Combining cashew gum with cyclophosphamide in murine melanoma model: A strategy for the reduction of side effects.

The understanding of cancer immunity and antitumor factors generated by natural polysaccharides is not yet fully comprehended. Polysaccharides, like cashew gum (CG), can exhibit immunomodulatory action and may assist in the antitumor process and side effects relieve. This study aimed to determine the antitumor effect of CG alone or in combination with cyclophosphamide (CTX), and its interactions with immune cells, in a murine melanoma model, using the B16-F10 cell line. Tumor growth inhibition, hematological, histopathological, ELISA, flow cytometry, immunofluorescence, and qRT-PCR analyses were performed to elucidate the antitumor potential, involvement of immune cells, and potential toxic effects. CG showed significant tumor growth inhibition, reaching up to 42.9 % alone and 51.4 % in combination with CTX, with mild toxicity to organs. CG enhanced leukocyte count, even in the presence of CTX. Furthermore, CG influenced the activation of tumor-associated macrophages (TAM), characterized by an increase in Il4, as well as a reduction in Ifng, Il1b, Tgfb, and Il6 gene expression. Nevertheless, these effects did not compromise the antitumor activity of CG. In summary, the combination of CG with CTX is a promising approach for leukopenia, one of the most important side effects of cancer treatment and deserves further investigation.

High M2-TAM Infiltration and STAT3/NF-κB Signaling Pathway as a Predictive Factor for Tumor Progression and Death in Cervical Cancer.

INTRODUCTION: The tumor microenvironment (TME) plays a crucial role in the progression, invasion, and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the CC TME, but studies on their correlation with CC progression are still controversial. This study aimed to investigate the relationship between TAM infiltration, the STAT3/NF-κB signaling pathway, and Overall Survival (OS) in CC patients. METHODS: In a retrospective study, 691 CC patients who had received a definitive histopathologic diagnosis of CC scored by the FIGO staging system and not undergone preoperative treatment were selected from a database. The effect of TAM infiltration on tumor progression biomarkers using Tissue Microarray (TMA) and immunohistochemistry was evaluated. Furthermore, the impact of the expression of these biomarkers and clinical-pathological parameters on recurrence-free (RF) and OS using Kaplan-Meier and multivariable Cox regression methods was also analyzed. RESULTS: High stromal CD163 + 204 + TAMs density and via STAT3 and NF-κB pathways was relevant to the expression of E-cadherin, Vimentin, MMP9, VEGFα, Bcl-2, Ki-67, CD25, MIF, FOXP3, and IL-17 (all p < 0.0001). In addition, elevated TNM staging IV had a strong association correlation with STAT3 and NF-κB pathways (p < 0.0001), CD25 (p < 0.001), VEGFα (p < 0.001), MIF (p < 0.0001), and Ki-67 (p < 0.0001). On the other hand, overall and recurrence survival was shown to be strongly influenced by the expression of SNAIL (HR = 1.52), E-cadherin (HR = 1.78), and Ki-67 (HR = 1.44). CONCLUSION: M2-TAM and via STAT3/NF-κB pathways had a strong effect on CC tumor progression which reverberated in the severity of clinicopathological findings, becoming an important factor of poor prognosis.

Tumor-associated macrophages impair NK cell IFN-γ production and contribute to tumor progression in clear cell renal cell carcinoma.

Tumor-associated macrophages (TAM) are abundant in several tumor types and usually correlate with poor prognosis. Previously, we demonstrated that anti-inflammatory macrophages (M2) inhibit NK cell effector functions. Here, we explored the impact of TAM on NK cells in the context of clear-cell renal cell carcinoma (ccRCC). Bioinformatics analysis revealed that an exhausted NK cell signature strongly correlated with an M2 signature. Analysis of TAM from human ccRCC samples confirmed that they exhibited an M2-skewed phenotype and inhibited IFN-γ production by NK cells. Moreover, human M0 macrophages cultured with conditioned media from ccRCC cell lines generated macrophages with an M2-skewed phenotype (TAM-like), which alike TAM, displayed suppressive activity on NK cells. Moreover, TAM depletion in the mouse Renca ccRCC model resulted in delayed tumor growth and reduced volume, accompanied by an increased frequency of IFN-γ-producing tumor-infiltrating NK cells that displayed heightened expression of T-bet and NKG2D and reduced expression of the exhaustion-associated co-inhibitory molecules PD-1 and TIM-3. Therefore, in ccRCC, the tumor microenvironment polarizes TAM toward an immunosuppressive profile that promotes tumor-infiltrating NK cell dysfunction, contributing to tumor progression. In addition, immunotherapy strategies targeting TAM may result in NK cell reinvigoration, thereby counteracting tumor progression.

