Mechanisms of HIV-1 Nucleocapsid Protein Inhibition by Lysyl-Peptidyl-Anthraquinone Conjugates

The Nucleocapsid protein NCp7 (NC) is a nucleic acid chaperone responsible for essential steps of the HIV-1 life cycle and an attractive candidate for drug development. NC destabilizes nucleic acid structures and promotes the formation of annealed substrates for HIV-1 reverse transcription elongation. Short helical nucleic acid segments bordered by bulges and loops, such as the Trans-Activation Response element (TAR) of HIV-1 and its complementary sequence (cTAR), are nucleation elements for helix destabilization by NC and also preferred recognition sites for threading intercalators. Inspired by these observations, we have recently demonstrated that 2,6-disubstituted peptidylanthraquinone-conjugates inhibit the chaperone activities of recombinant NC in vitro, and that inhibition correlates with the stabilization of TAR and cTAR stem-loop structures. We describe here enhanced NC inhibitory activity by novel conjugates that exhibit longer peptidyl chains ending with a conserved Nterminal lysine. Their efficient inhibition of TAR/cTAR annealing mediated by NC originates from the combination of at least three different mechanisms, namely, their stabilizing effects on nucleic acids dynamics by threading intercalation, their ability to target TAR RNA substrate leading to a direct competition with the protein for the same binding sites on TAR, and, finally, their effective binding to the NC protein. Our results suggest that these molecules may represent the stepping-stone for the future development of NC-inhibitors capable of targeting the protein itself and its recognition site in RNA

AS PRÁTICAS DE MATEMÁTICA E OS EFEITOS NA FORMAÇÃO DO PROFESSOR DE ANOS INICIAIS

Grounded on Foucauldian studies, we have attempted to understand how mathematics practices have produced effects on first-to-fourth-grade mathematics teachers. We have argued that such effects go beyond the borders of the pedagogical and the contents of this knowledge area, becoming part of a “general policy” of truth that comprehends the conceptions of scientific knowledge, mathematics and teaching of a particular time. The materials here considered were produced in a High School course in the 1990’s. We have realized that the practices of mathematics education in that period could be assessed from three emphases: a) education to teach mathematics through the “concrete”, the “logical knowledge” and the “abstract”, showing mathematics teaching practices from a constructivist, science-oriented perspective, b) “globalized teaching”, and c) “emphasis on reality”. This has enabled us to problematize the mathematical education of first-to-fourth grade teachers produced in those practices.A partir de los estudios foucaultianos buscamos comprender como las prácticas de matemática han producido efectos en la formación del maestro de matemática en la educación primaria y argumentamos que esos efectos traspasan los límites de lo pedagógico y de los contenidos de esa área de conocimiento. Ellos constituyen parte de una “política generalizada” de verdad, que abarca las concepciones de conocimiento científico, de matemática y de la enseñanza de cada época. Los materiales que consideramos son los producidos en un Curso de la Educación Secundaria, en la década de 1990. Delante de los análisis, percibimos que las prácticas de formación matemática, en ese período, pueden ser examinadas a partir de tres énfasis: a) La formación para enseñar matemática por lo “concreto”, por el “conocimiento lógico” y por lo “abstracto”, que permitió visualizar las prácticas dirigidas al enseñar matemática en una perspectiva constructivista, de cuño científico; b) La “enseñanza globalizada” y c) El “énfasis en la realidad”, que nos posibilitó poner en cuestión la formación matemática del maestro de la educación primaria producida en esas prácticas.A partir dos estudos foucaultianos, buscamos entender como as práticas de matemática têm produzido efeitos na formação do professor de matemática nos anos iniciais e argumentamos que esses efeitos ultrapassam as fronteiras do pedagógico e dos conteúdos disciplinares dessa área de conhecimento, fazendo parte de uma “política geral” de verdade que envolve as concepções de conhecimento científico, de matemática e de ensino de cada época. Os materiais que consideramos foram produzidos em um Curso de Nível Médio na década de 1990. Percebemos que as práticas de formação matemática, nesse período, podem ser examinadas a partir de três ênfases: a) a formação para ensinar matemática pelo “concreto”, “conhecimento lógico” e “abstrato”, o que permite visualizar as práticas voltadas ao ensinar matemática em uma perspectiva construtivista, de cunho científico, b) o “ensino globalizado” e c) a “ênfase na realidade”. Isso nos possibilita colocar em questão a formação matemática do professor de anos iniciais produzida nessas práticas

Detailed proteomic analysis on DM: insight into its hypoallergenicity.

