Drebrin Protects Assembled Actin from INF2-FFC-mediated Severing and Stabilizes Cell Protrusions.

Highly specialized cells, such as neurons and podocytes, have arborized morphologies that serve their specific functions. Actin cytoskeleton and its associated proteins are responsible for the distinctive shapes of cells. The mechanism of their cytoskeleton regulation - contributing to cell shape maintenance - is yet to be fully clarified. Inverted formin 2 (INF2), one of the modulators of the cytoskeleton, is an atypical formin that can both polymerize and depolymerize actin filaments depending on its molar ratio to actin. Prior work has established that INF2 binds to the sides of actin filaments and severs them. Drebrin is another actin-binding protein that also binds filaments laterally and stabilizes them, but the interplay between drebrin and INF2 on actin filament stabilization is not well understood. Here, we have used biochemical assays, electron microscopy, and total internal reflection fluorescence microscopy imaging to show that drebrin protects actin filaments from severing by INF2 without inhibiting its polymerization activity. Notably, truncated drebrin - DrbA1-300 - is sufficient for this protection, though not as effective as the full-length protein. INF2 and drebrin are abundantly expressed in highly specialized cells and are crucial for the temporal regulation of their actin cytoskeleton, consistent with their involvement in peripheral neuropathy.

A suite of designed protein cages using machine learning and protein fragment-based protocols.

Designed protein cages and related materials provide unique opportunities for applications in biotechnology and medicine, but their creation remains challenging. Here, we apply computational approaches to design a suite of tetrahedrally symmetric, self-assembling protein cages. For the generation of docked conformations, we emphasize a protein fragment-based approach, while for sequence design of the de novo interface, a comparison of knowledge-based and machine learning protocols highlights the power and increased experimental success achieved using ProteinMPNN. An analysis of design outcomes provides insights for improving interface design protocols, including prioritizing fragment-based motifs, balancing interface hydrophobicity and polarity, and identifying preferred polar contact patterns. In all, we report five structures for seven protein cages, along with two structures of intermediate assemblies, with the highest resolution reaching 2.0 Å using cryo-EM. This set of designed cages adds substantially to the body of available protein nanoparticles, and to methodologies for their creation.

A Suite of Designed Protein Cages Using Machine Learning Algorithms and Protein Fragment-Based Protocols.

Designed protein cages and related materials provide unique opportunities for applications in biotechnology and medicine, while methods for their creation remain challenging and unpredictable. In the present study, we apply new computational approaches to design a suite of new tetrahedrally symmetric, self-assembling protein cages. For the generation of docked poses, we emphasize a protein fragment-based approach, while for de novo interface design, a comparison of computational protocols highlights the power and increased experimental success achieved using the machine learning program ProteinMPNN. In relating information from docking and design, we observe that agreement between fragment-based sequence preferences and ProteinMPNN sequence inference correlates with experimental success. Additional insights for designing polar interactions are highlighted by experimentally testing larger and more polar interfaces. In all, using X-ray crystallography and cryo-EM, we report five structures for seven protein cages, with atomic resolution in the best case reaching 2.0 Å. We also report structures of two incompletely assembled protein cages, providing unique insights into one type of assembly failure. The new set of designed cages and their structures add substantially to the body of available protein nanoparticles, and to methodologies for their creation.

Neopentecostalismo, teología de la prosperidad y neoliberalismo. Hacia una lógica religiosa para el Homo oeconoimicus

El presente escrito tiene por objetivo demostrar que la relación entre la teología de la prosperidad, que se toma aquí específicamente en su expresión neopentecostal, y el neoliberalismo, entendido desde su dimensión de fuerza productora de subjetividad, se ha fortalecido dentro del actual marco de reproducción sistémica del capitalismo. Para esto se divide el escrito en tres partes: la primera, que se encarga de exponer conceptualmente el neopentecostalismo; la segunda, donde se expone la teología de la prosperidad; y, por último, aquella que trabaja la manera en que el fenómeno religioso neopentecostal, como ejemplo de fe de la prosperidad, se vincula con el neoliberalismo. De este modo, y a partir del método documental-bibliográfico, se puede evidenciar cómo es que el actual viraje del capitalismo se dirige hacia ciertas prácticas y discursos religiosos, de modo que pueda capturarlos y volverlos a su favor, ya que dichas prácticas y discursos permiten, entre otras cosas, una alternativa para curar, momentáneamente, el sufrimiento subjetivo que padece el Homo oeconomicus por vivir como manda el sistema.

