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O texto discute a relação entre a educação e a organização democrática do governo republicano. Para o autor, pelo menos desde Kant os teóricos clássicos da filosofia política estavam convencidos de que uma boa educação e uma ordem estatal republicana dependem uma da outra: formar cidadãos para a liberdade para que, como cidadãos autônomos institucionalizem uma educação pública que possibilite a seus filhos o caminho para a maioridade política. Mas ele constata hoje um divórcio entre as gêmeas teorias da democracia e da educação. Razões que podem ter levado a essa cisão ele localiza na combinação, por afinidades eletivas, entre uma concepção truncada de democracia, que dependeria de comunidades tradicionais e mesmo religiosas para reproduzir suas bases ético-culturais, e uma falsa concepção normativa de neutralidade do estado, que culmina concebendo os professores não mais como servidores públicos a serviço do estado democrático de direito, mas como servidores dos pais. Em contraposição ao desacoplamento entre a formação do cidadão autônomo e do governo autônomo dos cidadãos, entre pedagogia e teoria política, ele reconstrói, a partir dos clássicos da teoria social, a concepção sobre um nexo fundamental entre educação e liberdade política, entre formação e democracia. Longe de advogar por uma volta à escola tradicional, o autor chama a atenção para dois grandes desafios que juntas, pedagogia e teoria democrática precisam enfrentar: o impacto da revolução digital sobre a esfera pública e a crescente heterogeneidade cultural dos cidadãos, em especial nas democracias ocidentais, para que a educação torne a ser o lugar do aprendizado da cultura democrática.
O texto responde a críticas feitas ao pequeno livro publicado sob o título Reitifiação no qual o autor pretendia recuperar na herança da teoria de Marx o conceito reificação á luz da teoria do reconhecimento. O texto primeiro busca precisar o marco de referência dentro do qual foi feita originalmente a tentativa de recuperar o conceito reificação, enfatizando sua interpretação literal. Em seguida, o texto trata de problemas específicos que resultam da sugestão de entender reificação como uma forma de esquecimento do reconhecimento. Tomando como premissa que o próximo (Mitmensch) é reconhecido pré-cognitivamente, o autor defende que a rotinização e habitualização de práticas sociais com objetivos desumanizantes automatizados pode levar ao esquecimento do reconhecimento original da outra pessoa
Reduced external knee adduction moments in the second half of stance after total hip replacement have been reported in hip osteoarthritis patients. This reduction is thought to shift the load from the medial to the lateral knee compartment and as such increase the risk for knee osteoarthritis. The knee adduction moment is a surrogate for the load distribution between the medial and lateral compartments of the knee and not a valid measure for the tibiofemoral contact forces which are the result of externally applied forces and muscle forces. The purpose of this study was to investigate whether the distribution of the tibiofemoral contact forces over the knee compartments in unilateral hip osteoarthritis patients 1 year after receiving a primary total hip replacement differs from healthy controls. Musculoskeletal modeling on gait was performed in OpenSim using the detailed knee model of Lerner et al. (2015) for 19 patients as well as for 15 healthy controls of similar age. Knee adduction moments were calculated by the inverse dynamics analysis, medial and lateral tibiofemoral contact forces with the joint reaction force analysis. Moments and contact forces of patients and controls were compared using Statistical Parametric Mapping two-sample t-tests. Knee adduction moments and medial tibiofemoral contact forces of both the ipsi- and contralateral leg were not significantly different compared to healthy controls. The contralateral leg showed 14% higher medial tibiofemoral contact forces compared to the ipsilateral (operated) leg during the second half of stance. During the first half of stance, the lateral tibiofemoral contact force of the contralateral leg was 39% lower and the ratio 32% lower compared to healthy controls. In contrast, during the second half of stance the forces were significantly higher (39 and 26%, respectively) compared to healthy controls. The higher ratio indicates a changed distribution whereas the increased lateral tibiofemoral contact forces indicate a higher lateral knee joint loading in the contralateral leg in OA patients after total hip replacement (THR). Musculoskeletal modeling using a detailed knee model can be useful to detect differences in the load distribution between the medial and lateral knee compartment which cannot be verified with the knee adduction moment.