Duodenal mucosa of untreated celiac disease patients has altered expression of the GAS6 and PROS1 and the negative regulator tyrosine kinase TAM receptors subfamily.

Celiac disease (CD) is an immune-driven disease characterized by tissue damage in the small intestine of genetically-susceptible individuals. We evaluated here a crucial immune regulatory pathway involving TYRO3, AXL, and MERTK (TAM) receptors and their ligands PROS1 and GAS6 in duodenal biopsies of controls and CD patients. We found increased GAS6 expression associated with downregulation of PROS1 and variable TAM receptors levels in duodenum tissue of CD patients. Interestingly, CD3+ lymphocytes, CD68+, CD11c+ myeloid and epithelial cells, showed differential expressions of TAM components comparing CD vs controls. Principal component analysis revealed a clear segregation of two groups of CD patients based on TAM components and IFN signaling. In vitro validation demonstrated that monocytes, T lymphocytes and epithelial cells upregulated TAM components in response to IFN stimulation. Our findings highlight a dysregulated TAM axis in CD related to IFN signaling and contribute to a deeper understanding of the pathophysiology of CD.

Advancing Immunotherapies for HPV-Related Cancers: Exploring Novel Vaccine Strategies and the Influence of Tumor Microenvironment.

The understanding of the relationship between immunological responses and cancers, especially those related to HPV, has allowed for the study and development of therapeutic vaccines against these neoplasias. There is a growing number of studies about the composition and influence of the tumor microenvironment (TME) in the progression or establishment of the most varied types of cancer. Hence, it has been possible to structure immunotherapy approaches based on therapeutic vaccines that are even more specific and directed to components of TME and the immune response associated with tumors. Among these components are dendritic cells (DCs), which are the main professional antigen-presenting cells (APCs) already studied in therapy strategies for HPV-related cancers. On the other hand, tumor-associated macrophages are also potential targets since the profile present in tumor infiltrates, M1 or M2, influences the prognosis of some types of cancer. These two cell types can be targets for therapy or immunomodulation. In this context, our review aims to provide an overview of immunotherapy strategies for HPV-positive tumors, such as cervical and head and neck cancers, pointing to TME immune cells as promising targets for these approaches. This review also explores the potential of immunotherapy in cancer treatment, including checkpoint inhibitors, cytokine immunotherapies, immunotherapy vaccines, and cell therapies. Furthermore, it highlights the importance of understanding the TME and its effect on the design and achievement of immunotherapeutic methods.

Technology acceptance factors of e-commerce among young people: An integration of the technology acceptance model and theory of planned behavior.

This study aims to examine the factors involved in the technological acceptance of e-commerce among young university students. The research is focused on the articulation between the Technology Acceptance Model (TAM) and the Theory of Planned Behavior (TPB) by collecting secondary data and conducting a survey with 376 young university students, validated by using structural equations (SEM). The predominant factors and variables involved in the adoption of e-commerce by young university students in Medellín were identified. The results show that the attitude towards usage has a positive effect on usage intention because people consider a website to be useful and trust builds regarding usage intention, which will enable to make the transaction in an easier and safer way. In conclusion, perceived usefulness comes before attitude towards usage, and thus the main direct antecedent of the intention to use e-commerce is established.

A sensitive and inexpensive high-resolution melting-based testing algorithm for diagnosis of transient abnormal myelopoiesis and myeloid leukemia of Down syndrome.

