A spatially resolved single-cell lung atlas integrated with clinical and blood signatures distinguishes COVID-19 disease trajectories.

COVID-19 is characterized by a broad range of symptoms and disease trajectories. Understanding the correlation between clinical biomarkers and lung pathology during acute COVID-19 is necessary to understand its diverse pathogenesis and inform more effective treatments. Here, we present an integrated analysis of longitudinal clinical parameters, peripheral blood markers, and lung pathology in 142 Brazilian patients hospitalized with COVID-19. We identified core clinical and peripheral blood signatures differentiating disease progression between patients who recovered from severe disease compared with those who succumbed to the disease. Signatures were heterogeneous among fatal cases yet clustered into two patient groups: "early death" (<15 days until death) and "late death" (>15 days). Progression to early death was characterized systemically and in lung histopathological samples by rapid endothelial and myeloid activation and the presence of thrombi associated with SARS-CoV-2+ macrophages. In contrast, progression to late death was associated with fibrosis, apoptosis, and SARS-CoV-2+ epithelial cells in postmortem lung tissue. In late death cases, cytotoxicity, interferon, and T helper 17 (TH17) signatures were only detectable in the peripheral blood after 2 weeks of hospitalization. Progression to recovery was associated with higher lymphocyte counts, TH2 responses, and anti-inflammatory-mediated responses. By integrating antemortem longitudinal blood signatures and spatial single-cell lung signatures from postmortem lung samples, we defined clinical parameters that could be used to help predict COVID-19 outcomes.

Mainstreaming Flora Conservation Strategies into the Mitigation Hierarchy to Strengthen Environmental Impact Assessment.

The application of the mitigation hierarchy (MH) to mining projects is challenging in situations of locational overlap between endemic flora and mineral deposits. We review flora surveys conducted in connection with the environmental impact assessment of several iron ore mining projects in an area of high degree of endemism in Eastern Amazon to discuss the practical implications of anticipating conservation strategies. Desktop studies and secondary data review were conducted to guide field searches to determine the distribution of endemic flora, resulting in 45 out of 46 endemic plant species having their known distribution extended to new areas. A framework for positioning flora conservation strategies in the MH is presented. Specific habitat requirements and scarce knowledge about endangered and endemic flora species are a conservation obstacle, since essential information to define species conservation strategies may be lacking. We show that anticipating conservation strategies can minimize time-lag uncertainties related to restoration success and biodiversity offsets. The more effort is placed in the preventative steps of the MH, the smaller the time-lag between impact (biodiversity losses) and conservation outcomes (biodiversity gains), decreasing uncertainties and reducing risks to biodiversity.

Paraconsistent Annotated Logic Algorithms Applied in Management and Control of Communication Network Routes.

This paper presents a computational method based on non-classical logic dedicated to routing management and information stream control in communication networks. Paraconsistent logic (PL) was used to create an algorithmic structure whose main property is to accept contradiction. Moreover, a computational structure, the denominated paraconsistent data analyzer (PDAPAL2v), was constructed to perform routing management in communication networks. Direct comparisons of PDAPAL2v with a classical logic system that simulates routing conditions were made in the laboratory. In the conventional system, the paraconsistent algorithms were considered as binary logic gates, and in the tests, the same adjustment limits of PDAPAL2v were applied. Using a database with controlled insertion of noise, we obtained an efficacy of 97% in the detection of deteriorated packets with PDAPAL2v and 72% with the conventional simulation system. Functional tests were carried out, showing that PDAPAL2v is able to assess the conditions and degradation of links and perform the analysis and correlation of various inputs and variables, even if the signals have contradictory values. From practical tests in the laboratory, the proposed method represents a new way of managing and controlling communication network routes with good performance.

Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors.