The purpose of this paper is to demonstrate the relationship theology of prosperity, which is specifically taken in its neo-Pentecostal expression, and neoliberalism as necessary within the current framework of systemic reproduction of capitalism. For this, the writing is divided into three parts: the first, which is responsible for conceptually exposing neo-Pentecostalism; the second, where the theology of prosperity is exposed; and, finally, the one that works on the way in which the neo-Pentecostal religious phenomenon, as an example of faith in prosperity, is linked to neoliberalism. In this way, it can be evidenced how the current turn of capitalism is directed towards religion, so that it can capture it and turn it in its favor, since it allows an alternative to cure, momentarily, the subjective suffering of Homo oeconomicus that inhabits within the system that he himself produced.

O objetivo deste artigo é demonstrar que a relação entre a teologia da prosperidade, específicamente tomada em sua expressão neopentecostal, e o neoliberalismo, entendido a partir de sua dimensão de força produtora de subjetividade, tem se fortalecido no atual quadro de reprodução do capitalismo. Para isso, o escrito está dividido em três partes: a primeira, que se encarrega de expor conceitualmente o neopentecostalismo; a segunda, onde é exposta a teologia da prosperidade; e, por fim, a que trabalha a maneira como o fenômeno religioso neopentecostal, como exemplo de fé na prosperidade, se vincula ao neoliberalismo. Desta forma, e a partir do método bibliográfico-documental, pode-se evidenciar como a atual virada do capitalismo está voltada para a religião, de modo que possa capturá-la e transformá-la a seu favor, pois permite uma alternativa para curar, momentaneamente, o sofrimento subjetivo sofrido pelo homo oeconomicus por viver como manda o sistema.

Hacia una epistemología jurídica crítica: precisiones y distinciones sobre epistemología jurídica, métodos y metodología / Towards a critical legal epistemology: Precisions and distinctions on legal epistemology, method and methodology / Rumo a uma epistemologia jurídica crítica: esclarecimentos e distinções sobre epistemologia jurídica, métodos e metodologia

RESUMEN Se parte de la siguiente pregunta: ¿Qué métodos, enfoques y estrategias metodológicas son pertinentes en la investigación en derecho? El artículo presenta algunas precisiones sobre las nociones de epistemología jurídica, métodos y metodologías, distinguiéndolas y estableciendo las relaciones existentes entre ellas. Los resultados se establecen con base en los hallazgos de la revisión de fuentes documentales, donde el objetivo general fue determinar el estado de la discusión sobre métodos y metodologías aplicables al derecho. Del resumen analítico de las distintas fuentes se tomaron los elementos que permitieron describir las variadas posturas existentes sobre el problema, para finalmente defender la hipótesis sobre la necesidad de una epistemología jurídica crítica. Se concluye que una noción de epistemología jurídica parte de la consideración de que el derecho es una ciencia, con un objeto de estudio propio, que recoge las metodologías propuestas por las ciencias sociales y que, aunque las investigaciones que se realizan en derecho van desde la validez hasta la eficacia, una investigación con pertinencia para estos tiempos requiere incluir la mirada certera de una epistemología jurídica crítica.

ABSTRACT The text starts from the following question: what methods, approaches and methodologies are relevant in law research? The development of the article presents some details about the notions of legal epistemology, methods and methodologies, distinguishing them but establishing the relationships between them. The results are developed based on the findings of the review of documentary sources, where the general objective was to determine the status of the discussion on methods and methodologies applicable to the law. From the analytical summary of the different sources elements are taken that allowed to describe different positions on the problem, to finally defend the hypothesis about the need for a critical legal epistemology. It is concluded that a notion of legal epistemology starts from the consideration that law is a science, with an object of its own study, which includes the methodologies proposed by the social sciences and that although the investigations carried out in law range from validity until effective, an investigation relevant to our times requires a look at what a critical legal epistemology would be.