Successful therapy in cow milk (CM) protein allergy rests upon completely eliminating CM proteins from the child's diet: it is thus necessary to provide a replacement food. Donkey milk (DM) has recently aroused scientific and clinical interest, above all among paediatric allergologists. A deeper knowledge of proteins in DM is necessary to evaluate the immunological and physiological properties of this natural substitute for cow's milk. The paper offers a detailed comparative analysis among the protein fractions of DM, CM and human milk, following an extensive proteomic study of the casein and whey proteins of DM performed by narrow pH range 2-DE. The detailed protein composition and structural features reported in this study provide insight into the molecular reasons for the hypoallergenicity of DM. Whole DM might constitute a valid substitute of CM in feeding children with CM protein allergy and it might also constitute the basis for formulas suitable for allergic subjects in the first year of life

Vulvar Lymphangiosarcoma in a Bitch

Background: Lymphangiosarcoma (LSA) is a rare, highly malignant and infiltrative neoplasm of the lymphatic endothelium of dogs and cats. It is mostly reported in medium to large breed dogs, over 5-year-old, with no sexual predisposition. Affected animals present fluctuating and diffuse swelling, covering both dermis and subcutaneous tissue, spreading through lymphatic and haematic vessels. Histologically, LSA is characterized by connected channels devoid of conspicuous haematic elements. Treatment depends on location of the neoplasm, staging, and possibility of curative surgical excision. Chemotherapy and radiotherapy can increase survival time. In this report, we describe a rare case of vulvar LSA in a dog. This is the first Brazilian report of LSA in dogs so far.Case: A 3-year-old, female, mixed breed dog was presented for evaluation of vesicle-bullous lesions in the vulvar and perivulvar region with progressive growth along 6 month. Histopathology revealed neoplastic proliferation in the superficial dermis, advancing through the profound dermis. The histological lesion pattern was consistent with angiosarcoma, which united along with macroscopic pattern of the tumor, and the presence of multiple anastomosed vascular structures without erythrocytes within it at microscopy, was compatible with LSA. No evidence of metastasis or lymphadenopathy was found on survey radiography and ultrasound. We performed a surgical excision, and remaining wound was reconstructed with an advancement skin flap. Despite wide surgical resection, neoplastic cells could be found in surgical borders, as well as a metastatic inguinal lymph node. Postoperative chemotherapy based on doxorubicin as a single agent was administrated. Disease free interval (DFI) was one month after surgery, when small bullous lesions were observed near the surgical site, and histopathological exam confirmed LSA. Three months after the surgical procedure, the patient presented with worsening of the lesions, anorexia, and apathy. The owner opted for euthanasia. Total survival time was five months.Discussion: The LSA occurs often in dogs above five years old, unlike this case, in which the patient was 3 years old. Several anatomic locations were cited in other reports. In this case, the lesion was in both the vulvar and perivulvar regions, which is an uncommon location of LSA, described as secondarily affected region in one report only. Despite absence of metastasis in this case, lungs, kidneys, bone marrow, and spleen can be affected. Histopathologic exam is the golden standard for a definitive diagnose of LSA. Diagnosing LSA may be challenging due to its resemblance to hemangiosarcoma, and confirmation is only possible if histopathology detects an absence of red blood cells in the lymphatic channels. Prognosis is poor due to LSA aggressive and infiltrative features. Doxorubicin demonstrated good clinical response in other dogs. Chemotherapy protocols, whether alone or in combination with cyclophosphamide, have been proving to be promising in dogs with soft tissue sarcomas, such as LSA. Surgical approach is the most appropriate and it may be associated with radiotherapy or chemotherapy, especially if complete resection of the tumor is not possible. In this report, even though it was a young animal, the location and extension of the lesion did not contribute to the good prognosis, even after adding adjuvant chemotherapy to the treatment

Amiodarone and metabolite MDEA inhibit Ebola virus infection by interfering with the viral entry process

Ebola virus disease (EVD) is one of the most lethal transmissible infections characterized by a high fatality rate, and a treatment has not been developed yet. Recently, it has been shown that cationic amphiphiles, among them the antiarrhythmic drug amiodarone, inhibit filovirus infection. In the present work, we investigated how amiodarone interferes with Ebola virus infection. Wild-type Sudan ebolavirus and recombinant vesicular stomatitis virus, pseudotyped with the Zaire ebolavirus glycoprotein, were used to gain further insight into the ability of amiodarone to affect Ebola virus infection. We show that amiodarone decreases Ebola virus infection at concentrations close to those found in the sera of patients treated for arrhythmias. The drug acts by interfering with the fusion of the viral envelope with the endosomal membrane. We also show that MDEA, the main amiodarone metabolite, contributes to the antiviral activity. Finally, studies with amiodarone analogues indicate that the antiviral activity is correlated with drug ability to accumulate into and interfere with the endocytic pathway. Considering that it is well tolerated, especially in the acute setting, amiodarone appears to deserve consideration for clinical use in EV