Leishmania major, as other protozoan parasites, plague human kind since pre-historic times but it remains a worldwide ailment for which the therapeutic arsenal remains scarce. Although L. major is pteridine- and purine-auxotroph, well-established folate biosynthesis inhibitors, such as methotrexate, have poor effect over the parasite survival. The lack of efficiency is related to an alternative biochemical pathway in which pteridine reductase 1 (PTR1) plays a major role. For this reason, this enzyme has been considered a promising target for anti-leishmanial drug development and several inhibitors that share the substrate scaffold have been reported. In order to design a novel class of PTR1 inhibitors, we employed the thiazolidinone ring as a bioisosteric replacement for pteridine/purine ring. Among seven novel thiazolidine-2,4-dione derivatives reported herein, 2d was identified as the most promising lead by thermal shift assays (ΔTm = 11 °C, p = 0,01). Kinetic assays reveal that 2d has IC50 = 44.67 ± 1.74 µM and shows a noncompetitive behavior. This information guided docking studies and molecular dynamics simulations (50 000 ps) that supports 2d putative binding profile (H-bonding to Ser-111 and Leu-66) and shall be useful to design more potent inhibitors.

Paraconsistent analysis network applied in the treatment of Raman spectroscopy data to support medical diagnosis of skin cancer.

Paraconsistent logic (PL) is a type of non-classical logic that accepts contradiction as a fundamental concept and has produced valuable results in the analysis of uncertainties. In this work, algorithms based on a type of PL-paraconsistent annotated logic of two values (PAL2v)-are interconnected into a network of paraconsistent analysis (PANnet). PANnet was applied to a dataset comprising 146 Raman spectra of skin tissue biopsy fragments of which 30 spectra were determined to represent normal skin tissue (N), 96 were determined to represent tissue with basal cell carcinoma, and 19 were determined to be tissue with melanoma (MEL). In this database, paraconsistent analysis was able to correctly discriminate 136 out of a total of 145 fragments, obtaining a 93.793 % correct diagnostic accuracy. The application of PAL2v in the analysis of Raman spectroscopy signals produces better discrimination of cells than conventional statistical processes and presents a good graphical overview through its associated lattice structure. The technique of PAL2v-based data processing can be fundamental in the development of a computational tool dedicated to support the diagnosis of skin cancer using Raman spectroscopy.

Fut3 role in breast invasive ductal carcinoma: Investigating its gene promoter and protein expression.

Fucosylated glycans synthesized by α1,3/4-fucosyltransferase (FUT3) enzyme play an important role in breast cancer prognosis and metastasis, being involved in the binding of circulating tumor cells to the endothelium and being related to tumor stage, metastatic potential and chemoresistance. Despite the pro-tumor action of this enzyme, studies have demonstrated its role in natural killer-induced cytotoxicity through the recognition of sialyl Lewis X by C-type lectin receptors and through extrinsic apoptosis pathway triggered by Apo2L-TRAIL. This study aimed to investigate the expression pattern of FUT3 in invasive breast carcinoma (IDC) from patients of Pernambuco state, Northeast of Brazil, and genotype FUT3 promoter region to identify possible SNPs that could be associated with variations in FUT3 expression. Immunohistochemistry assay was used to access the FUT3 expression in normal (n=11) and tumor tissues (n=85). DNA sequencing was performed to genotype the FUT3 promoter region in patients with IDC (n=109) and healthy controls (n=110). Our results demonstrated that the absence of FUT3 enzyme is related to breast's IDC. The non-expression of FUT3 was more frequent in larger lesions and also in HER2 negative IDC tumors. Genomic analysis showed that two variations localized in FUT3 promoter region are possibly associated with IDC. Our results suggest that minor allele T of SNP rs73920070 (-6933 C>T) confers protection whereas minor allele T of SNP rs2306969 (-6951 C>T) triggers to susceptibility to IDC in the population of Pernambuco state, Northeast of Brazil.

Synthesis and antimicrobial activities of 5-Arylidene-thiazolidine-2,4-dione derivatives.