Patients with Down syndrome (DS) are commonly affected by a pre-leukemic disorder known as transient abnormal myelopoiesis (TAM). This condition usually undergoes spontaneous remission within the first 2 months after birth; however, in children under 5, 20%-30% of cases evolve to myeloid leukemia of Down syndrome (ML-DS). TAM and ML-DS are caused by co-operation between trisomy 21 and acquired mutations in the GATA1 gene. Currently, only next-generation sequencing (NGS)-based methodologies are sufficiently sensitive for diagnosis in samples with small GATA1 mutant clones (≤10% blasts). Alternatively, this study presents research on a new, fast, sensitive, and inexpensive high-resolution melting (HRM)-based diagnostic approach that allows the detection of most cases of GATA1 mutations, including silent TAM. The algorithm first uses flow cytometry for blast count, followed by HRM and Sanger sequencing to search for mutations on exons 2 and 3 of GATA1. We analyzed 138 samples of DS patients: 110 of asymptomatic neonates, 10 suspected of having TAM, and 18 suspected of having ML-DS. Our algorithm enabled the identification of 33 mutant samples, among them five cases of silent TAM (5/110) and seven cases of ML-DS (7/18) with blast count ≤10%, in which GATA1 alterations were easily detected by HRM. Depending on the type of genetic variation and its location, our methodology reached sensitivity similar to that obtained by NGS (0.3%) at a considerably reduced time and cost, thus making it accessible worldwide.

Tumor-associated macrophages (TAMs) modulate response to HER2-targeted agents in a humanized mouse model of breast cancer.

PURPOSE: Tumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer. METHODS: A xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively). RESULTS: Tumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion. CONCLUSIONS: Activity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.

Augmented reality for virtual training in the construction industry.

BACKGROUND: Technology has evolved in surprising ways, and augmented reality (AR) has positioned itself as one of the technologies with outstanding value. Its importance in education is still being debated, but its incorporation in business training has been left out. OBJECTIVE: This study aims to determine variables that explain the intention to use this technology in construction training, focused on preventing injuries and disabilities. METHODS: This study was carried out using the Technology Acceptance Model (TAM) through the structural equation method. The variables: perceived ease of use, perceived usefulness, attitude toward using, and behavioral intention to use were incorporated. An AR app was developed that addresses the teaching of safety elements on scaffolding, and we collected data from Chilean construction companies. RESULTS: The results show that perceived usefulness and perceived ease of use explain the attitude towards using augmented reality, while perceived usefulness and attitude towards using explain behavioral intention to use. CONCLUSIONS: These findings enrich AR's literature in the construction industry and have high business managers' implications. It may allow them to implement this technology more likely to succeed in their virtual business training to prevent injury-related disability.

A influência de macrófagos M1, M2 e TAM, e do receptor P2X7 na invasividade e resistência de neuroblastoma / The influence of different macrophages' phenotypes, and of the P2X7 receptor, on the invasiveness and chemoresistance of neuroblastoma