RESUMO Começa com a seguinte pergunta: Quais métodos, abordagens e estratégias metodológicas são relevantes na pesquisa em direito? O artigo apresenta alguns esclarecimentos sobre as noções de epistemologia jurídica, métodos e metodologias, distinguindo-as e estabelecendo as relações entre elas. Os resultados são estabelecidos com base na revisão de fontes documentais, onde o objetivo geral era determinar o status da discussão sobre métodos e metodologias aplicáveis à lei. A partir do resumo analítico das diferentes fontes, foram tomados os elementos que permitiram descrever as várias posições existentes sobre o problema, para finalmente defender a hipótese sobre a necessidade de uma epistemologia jurídica crítica. Conclui-se que uma noção de epistemologia jurídica parte da consideração de que o direito é uma ciência, com objeto de estudo próprio, que inclui as metodologias propostas pelas ciências sociais e que, embora a pesquisa em direito varie de validade à eficácia, uma investigação relevante para esses tempos exige a inclusão de uma aparência precisa de uma epistemologia jurídica crítica.

Switch from epoetin to darbepoetin alfa in hemodialysis: dose equivalence and hemoglobin stability.

AIM: The objective of the study reported here was to describe dose equivalence and hemoglobin (Hb) stability in a cohort of unselected hemodialysis patients who were switched simultaneously from epoetin alfa to darbepoetin alfa. METHODS: This was a multicenter, observational, retrospective study in patients aged ≥18 years who switched from intravenous (IV) epoetin alfa to IV darbepoetin alfa in October 2007 (Month 0) and continued on hemodialysis for at least 24 months. The dose was adjusted to maintain Hb within 1.0 g/dL of baseline. RESULTS: We included 125 patients (59.7% male, mean [standard deviation (SD)] age 70.4 [13.4] years). No significant changes were observed in Hb levels (mean [SD] 11.9 [1.3] g/dL, 12.0 [1.5], 12.0 [1.5], and 12.0 [1.7] at Months -12, 0, 12 and 24, respectively, P=0.409). After conversion, the erythropoiesis-stimulating agent (ESA) dose decreased significantly (P<0.0001), with an annual mean of 174.7 (88.7) international units (IU)/kg/week for epoetin versus 95.7 (43.4) (first year) and 91.4 (42.7) IU/kg/week (second year) for darbepoetin (65% and 64% reduction, respectively). The ESA resistance index decreased from 15.1 (8.5) IU/kg/week/g/dL with epoetin to 8.1 (3.9) (first year) and 7.9 (4.0) (second year) with darbepoetin (P<0.0001). The conversion rate was 354:1 in patients requiring high (>200 IU/kg/week) doses of epoetin and 291:1 in patients requiring low doses. CONCLUSION: In patients on hemodialysis receiving ESAs, conversion from epoetin alfa to darbepoetin alfa was associated with an approximate and persistent reduction of 65% of the required dose. To maintain Hb stability, a conversion rate of 300:1 seems to be appropriate for most patients receiving low doses of epoetin alfa (≤200 IU/kg/week), while 350:1 would be better for patients receiving higher doses.

As tensões da dignidade humana: conceituação e aplicação no direito internacional dos direitos humanos / Tensions of human dignity: conceptualization and application to international human rights law / Las tensiones de la dignidad humana: conceptualización y aplicación en el derecho internacional de los derechos humanos

Este artigo é resultado da pesquisa "Dignidade Humana: conceituação filosófica e aplicação jurídica" apresentada pelo Grupo de Pesquisa POLITEIA da Escola de Filosofia da Universidade Industrial de Santander, classificado na categoria B por COLCIENCIAS. Neste texto, fazemos uma reconstrução conceitual de três tensões do conceito de dignidade humana: i) a tensão entre seu caráter natural e seu caráter artificial (ou consensual ou positivo); ii) a tensão entre seu caráter abstrato e seu caráter concreto e iii) a tensão entre seu caráter universal e seu caráter particular. Em um primeiro momento, expomos os principais elementos teóricos das tensões. Posteriormente, as tensões são ilustradas mediante quatro Instrumentos de Direito Internacional dos Direitos Humanos e cinco sentenças da Corte Interamericana de Direitos Humanos. No final, apresentamos conclusões.