Motivadores da imersão em redes e abordagens empreendedoras causal e effectual

Research aim: To describe possible distinct effects between the causation and effectuation approach regarding the perception of factors that motivate business networking.Method/Approach: We present a quantitative research carried out through convenience sampling, a type of non-probabilistic sampling. We conducted a factor analysis and analysis of variance (ANOVA).Originality/Relevance: There are only a few studies that associate the engagement of entrepreneurs in networks with entrepreneurial actions guided by the two different logics: causation, which emphasizes the selection of means to create the desired effect; and effectuation, which emphasizes possible effects to be created through the means available.Main findings: The findings show that there are significant differences between causal and effectual approaches to entrepreneurship and factors that motivate the participation in networks. The causal and effectual logic are not mutually exclusive; however, the intensity in each one entailed differences in the factors that motivate entrepreneurs to engage in networks. The research shows that causal and effectual entrepreneurs were motivated to participate in networks focusing mainly on benefits for the company.Theoretical/Methodological contributions: This research contributes not only to network studies, but also to entrepreneurship, considering that it highlights possible differences among the factors that motivate the insertion in networks by causal and effectual entrepreneurs. In addition, our study also explored the effect of different control variables on the perception of benefits from networking; these variables, however, had no influence on the perception of such benefits.Objetivo del estudio: Describa los posibles efectos diferentes entre la lógica de causation y de effectuation en la percepción de los factores que motivan la participación de los empresarios en las redes.Metodología: La investigación fue cuantitativa, descriptiva, con una muestra no probabilística debido a la accesibilidad. Los datos fueron sometidos a análisis factorial y ANOVA.Originalidad / Relevancia: Existen pocos estudios que asocian la inmersión de los empresarios en redes con la acción empresarial basada en diferentes lógicas: la acción causal, que enfatiza la selección de medios para crear el efecto deseado; y, la acción effectual que enfatiza los posibles efectos que se crearán con los medios disponibles.Principales resultados: Los resultados mostraron que existen diferencias significativas entre los estilos de acción empresarial "causal" y effectual y los factores que motivan la participación en las redes. Las lógicas causal" y effectual no eran mutuamente excluyentes, sin embargo, la intensidad de cada una mostró diferencias con respecto a los factores que motivan a los empresarios a participar en las redes. La investigación mostró que los empresarios guiados por acciones causal o effectual estaban motivados para participar en redes, centrándose principalmente en las expectativas de beneficios para las empresas.Contribuciones teóricas / metodológicas:La contribución se aplica tanto al estudio de las redes, como al emprendimiento, ya que resalta las posibles diferencias entre los factores que motivan la inserción en las redes de emprendedores guiados por el pensamiento causal y emprendedores guiados por el pensamiento effectual. Además, el estudio exploró el efecto de diferentes variables de control sobre la percepción de ventajas para la inmersión en redes y demostró la ausencia de diferencias.Objetivo do estudo: Descrever possíveis efeitos distintos entre as lógicas Causation e Effectuation na percepção de fatores que motivam a participação de empreendedores em redes.Metodologia/abordagem: A pesquisa foi quantitativa, descritiva, com amostra não probabilística por acessibilidade. Os dados foram submetidos à análise fatorial e ANOVA.Originalidade/Relevância: São escassos os estudos que associam a imersão dos empreendedores em redes à ação empreendedora com base em diferentes lógicas: ação causal, que enfatiza a seleção de meios para a criação do efeito desejado e a ação effectual, que enfatiza possíveis efeitos a serem criados com os meios disponíveis.Principais resultados: Os resultados mostraram que há diferenças significativas entre estilos de ação empreendedora causal e effectual e fatores que motivam a participação em redes. As lógicas causal e effectual não se mostraram excludentes, entretanto, a intensidade de cada uma apresentou diferenças quanto aos fatores que motivam empreendedores à participação em redes. A pesquisa mostrou que empreendedores orientados pela ação causal ou effectual foram motivados a participar em redes, focando principalmente em expectativas de benefícios para as empresas.Contribuições teóricas/metodológicas: A contribuição aplica-se tanto ao estudo de redes, como também do empreendedorismo, por evidenciar possíveis diferenças entre os fatores que motivam a inserção em redes por empreendedores orientados pelo pensamento causal e empreendedores orientados pelo pensamento effectual. Além disso, o estudo explorou o efeito de diferentes variáveis de controle sobre a percepção de vantagens para imersão em redes e identificou que elas não exerceram influência.