O neuroblastoma é um tumor sólido muito comum em crianças. O estágio mais avançado da doença é altamente agressivo e invasivo, além de pouco responsivo à terapia, que é limitada por mecanismos de resistência e reincidência relacionados à metástase. Muitos estudos tem sido feitos para identificar mecanismos de invasão e quimioresistência de células tumorais, afim de aumentar a sobrevida dos pacientes com câncer. Nesse trabalho, nós estudamos o efeito dos macrófagos, as células imunes mais abundantes no microambiente tumoral, os TAMs (do inglês tumor-associated macrophage) e do receptor P2X7, um purinoreceptor acionado por ATP, nesses processos. Os TAMs respondem e atuam de acordo com a miríade de fatores que encontram, podendo gerar populações heterogêneas e com funções distintas, tanto antitumorais, como pró-tumorais. Altos níveis de ATP extracelular são encontrados no microambiente tumoral, podendo então ativar o receptor P2X7. Este receptor tem sido relacionado tanto a funções inflamatórias como funções na resolução da inflamação de macrófagos. Além disso, o receptor P2X7 está envolvido em uma variedade de eventos celulares, incluindo a secreção de mediadores pró-inflamatórios, a proliferação celular e a apoptose de células tumorais. Primeiramente, foi avaliado o papel do receptor P2X7 na polarização de macrófagos da derivados medula óssea de camundongos wild-type e nocaute para o P2X7 na presença e ausência de fatores secretados por células de neuroblastoma, e então foi estudada a influência desses diferentes macrófagos polarizados em eventos celulares de grande relevância clínica para o neuroblastoma: a invasividade e quimiorresistência. Os resultados demonstraram que, apesar do reconhecido envolvimento do receptor P2X7 na inflamação, a ausência deste receptor não atenua a expressão de marcadores característicos do fenótipo inflamatório, M1. O aumento da expressão do receptor P2Y2, também envolvido na inflamação, nessas células, sugere um mecanismo genético de compensação para não atenuação da inflamação em macrófagos que não expressam o receptor P2X7. Contudo, a ausência do receptor P2X7 levou a alterações no fenótipo alternativo, M2, de modo que a expressão de Tnf, marcador de M2, não foi reprimido. TAMs noucates para P2X7 tiveram a expressão de arg1, marcador de M2, suprimida, reforçando a importância do receptor P2X7 no estabelecimento de fenótipos ativados alternativamente. Nossos dados também sugerem que ausência do receptor P2X7 em TAMs permite a aquisição de um fenótipo capaz de tornar as células de neuroblastoma que expressam P2X7 mais invasivas e mais quimioresistentes à vincristina. Por outro lado, TAMs, independentemente da presença ou ausência do receptor P2X7, induziram a proliferação e quimioresistência das células de neuroblastoma silenciadas para o receptor P2X7, o que nos leva a concluir que o receptor P2X7 em TAMs é desfavorável à progressão de tumores expressando P2X7

Neuroblastoma is a highly common childhood solid tumor. The most advanced stage of the disease is highly aggressive and invasive, besides from being poorly responsive to therapies, which are limited by resistance and recurrence mechanisms related to metastasis. Several studies attempt to identify invasion and resistance mechanisms of the tumor cells in order to increase overall survival of the patients. On the present work, we investigated the effect of macrophages, the most abundant immune cells on the tumor microenvironment, called TAMs (tumor-associated macrophages), and of the P2X7 receptor, an ATP-gated purinoceptor, on these processes. TAMs and cancer cells crosstalk, and behave accordingly to a miriad of factors present at the TME, generating heterogeneous populations with distinct functionalities, either pro- or antitumor. High extracellular levels of ATP are found in the TME, being able to activate the P2X7 receptor. This receptor mediates both pro- and anti-inflammatory functions in macrophages. In addition, it is involved in several cellular events, including the secretion of pro-inflammatory mediators, cell proliferation and tumor cell apoptosis. At first, we evaluated the role of the P2X7 receptor on the polarization of bone marrow-derived macrophages (BMDM), either wild-type or knockout for the P2X7 receptor, in presence or absence or factors secreted by neuroblastoma cells. Next, we investigated the influence of the polarized macrophages in highly relevant cellular events for neuroblastoma, such as invasiveness and chemoresistance. Our results showed that, despite the known involvement of P2X7 receptor on inflammation, its absence did not decrease the expression if inflammatory markers of M1 macrophage populations. An increase in the expression of the P2Y2 receptor, also involved in inflammation, on these cells suggest a genetic compensation mechanism for preventing attenuation of inflammation when P2X7 is lacking. However, P2X7 receptor absence did compromise the M2 phenotype, driving the expression of Tnf. TAMs knockout for the P2X7 receptor were not able to express arg1, also an M2 marker, reinforcing a role of the P2X7 receptor on establishing alternative macrophage phenotypes. Our data also suggest that TAMs lacking the P2X7 receptor acquire a phenotype capable of turning P2X7R-expressing neuroblastoma cells more invasive and chemoresistant to vincristine. On the other hand, TAMs, independently on the presence of the P2X7 receptor, induced proliferation and resistance of neuroblastoma cells silenced for P2X7 receptor expression, leading us to the conclusion that the P2X7 receptor in TAMs is unfavorable for the progression of P2X7R-expressing tumors

Gas6 drives Zika virus-induced neurological complications in humans and congenital syndrome in immunocompetent mice.

Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations are still not fully understood. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate that there is a correlation between ZIKV neurological complications with higher Gas6 levels and the downregulation of genes associated with anti-viral response, as type I IFN due to Socs1 upregulation. Also, Gas6 gamma-carboxylation is essential for ZIKV invasion and replication in monocytes, the main source of this protein, which was inhibited by warfarin. Conversely, Gas6 facilitates ZIKV replication in adult immunocompetent mice and enabled susceptibility to transplacental infection. Our data indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.

Proposing a TAM-SDT-Based Model to Examine the User Acceptance of Massively Multiplayer Online Games.

This study is focused on the massively multiplayer online games' acceptance. In general, while specialized literature reveals that the online gaming industry has grown strongly in recent years, little evidence is identified on its user acceptance. In this manner, the present study is an attempt to fill this gap. Concretely, two aims are defined: (1) proposing an acceptance model to predict the continuance usage of massively multiplayer online games, and (2) knowing how this continuance usage encourages social well-being. The model proposed employing the structural equation modeling with partial least squares (PLS-SEM) methodology. This PLS-SEM model has been defined using a combination of the technology acceptance model (TAM) and the self-determination theory (SDT), comprising eight constructs: (1) autonomy and competence, (2) relatedness, (3) achievement and challenge, (4) flow experience, (5) perceived enjoyment, (6) social well-being, (7) perceived ease of use, and (8) continuance intention. The findings reveal that continuance intention impacts on social well-being. Moreover, the pivotal role of flow experience for continuance intention has been demonstrated. Additionally, continuance intention has been impacted by the perceived enjoyment, showing that it is a key construct for the acceptance of massively multiplayer online games. Thus, two contributions are highlighted. First, these results provide the gaming industry and software developer companies with considerations on gamers' motivations in the online game design, in order to stimulate and incentivize its use. Second, the present study can be useful for academicians and practitioners to understand the online gamers' emotions and well-being, showing some light over their psychology and mental health. Finally, limitations and future directions are exposed.

TAM and TIM receptors mRNA expression in Zika virus infected placentas.

To investigate the role of TYRO3, AXL and TIM1 receptors in the Zika virus (ZIKV) cycle, we determined their mRNA expression in different placental sites of ZIKV infected tissue during pregnancy. Unexpectedly, the ZIKV infection was not related with mRNA upregulation of these receptors or changes in expression of type I and III interferons in different placental sites. Instead, a decrease of TYRO3 mRNA expression was observed in positive sites of ZIKV positive placentas in comparison to negative sites. The basis of this downregulation can help to understand how ZIKV persists in placental tissue during pregnancy.

Using Cytometry for Investigation of Purinergic Signaling in Tumor-Associated Macrophages.

Tumor-associated macrophages are widely recognized for their importance in guiding pro-tumoral or antitumoral responses. Mediating inflammation or immunosuppression, these cells support many key events in cancer progression: cell growth, chemotaxis, invasiveness, angiogenesis and cell death. The communication between cells in the tumor microenvironment strongly relies on the secretion and recognition of several molecules, including damage-associated molecular patterns (DAMPs), such as adenosine triphosphate (ATP). Extracellular ATP (eATP) and its degradation products act as signaling molecules and have extensively described roles in immune response and inflammation, as well as in cancer biology. These multiple functions highlight the purinergic system as a promising target to investigate the interplay between macrophages and cancer cells. Here, we reviewed purinergic signaling pathways connecting cancer cells and macrophages, a yet poorly investigated field. Finally, we present a new tool for the characterization of macrophage phenotype within the tumor. Image cytometry emerges as a cutting-edge tool, capable of providing a broad set of information on cell morphology, expression of specific markers, and its cellular or subcellular localization, preserving cell-cell interactions within the tumor section and providing high statistical strength in small-sized experiments. Thus, image cytometry allows deeper investigation of tumor heterogeneity and interactions between these cells. © 2020 International Society for Advancement of Cytometry.