El presente artículo es resultado de la investigación "Dignidad Humana: conceptualización filosófica y aplicación jurídica" adelantada por el Grupo de Investigación POLITEIA de la Escuela de Filosofía de la Universidad Industrial de Santander, clasificado en categoria B por COLCIENCIAS. En este texto se realiza una reconstrucción conceptual de tres tensiones del concepto de dignidad humana: i) la tensión entre su carácter natural y su carácter artificial (o consensual o positivo); ii) la tensión entre su carácter abstracto y su carácter concreto y iii) la tensión entre su carácter universal y su carácter particular. En un primer momento se exponen los principales elementos teóricos de las tensiones. Posteriormente, las tensiones se ilustran mediante cuatro instrumentos de Derecho Internacional de los Derechos Humanos y cinco sentencias de la Corte Interamericana de Derechos Humanos. Al final se presentan las conclusiones lo anterior.

This article is the result of the research conducted on "Human Dignity: Philosophical conceptualization and the implementation of law" promoted by the POLITEIA Research Group from the School of Philosophy at the Universidad Industrial de Santander, classified as category B by COLCIENCIAS. This text formulates a three-strand conceptual reconstruction of the concept of human dignity: i) the tension between its natural and artificial character (either consensual or positive), ii) the tension between its abstract and concrete character, and iii) the tension between its universal and individual character. First, the main theoretical elements of these tensions are outlined. After that, the tensions are illustrated using four Instruments of International Human Rights Law and five trials by the Inter-American Court of Human Rights. Finally, conclusions regarding the tensions are presented.

Antiproteinuric efficacy of losartan in comparison with amlodipine in non-diabetic proteinuric renal diseases: a double-blind, randomized clinical trial.

BACKGROUND: Proteinuria is a significant independent determinant of the progression of chronic renal diseases. It induces an increased synthesis of angiotensin II, endothelin and profibrogenic growth factors, such as transforming growth factor-beta (TGF-beta), by mesangial and tubular cells. The antiproteinuric effect of angiotensin-converting enzyme inhibitors (ACEIs) in diabetic and non-diabetic nephropathies predicts long-term renoprotection afforded by these drugs. Angiotensin II receptor antagonists are renoprotective in patients with type 2 diabetes, but studies about their effect in non-diabetic proteinuric nephropathies are very scarce. METHODS: We randomly assigned 97 patients with non-diabetic nephropathies and proteinuria >1.5 g/24 h to treatment with losartan (50 mg daily) or amlodipine (5 mg daily) for 20 weeks. Doses of the study medications were titrated to achieve a target blood pressure <140/90 mmHg in both groups. Primary outcome was the decrease in the level of 24 h proteinuria. Secondary outcomes were changes in the plasma and urinary levels of TGF-beta. RESULTS: The baseline characteristics in both groups were similar. Proteinuria decreased by 32.4% (95% confidence interval -38.4 to -21.8%) after 4 weeks of treatment and by 50.4% (-58.9 to -40.2%) after 20 weeks in the losartan group, whereas no significant proteinuria changes were observed in the amlodipine group (P < 0.001). There was no significant correlation between the level of baseline proteinuria and the proteinuria decrease induced by losartan. Both losartan and amlodipine induced a similar and significant blood pressure reduction. Target blood pressure was achieved with the initial dose of study medication (50 mg daily) in 76% of losartan group patients and in 68% of the amlodipine group patients (5 mg daily). Urinary TGF-beta significantly decreased with losartan (-22.4% of the baseline values after 20 weeks of treatment), whereas it tended to increase with amlodipine (between-group difference P < 0.05). A significant correlation between proteinuria decrease and urinary TGF-beta reduction was found in the losartan group (r = 0.41, P < 0.005). Serum creatinine and serum potassium remained stable during the study in both groups. CONCLUSIONS: Losartan induced a drastic decrease in proteinuria accompanied by a reduction in urinary excretion of TGF-beta in patients with non-diabetic proteinuric renal diseases.