Antibiotic resistance is considered one of the world's major public health concerns. The main cause of bacterial resistance is the improper and repeated use of antibiotics. To alleviate this problem, new chemical substances against microorganisms are being synthesized and tested. Thiazolidines are compounds having many pharmacological activities including antimicrobial activities. For this purpose some thiazolidine derivatives substituted at position 5 in the thiazolidine nucleus were synthesized and tested against several microorganisms. Using a disc diffusion method, antimicrobial activity was verified against Gram-positive, Gram-negative, and alcohol acid resistant bacteria and yeast. The minimum inhibition concentrations (MIC) and minimum bactericidal concentrations (MBC) were determined. All derivatives showed antimicrobial activity mainly against Gram-positive bacteria, with MIC values ranging from 2 to 16 µg/mL.

Trans-sialidase from Trypanosoma cruzi enhances the adhesion properties and fibronectin-driven migration of thymocytes.

In experimental Trypanosoma cruzi infections, severe thymic atrophy leads to release of activated CD4(+)CD8(+) double-positive (DP) T cells to the periphery. In humans, activated DP T cells are found in the blood in association with severe cardiac forms of human chronic Chagas disease. The mechanisms underlying the premature thymocyte release during the chagasic thymic atrophy remain elusive. We tested whether the migratory properties of intrathymic thymocytes are modulated by the parasite trans-sialidase (TS). We found that TS affected the dynamics of thymocytes undergoing intrathymic maturation, and these changes were accompanied by an increase in the number of recent DP thymic emigrants in the peripheral lymphoid organs. We demonstrated that increased percentages of blood DP T cell subsets were associated with augmented antibody titers against TS in chagasic patients with chronic cardiomyopathy. In vitro studies showed that TS was able to activate the MAPK pathway and actin filament mobilization in thymocytes. These effects were correlated with its ability to modulate the adhesion of thymocytes to thymic epithelial cells and their migration toward extracellular matrix. These findings point to effects of TS that could influence the escape of immature thymocytes in Chagas disease.

Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides.

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1-7). Parasite infection decreased Ang-(1-7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1-7) decreased the level of infection in an A779 (specific antagonist of Ang-(1-7) receptor, MAS)-sensitive manner. 10(-7) M PD123319, an AT(2) receptor antagonist, partially reversed the effects of Ang-(1-7) and Ang II. However, 10(-6) M losartan, an antagonist of the AT(1) receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10(-8) M Ang II or 10(-8) M Ang-(1-7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10(-7) M A779. 10(-6) M dibutyryl-cAMP increased the level of infection and 10(-7) M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1-7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1-7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus.

House and street: narratives of professional identity among nurses.

This study describes narratives of professional identity among nurses in Rio de Janeiro, Brazil. Semistructured interviews were carried out with 27 nursing professionals working in public hospitals in the city of Rio de Janeiro; in addition, the male:female ratio of graduate students of a nurse faculty in Rio de Janeiro was evaluated. Although the meaning of nursing is changing in Brazil, it is still strongly influenced by traditional values. We are observing in the last decades a shift in the meaning of nursing all over the world: from a female, domestic, and unvalued vocation to a more technical, masculine, and higher status profession. In Brazil, a coexistence of these two meanings, with a preponderance of the old traditional one, was observed. Change comes slowly. When the old model is challenged, it is often observed that the number of nurses per service decreases. The nurse often becomes the manager or leader of the unit. In these situations, patient care is displaced to less well trained individuals like technicians and nurse assistants who are not as well paid and, therefore, cost less to the system, while the responsibility of the results remains in the nurse's domain.

Simulation of mixed models in augmented block design

The augmented block design is widely used in breeding programs, with non-replicated treatments generally being selection units, and replicated treatments being standard cultivars. Originally, an intrablock analysis (fixed model) was proposed. Although non-replicated treatments and/or blocks can be considered of random nature, mixed linear models could be used instead. This work evaluated such an approach, using computer simulation. Populations consisted of sets of randomly generated inbred lines. Molecular marker data were also simulated to allow the estimation of the genetic covariance matrix. Different conditions were considered, varying heritability and the coefficient b of Smith of soil heterogeneity. For each condition 100 simulations were performed, considering four linear models, varying respectively the nature of the effects of blocks and non-replicated treatments (fixed - F, or random - R): FF, FR, RF and RR. In relation to FF, the mixed models were more efficient under low to intermediate heritability and high b. Mixed models could improve inference in breeding programs using the augmented block design and the choice of the model should rely on the kind of selection. If this is truncated, the RF model should be preferred; if it is not, then the RR model would be more suitable.