Microangiopatía trombótica sistémica asociada a mutaciones del complemento en trasplante renal donante vivo. reporte de caso / Systemic thrombotic microangiopathy associated with complement pathway mutations in living donor kidney transplant. case report

RESUMEN El síndrome urémico hemolítico (SUH) se caracteriza por la presencia de anemia hemolítica, plaquetopenia e insuficiencia renal aguda. Si bien se distingue clásicamente en típico o infeccioso y atípico, es menester reconocer situaciones clínicas en las que se pone de manifiesto, como por ejemplo, embarazo, puerperio inmediato, tumores, trasplante, drogas, etc., condiciones clínicas que han sido denominadas amplificadoras del complemento. La recurrencia postrasplante delsíndrome urémico hemolítico atípico (SUHa) ha sido descrita en porcentajes variables en pacientes con mutaciones del factor H, factor B, factor I y C3, y gen de la trombomodulina, en reportes de casos aislados. Se presenta el caso de una paciente con enfermedad renal crónica (ERC) secundaria a agenesia renal, receptora preemptive de un riñón de donante vivo relacionado que presentó disfunción del injerto renal secundaria a microangiopatía trombótica, asociado a complicación neurológica, hemorragias, disfunción orgánica múltiple y óbito. Se describen los hallazgos del estudio genético y anatomopatológico de necropsia.

ABSTRACT Hemolytic uremic syndrome (HUS) is characterized by the presence of hemolytic anemia, thrombocytopenia and acute kidney injury. Although it is usually distinguished as typical or infectious and atypical, it is necessary to recognize clinical situations in which it is revealed, such as pregnancy, immediate postpartum period, tumors, transplantation, drugs, etc., i.e. clinical conditions that have been called complement-amplifying conditions. Post-transplantation recurrence of atypical hemolytic uremic syndrome (aHUS) has been described in variable percentages in patients with mutations of factor H, factor B, factor I and C3, and thrombomodulin gene, in reports of isolated cases. We present the case of a patient with chronic kidney disease (CKD) secondary to renal agenesis, a preemptive recipient of a related living donor kidney, which presented renal graft dysfunction secondary to thrombotic microangiopathy, associated with neurological complications, hemorrhages, multiple organ dysfunction and death. The findings of the genetic and pathological autopsy study are described.

Junin Virus Triggers Macrophage Activation and Modulates Polarization According to Viral Strain Pathogenicity.

The New World arenavirus Junin (JUNV) is the etiological agent of Argentine hemorrhagic fever (AHF). Previous studies of human macrophage infection by the Old-World arenaviruses Mopeia and Lassa showed that while the non-pathogenic Mopeia virus replicates and activates human macrophages, the pathogenic Lassa virus replicates but fails to activate human macrophages. Less is known in regard to the impact of New World arenavirus infection on the human macrophage immune response. Macrophage activation is critical for controlling infections but could also be usurped favoring immune evasion. Therefore, it is crucial to understand how the JUNV infection modulates macrophage plasticity to clarify its role in AHF pathogenesis. With this aim in mind, we compared infection with the attenuated Candid 1 (C#1) or the pathogenic P strains of the JUNV virus in human macrophage cultures. The results showed that both JUNV strains similarly replicated and induced morphological changes as early as 1 day post-infection. However, both strains differentially induced the expression of CD71, the receptor for cell entry, the activation and maturation molecules CD80, CD86, and HLA-DR and selectively modulated cytokine production. Higher levels of TNF-α, IL-10, and IL-12 were detected with C#1 strain, while the P strain induced only higher levels of IL-6. We also found that C#1 strain infection skewed macrophage polarization to M1, whereas the P strain shifted the response to an M2 phenotype. Interestingly, the MERTK receptor, that negatively regulates the immune response, was down-regulated by C#1 strain and up-regulated by P strain infection. Similarly, the target genes of MERTK activation, the cytokine suppressors SOCS1 and SOCS3, were also increased after P strain infection, in addition to IRF-1, that regulates type I IFN levels, which were higher with C#1 compared with P strain infection. Together, this differential activation/polarization pattern of macrophages elicited by P strain suggests a more evasive immune response and may have important implications in the pathogenesis of AHF and underpinning the development of new potential therapeutic strategies.

Viral receptors for flaviviruses: Not only gatekeepers.