Em alguns de seus trabalhos Talcott Parsons descreveu o estabelecimento das sociedades modernas como um processo de diferenciação de diversas esferas de reconhecimento recíproco. Neste texto eu uso a teoria social do reconhecimento de Parsons para examinar características de conflitos sociais recentes. Começo expondo a descrição que Parsons fez das lutas por reconhecimento ocorridas nas sociedades altamente industrializadas de sua época. Depois tomo a concepção de Parsons sobre conflitos por reconhecimento normativamente orientados para indicar tendências que levaram a uma gradual erosão das estruturas de pacificação social postuladas por Parsons nas últimas décadas do século 20. Descrevo as consequências iniciais dessa desintegração como uma “barbarização” dos conflitos sociais. Por barbarizado entendo um estágio da sociedade em que as lutas por reconhecimento social escalaram e se tornaram anômicas, uma vez que não podem mais ser resolvidas nas esferas sistêmicas estabelecidas de negociação. Este texto revela a importância do conceito de reconhecimento para a teoria social ao acompanhar Parsons na análise de transformações estruturais que atualmente emergem em resposta a conflitos sociais. Resumo do editor.
Objective: Many patients with localized prostate cancer (PCa) do not immediately undergo radical prostatectomy (RP) after biopsy confirmation. The aim of this study was to investigate the influence of “time-from-biopsy-to- prostatectomy” on adverse pathological outcomes.
Materials and Methods: Between January 2014 and December 2019, 437 patients with intermediate- and high risk PCa who underwent RP were retrospectively identified within our prospective institutional database. For the aim of our study, we focused on patients with intermediate- (n = 285) and high-risk (n = 151) PCa using D'Amico risk stratification. Endpoints were adverse pathological outcomes and proportion of nerve-sparing procedures after RP stratified by “time-from-biopsy-to-prostatectomy”: ≤3 months vs. >3 and < 6 months. Medians and interquartile ranges (IQR) were reported for continuously coded variables. The chi-square test examined the statistical significance of the differences in proportions while the Kruskal-Wallis test was used to examine differences in medians. Multivariable (ordered) logistic regressions, analyzing the impact of time between diagnosis and prostatectomy, were separately run for all relevant outcome variables (ISUP specimen, margin status, pathological stage, pathological nodal status, LVI, perineural invasion, nerve-sparing).
Results: We observed no difference between patients undergoing RP ≤3 months vs. >3 and <6 months after diagnosis for the following oncological endpoints: pT-stage, ISUP grading, probability of a positive surgical margin, probability of lymph node invasion (LNI), lymphovascular invasion (LVI), and perineural invasion (pn) in patients with intermediate- and high-risk PCa. Likewise, the rates of nerve sparing procedures were 84.3 vs. 87.4% (p = 0.778) and 61.0% vs. 78.8% (p = 0.211), for intermediate- and high-risk PCa patients undergoing surgery after ≤3 months vs. >3 and <6 months, respectively. In multivariable adjusted analyses, a time to surgery >3 months did not significantly worsen any of the outcome variables in patients with intermediate- or high-risk PCa (all p > 0.05).
Conclusion: A “time-from-biopsy-to-prostatectomy” of >3 and <6 months is neither associated with adverse pathological outcomes nor poorer chances of nerve sparing RP in intermediate- and high-risk PCa patients.