Characterization and significance of ACE2 and Mas receptor in human colon adenocarcinoma

Introduction: A new arm of the renin–angiotensin system (RAS) has been recently characterized; this includes angiotensin converting enzyme (ACE)2 and angiotensin (Ang)1-7, a heptapeptide acting through the Mas receptor (MasR). Recent studies show that Ang1-7 has an antiproliferative action on lung adenocarcinoma cells. The aim of this study was to characterize RAS expression in human colon adenocarcinoma and to investigate whether Ang1-7 exerts an antiproliferative effect on human colon adenocarcinoma cells. Materials and methods: Gene, protein expression and enzymatic activity of the main components of the RAS were determined on non-neoplastic colon mucosa as well as on the tumor mass and the mucosa taken 5 cm distant from it, both collected from patients with colon adenocarcinoma. Two different human colon cancer cell lines were treated with AngII and Ang1-7. Results: The novel finding of this study was that MasR was significantly upregulated in colon adenocarcinoma compared with non-neoplastic colon mucosa, which showed little or no expression of it. ACE gene expression and enzymatic activity were also increased in the tumors. However, AngII and Ang1-7 did not have any pro-/antiproliferative effects in the cell lines studied. Conclusions: The data suggest that upregulation of the MasR could be used as a diagnostic marker of colon adenocarcinoma

Observed 1970-2005 cooling of summer daytime temperatures in coastal California

This study evaluated 1950–2005 summer [June–August (JJA)] mean monthly air temperatures for two California air basins: the South Coast Air Basin (SoCAB) and the San Francisco Bay Area (SFBA). The study focuses on the more rapid post-1970 warming period, and its daily minima temperature Tmin and maxima temperature Tmax values were used to produce average monthly values and spatial distributions of trends for each air basin. Additional analyses included concurrent SSTs, 40-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-40) sea level coastal pressure gradients, and GCM-downscaled average temperature Tave values. Results for all 253 California National Weather Service (NWS) Cooperative Observer Program (COOP) sites together showed increased Tave values (0.23°C decade−1); asymmetric warming, as Tmin values increase faster than Tmax values (0.27° versus 0.04°C decade−1) and thus decreased daily temperature range (DTR) values (0.15°C decade−1). The spatial distribution of observed SoCAB and SFBA Tmax values exhibited a complex pattern, with cooling (−0.30°C decade−1) in low-elevation coastal areas open to marine air penetration and warming (0.32°C decade−1) in inland areas. Results also showed that decreased DTR values in the basins arose from small increases at inland sites (0.16°C decade−1) combined with large decreases (−0.58°C decade−1) at coastal sites. It is also possible that some of the current observed temperature trends could be associated with low-frequency decadal variability, expected even with a constant radiative forcing. Previous studies suggest that cooling JJA Tmax values in coastal California were a result of increased irrigation, coastal upwelling, or cloud cover. The current hypothesis is that they arise (as a possible “reverse reaction”) from the global warming of inland areas, which results in increased sea-breeze flow activity. GCM model Tave warming decreased from 0.13°C decade−1 at inland sites to 0.08°C decade−1 in coastal areas. Sea level pressure increased in the Pacific high and decreased in the thermal low. The corresponding gradient thus showed a trend of 0.04 hPa 100 km−1 decade−1, supportive of the hypothesis of increased sea-breeze activity

Diagnostic aspects of juvenile ossificant fibroma: A case study

Juvenile ossifying fibroma is an uncommon, fast-growing benign neoplasm classified within the group of fibro-osseous lesions that directly affect the face and the jaws. Although it is not followed by metastasis, it usually presents a highly aggressive nature. It is histopathologically divided into two patterns: trabecular and psammomatoid. It can be differentiated through the age of the patients, anatomic location and behavior of the lesion. In this context, this paper reports on the findings of a rare pathology case: juvenile ossifying fibroma, focusing primarily on its clinical, medical imaging and histopathological features characteristics, in order to familiarize the dentist, provide correct diagnosis and the most appropriate treatment