Arboviruses have been a huge threat for human health since the discovery of yellow fever virus in 1901. Arboviruses are arthropod born viruses, mainly transmitted by mosquitoes and ticks, responsible for more than thousands of deaths annually. The Flavivirideae family is probably the most clinically relevant, as it is composed of very important agents, such as dengue, yellow fever, West Nile, Japanese encephalitis, and, recently, Zika virus. Intriguingly, despite their structural and genomic similarities, flaviviruses may cause conditions ranging from mild infections with fever, cutaneous rash, and headache, to very severe cases, such as hemorrhagic fever, encephalitis, Guillain-Barré syndrome, and microcephaly. These differences may greatly rely on viral burden, tissue tropism, and mechanisms of immune evasion that may depend on both viral and host genetic factors. Unfortunately, very little is known about the biology of these factors, and how they orchestrate these differences. In this context, viral structural proteins and host cellular receptors may have a great relevance, as their interaction dictates not only viral tissue tropism, but also a plethora on intracellular mechanisms that may greatly account for either failure or success of infection. A great number of viral receptors have been described so far, although there is still a huge gap in understanding their overall role during infection. Here we discuss some important aspects triggered after the interaction of flaviviruses and host membrane receptors, and how they change the overall outcome of the infection.

Effect of intra-oral aging on t→m phase transformation, microstructure, and mechanical properties of Y-TZP dental ceramics.

The aim of the present study was to evaluate the influence of intra-oral aging on the tetragonal-to-monoclinic (t→m) phase transformation of two Y-TZP dental ceramics - Lava Frame (Frame) and Lava Plus (Plus) - and determine the impact of this response on their microstructures and mechanical properties: flexural strength, Young's modulus, microhardness and fracture toughness. Standardized ceramic specimens were analyzed by X-ray diffraction (XRD), scanning electron microscopy (SEM) and atomic force microscopy (AFM). After the baseline analysis, the specimens were attached to personalized intra-oral resin appliances and exposed to the oral cavity of 20 subjects for 60 days and then analyzed again. Specimens produced for mechanical properties evaluation were also analyzed before and after the 60-day intra-oral aging. The data were analyzed using two-way ANOVA and Tukey HSD's post hoc test (α=0.05). Weibull analysis was used to evaluate the strength reliability. Both Y-TZP ceramics suffered t→m phase transformation after 60-day intra-oral aging (Plus=4.7%/Frame=7.7%). SEM and AFM analyses showed dislodgement of ZrO2 grains and a significant increase in roughness after intra-oral aging for both ceramics. Both Y-TZP ceramics suffered a decrease on flexural strength, Young's modulus and fracture toughness after intra-oral aging (p<0.05). Only Plus presented a decrease of microhardness after intra-oral aging (p<0.05). Intra-oral aging for 60 days produced t→m phase transformation, changed the microstructure and decreased the mechanical properties of two Y-TZP dental ceramics.

Technology acceptance model & realidad aumentada: estudio en desarrollo

Introducción. Este artículo presenta el proyecto de investigación I+D, financiado por el Ministerio de Economía y Competitividad de España (EDU5746-P-Proyecto Rafodiun), para conocer el nivel de adopción de una tecnología o modelo TAM, formulado por Davies (1989). Se presentan las características del modelo, se formula uno para el análisis de la RA, así como el instrumento para su diagnóstico. Objetivo. Establecer el grado de motivación y nivel de satisfacción que despierta en los estudiantes universitarios el hecho de participar en experiencias formativas apoyadas en RA, e indagar sobre las dificultades técnicas, curriculares y organizativas que pudiera tener la RA para ser aplicada a los contextos de formación universitaria. Materiales y métodos. Se utilizó el Modelo de Aceptación de la Tecnología (TAM), formulado inicialmente por Davies(1989). Resultados. La investigación se llevó a cabo mediante estudios experimentales realizados con estudiantes de diferentes estudios universitarios, que interaccionen con diferentes objetos de aprendizaje producidos bajo la arquitectura de la RA, algunos de los cuales pueden observarse en el sitio web del RA del "Secretariado de Recursos Audiovisuales y Nuevas Tecnologías" de la Universidad de Sevilla (http://ra.sav.us.es/). Conclusiones. La RAes una tecnología que se está presentando como de verdadera utilidad y con diferentes posibilidades para facilitar el aprendizaje por parte de los estudiantes en diferentes áreas curriculares, pero sobre la que se debe reconocer que se están efectuando más análisis tecnológicos que investigaciones sobre su aplicación en el terreno educativo.