Embora a ideia de “patologias sociais” ou “enfermidades” de uma sociedade inteira tenha sido bastante comum desde o Segundo Discurso de Rousseau, e especialmente proeminente dentro da tradição da teoria crítica, não está claro a quem exatamente se referea proposição de ter adoecido. Será apenas um número suficiente de pessoas individuais, será o coletivo entendido como um macro-sujeito, ou é a “sociedade” em si que foi acometida por uma desorganização específica de suas instituições sociais, afetando sua eficiência funcional de tal forma que se pode falar de uma “doença” especificamente social? Para todas as três atribuições, ou seja, as pessoas individualmente com suas doenças, a coletividade com a sua síndrome clínica particular, ou a própria sociedade como adoecida, podem ser encontrados casos na literatura correspondente. A fim de encontrar uma saída para essas perplexidades conceituais que estão no cerne dessa maneira de falar, abordo as propostas teóricas de Alexander Mitscherlich e Sigmund Freud, ambos defensores de um conceito específico de “patologias sociais” ou “enfermidades” baseado em ideias psicanalíticas. O resultado da minha reconstrução crítica será que somente uma compreensão da sociedade como uma entidade orgânica permite um uso não redutor da ideia de “patologias sociais”.
MicroRNAs (miRNAs) have emerged as critical posttranscriptional regulators of the immune system, including function and development of regulatory T (Treg) cells. Although this critical role has been firmly demonstrated through genetic models, key mechanisms of miRNA function in vivo remain elusive. Here, we review the role of miRNAs in Treg cell development and function. In particular, we focus on the question what the study of miRNAs in this context reveals about miRNA biology in general, including context-dependent function and the role of individual targets vs. complex co-targeting networks. In addition, we highlight potential technical pitfalls and state-of-the-art approaches to improve the mechanistic understanding of miRNA biology in a physiological context.
Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.
Although cyclophosphamide (CP) has been used successfully in the clinic for over 50 years, it has so far not been possible to elucidate the mechanism of action and to use it for improvement. This was not possible because the basis of the mechanism of action of CP, which was found by lucky coincidence, is apoptosis, the discovery of which was honored with the Nobel Prize only in 2002. Another reason was that results from cell culture experiments were used to elucidate the mechanism of action, ignoring the fact that in vivo metabolism differs from in vitro conditions. In vitro, toxic acrolein is formed during the formation of the cytotoxic metabolite phosphoreamidemustard (PAM), whereas in vivo proapoptotic hydroxypropanal (HPA) is formed. The CP metabolites formed in sequence 4-hydroxycyclophosphamide (OHCP) are the main cause of toxicity, aldophosphamide (ALDO) is the pharmacologically active metabolite and HPA amplifies the cytotoxic apoptosis initiated by DNA alkylation by PAM. It is shown that toxicity is drastically reduced but anti-tumor activity strongly increased by the formation of ALDO bypassing OHCP. Furthermore, it is shown that the anti-tumor activity against advanced solid P388 tumors that grow on CD2F1 mice is increased by orders of magnitude if DNA damage caused by a modified PAM is poorly repairable. View Full-Text
Motivation: Calculating the magnitude of treatment effects or of differences between two groups is a common task in quantitative science. Standard effect size measures based on differences, such as the commonly used Cohen's, fail to capture the treatment-related effects on the data if the effects were not reflected by the central tendency. The present work aims at (i) developing a non-parametric alternative to Cohen’s d, which (ii) circumvents some of its numerical limitations and (iii) involves obvious changes in the data that do not affect the group means and are therefore not captured by Cohen’s d.
Results: We propose "Impact” as a novel non-parametric measure of effect size obtained as the sum of two separate components and includes (i) a difference-based effect size measure implemented as the change in the central tendency of the group-specific data normalized to pooled variability and (ii) a data distribution shape-based effect size measure implemented as the difference in probability density of the group-specific data. Results obtained on artificial and empirical data showed that “Impact”is superior to Cohen's d by its additional second component in detecting clearly visible effects not reflected in central tendencies. The proposed effect size measure is invariant to the scaling of the data, reflects changes in the central tendency in cases where differences in the shape of probability distributions between subgroups are negligible, but captures changes in probability distributions as effects and is numerically stable even if the variances of the data set or its subgroups disappear.
Conclusions: The proposed effect size measure shares the ability to observe such an effect with machine learning algorithms. Therefore, the proposed effect size measure is particularly well suited for data science and artificial intelligence-based knowledge discovery from big and heterogeneous data.