento ferroviário requer especial atenção. O material foi caracterizado e submetido a ensaios de cargas repetidas, deformação permanente e ao Índice de Suporte Califórnia (CBR). Na avaliação “in situ” das propriedades mecânicas foi utilizado o Dynamic Cone Penetrometer. Ao se utilizar normas de seleção de materiais da AREMA, solos com predominância de finos são descartados por não satisfazerem os critérios de índice de plasticidade, granulometria e CBR. Porém, quando trata-se de solo tropical laterítico, este material possui cimentação natural, devido à grande concentração de óxido-hidróxido de Fe e Al, que proporciona a ele um comportamento estrutural peculiar. Resultados obtidos de módulo resiliente elevado e baixa deformação permanente validam o uso do SAFL.

Global biodiversity is threatened by land-use changes through human activities. This is mainly due to the conversion of continuous forests into forest fragments surrounded by anthropogenic matrices. In general, sensitive species are lost while species adapted to disturbances succeed in altered environments. However, whether the interactions performed by the persisting species are also modified, and how it scales up to the network level throughout the landscape are virtually unknown in most tropical hotspots of biodiversity. Here we evaluated how landscape predictors (forest cover, total core area, edge density, inter-patch isolation) and local characteristics (fruit availability, vegetation complexity) affected understory birds seed-dispersal networks in 19 forest fragments along the hyperdiverse but highly depauperate northeast distribution of the Brazilian Atlantic Forest. Also, our sampled sites were distributed in two regions with contrasting land cover changes. We used mist nets to obtain samples of understory bird food contents to identify the plant species consumed and dispersed by them. We estimated network complexity on the basis of the number of interactions, links per species, interaction evenness, and modularity. Our findings showed that the number of interactions increased with the amount of forest cover, and it was significantly lower in the more deforested region. None of the other evaluated parameters were affected by any other landscape or local predictors. We also observed a lack of significant network structure compared to null models, which we attribute to a pervasive impoverishment of bird and plant communities in these highly modified landscapes. Our results demonstrate the importance of forest cover not only to maintain species diversity but also their respective mutualistic relationships, which are the bases for ecosystem functionality, forest regeneration and the provision of ecological services.

Macrophages metabolic reprogramming in response to microbial insults is a major determinant of pathogen growth or containment. Here, we reveal a distinct mechanism by which stimulator of interferon genes (STING), a cytosolic sensor that regulates innate immune responses, contributes to an inflammatory M1-like macrophage profile upon Brucella abortus infection. This metabolic reprogramming is induced by STING-dependent stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), a global regulator of cellular metabolism and innate immune cell functions. HIF-1α stabilization reduces oxidative phosphorylation and increases glycolysis during infection with B. abortus and, likewise, enhances nitric oxide production, inflammasome activation and IL-1β release in infected macrophages. Furthermore, the induction of this inflammatory profile participates in the control of bacterial replication since absence of HIF-1α renders mice more susceptible to B. abortus infection. Mechanistically, activation of STING by B. abortus infection drives the production of mitochondrial reactive oxygen species (mROS) that ultimately influences HIF-1α stabilization. Moreover, STING increases the intracellular succinate concentration in infected macrophages, and succinate pretreatment induces HIF-1α stabilization and IL-1β release independently of its cognate receptor GPR91. Collectively, these data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during B. abortus infection that is orchestrated by STING via HIF-1α pathway and highlight the metabolic reprogramming of macrophages as a potential treatment strategy for bacterial infections.

Abstract Carbon nanostructures have been extensively studied due to combination of properties they present. With different geometries and reactivities, carbon nanotubes, graphene and fullerene were oxidized and modified with octadecylamine (ODA) in order to decrease van der Waals’s interaction and consequently improve the polymer-carbon nanostructures affinity for use in nanocomposites. Nanostructures were characterized as morphology, chemical structure, molecular conformation and thermal properties. All nanostructures showed results that confirm the modification with ODA, without geometry being altered. Modified nanostructures showed different percentages of ODA: graphene 86%, carbon nanotubes 83% and fullerene 63%. It was attributed to distinct reactivities, shapes and specific surface area available, due to different amounts of reactive terminals obtained before oxidation reactions. However, they showed a lower interfacial interaction, which is highly favorable for use in polymer nanocomposites.

Platelet-rich plasma (PRP) has been extensively studied as a biomaterial for wound treatment, and the heterologous PRP is usefulin the event that obtaining the patient’s own blood is impossible. This study aimed to evaluate and compare wound healing in rabbits and quantify the collagen in experimentally induced wounds in a control group and in a group treated with heterologous PRP gel. We hypothesize that this gelis capable of promoting proper healing with no adverse reactions, increased collagen content. The clinical aspects of coloring, edema, hyperemia, exudation, crust, granulation, pain sensitivity, and retraction index of the wounds were measuredon days 7, 14, and 17 after the injury. Collagen quantification by Picrosirius staining and evaluation under polarized light was performed on the 17th day. Crust was present in both groups at all evaluated time points, with the absence of other clinical signs. The wound contraction rate and collagen quantity did not differ between groups. In conclusion, the suggested hypothesis was partially confirmed; the heterologous PRP gel was unable to increase the amount of collagen and accelerate the wound healing process, however, wound healing was efficient and similar in both groups and there was no local adverse reaction. Thus, despite the scarcity of studies in the literature, the heterologous PRP gel is an effective alternative treatment for wounds in the absence of other sources of PRP.

Objetivou-se verificar a influência da composição corporal na CAER de animais submetidos a diferentes tipos de treino físico. Foram utilizados 23 ratos Wistar, divididos em grupos de acordo com o protocolo de treino: controle (CTLE); treino aeróbio (TAE); treino anaeróbio (TAN); e treino físico concorrente (TCc). Foi realizado o Teste de carga crítica (CC) para a determinação do limiar anaeróbio no início e no final do período de treino. O TAE foi composto por exercício de natação com intensidade correspondente a 70% do Limiar Anaeróbio; o TAN por meio de saltos aquáticos com sobrecarga de 50% do peso corporal de cada animal; e o TCc pela combinação dos protocolos aeróbio e anaeróbio, descritos anteriormente. Após quatro semanas de treino, foi coletado e mensurado o peso do tecido adiposo epididimal e dos músculos sóleo, plantar e gastrocnêmio. Foi utilizada a análise de dispersão para a elaboração e gráficos e a análise do modelo de regressão linear simples para identificar a interferência de cada uma das variáveis na CAER. A Gordura Corporal demonstrou influência positiva de 5% na relação com o Limiar Anaeróbio. Os músculos sóleo e gastrocnêmio mostraram influência negativa de 13,1% e 37,0%, respectivamente. Enquanto o músculo plantar não mostrou qualquer influência no limiar anaeróbio. A composição corporal influenciou na CAER dos animais analisados. Além disso, notou-se que a gordura corporal favoreceu a flutuabilidade, enquanto a maior massa muscular a prejudicou.