Introduction. This article introduces a R+D Project funded by Ministerio de Economía y Competitividad de España (EDU-5746-P-Proyecto Rafodiun) to get to know the degree of adoption of a TAM model or technology formulated by Davis (1989). The characteristics of the model are introduced and one is formulated for the RA analysis, along with the instrument for its diagnosis. Objective. Establish the motivation and satisfaction degrees the fact of participating in experiences supported by RAproduce among university students, and delve into the technical, curricular and organizational difficulties RA could have for being applied in university formation contexts. Materials and methods. The Technology Acceptance Model (TAM), initially formulated by Davis (1989) was used. Results. The research work was performed by means of experimental studies made with students from several university areas, who interact with different learning objects produced under RA´s architecture, some of which can be seen at RA´s website of "Secretariado de Recursos Audiovisuales y Nuevas Tecnologías", Universidad de Sevilla (http://ra.sav.us.es/). Conclusions. RA is a really useful technology, with several possibilities to make learning easier for students from different curricular areas, but it is also necessary to recognize that more technological analysis than research on its application in the education field are being made.

Introdução. Este artigo apresenta o projeto de investigação I+D, financiado pelo Ministério de Economia e Competitividade da Espanha (EDU5746-P-Projeto Rafodiun), para conhecer o nível de adoção de uma tecnologia ou modelo TAM, formulado por Davies (1989). Se apresentam as características do modelo, se formula um para a análise da RA, assim como o instrumento para seu diagnóstico. Objetivo. Estabelecer o grau de motivação e nível de satisfação que desperta nos estudantes universitários o fato de participar em experiências formativas apoiadas em RA, e indagar sobre as dificuldades técnicas, curriculares e organizativas que pudesse ter a RApara ser aplicada aos contextos de formação universitária. Materiais e métodos. Se utilizou o Modelo de Aceitação da Tecnologia (TAM), formulado inicialmente por Davies (1989). Resultados. A investigação se levou a cabo mediante estudos experimentais realizados com estudantes de diferentes estudos universitários, que interagem com diferentes objetos de aprendizagem produzidos sob a arquitetura da RA, alguns dos quais podem observar-se na página web do RA do "Secretariado de Recursos Audiovisuais e Novas Tecnologias" da Universidade de Sevilla (http://ra.sav.us.es/). Conclusões. A RA é uma tecnologia que se está apresentando como de verdadeira utilidade e com diferentes possibilidades para facilitar a aprendizagem por parte dos estudantes em diferentes áreas curriculares, mas sobre a que se deve reconhecer que se estão efetuando mais análise tecnológicos que investigações sobre sua aplicação no terreno educativo.

Much More than M1 and M2 Macrophages, There are also CD169(+) and TCR(+) Macrophages.

Monocytes are considered to be precursor cells of the mononuclear phagocytic system, and macrophages are one of the leading members of this cellular system. Macrophages play highly diverse roles in maintaining an organism's integrity by either directly participating in pathogen elimination or repairing tissue under sterile inflammatory conditions. There are different subpopulations of macrophages and each one has its own characteristics and functions. In this review, we summarize present knowledge on the polarization of macrophages that allows the generation of subpopulations called classically activated macrophages or M1 and alternative activated macrophages or M2. Furthermore, there are macrophages that their origin and characterization still remain unclear but have been involved as main players in some human pathologies. Thus, we also review three other categories of macrophages: tumor-associated macrophages, CD169(+) macrophages, and the recently named TCR(+) macrophages. Based on the literature, we provide information on the molecular characterization of these macrophage subpopulations and their specific involvement in several human pathologies such as cancer, infectious diseases, obesity, and asthma. The refined characterization of the macrophage subpopulations can be useful in designing new strategies, supplementing those already established for the treatment of diseases using macrophages as a therapeutic target.