O delineamento em blocos aumentados é amplamente utilizado em programas de melhoramento, geralmente com tratamentos não-repetidos correspondentes a unidades de seleção, e tratamentos repetidos sendo cultivares comerciais. Originalmente, uma análise intrablocos (modelo fixo) foi sugerida. No entanto, se os tratamentos não-repetidos e/ou blocos puderem ser considerados de natureza aleatória, modelos lineares mistos poderiam ser utilizados. Este estudo objetivou a avaliação de tal abordagem, utilizando simulação. Linhagens endogâmicas foram geradas aleatoriamente, bem como dados de marcação molecular, para estimar a matriz de covariâncias genéticas. Variaram-se a herdabilidade e o coeficiente b de heterogeneidade de solo de Smith; em cada condição, 100 simulações foram feitas, considerando 4 modelos lineares, variando respectivamente a natureza dos efeitos de bloco e de tratamentos não-repetidos (fixo -- F, ou aleatório -- A): FF, FA, AF e AA. Em relação ao modelo FF, os modelos mistos foram mais eficientes especialmente sob herdabilidade baixa a intermediária e alto b. Modelos mistos podem melhorar a inferência em programas de melhoramento utilizando o delineamento, e a escolha do modelo deve se basear no tipo de seleção. Se esta for truncada, o modelo AF deveria ser preferido; se não for, então o modelo AA é mais apropriado.

Simulation of mixed models in augmented block design

The augmented block design is widely used in breeding programs, with non-replicated treatments generally being selection units, and replicated treatments being standard cultivars. Originally, an intrablock analysis (fixed model) was proposed. Although non-replicated treatments and/or blocks can be considered of random nature, mixed linear models could be used instead. This work evaluated such an approach, using computer simulation. Populations consisted of sets of randomly generated inbred lines. Molecular marker data were also simulated to allow the estimation of the genetic covariance matrix. Different conditions were considered, varying heritability and the coefficient b of Smith of soil heterogeneity. For each condition 100 simulations were performed, considering four linear models, varying respectively the nature of the effects of blocks and non-replicated treatments (fixed - F, or random - R): FF, FR, RF and RR. In relation to FF, the mixed models were more efficient under low to intermediate heritability and high b. Mixed models could improve inference in breeding programs using the augmented block design and the choice of the model should rely on the kind of selection. If this is truncated, the RF model should be preferred; if it is not, then the RR model would be more suitable.

O delineamento em blocos aumentados é amplamente utilizado em programas de melhoramento, geralmente com tratamentos não-repetidos correspondentes a unidades de seleção, e tratamentos repetidos sendo cultivares comerciais. Originalmente, uma análise intrablocos (modelo fixo) foi sugerida. No entanto, se os tratamentos não-repetidos e/ou blocos puderem ser considerados de natureza aleatória, modelos lineares mistos poderiam ser utilizados. Este estudo objetivou a avaliação de tal abordagem, utilizando simulação. Linhagens endogâmicas foram geradas aleatoriamente, bem como dados de marcação molecular, para estimar a matriz de covariâncias genéticas. Variaram-se a herdabilidade e o coeficiente b de heterogeneidade de solo de Smith; em cada condição, 100 simulações foram feitas, considerando 4 modelos lineares, variando respectivamente a natureza dos efeitos de bloco e de tratamentos não-repetidos (fixo -- F, ou aleatório -- A): FF, FA, AF e AA. Em relação ao modelo FF, os modelos mistos foram mais eficientes especialmente sob herdabilidade baixa a intermediária e alto b. Modelos mistos podem melhorar a inferência em programas de melhoramento utilizando o delineamento, e a escolha do modelo deve se basear no tipo de seleção. Se esta for truncada, o modelo AF deveria ser preferido; se não for, então o modelo AA é mais apropriado.