Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5-FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.View less
Concedida a Cássio Tavares, Marcela Cristina Evaristo e Maria Lúcia Zoega de Souza. Originalmente publicada na revista Magma, n. 5, p. 13-42, São Paulo, dez /1998. DOI: https://doi.org/10.11606/issn.2448-1769.mag.1998.87221
O título alude ao livro de Antonio Candido, Teresina etc. Rio de Janeiro: Ouro sobre azul, 2007.
Uma primeira versão deste texto foi publicada, com cortes, devido a limitações de espaço, no boletim online do IEB, logo depois da morte de Antonio Candido, a convite de Sandra Nitrini. Uma tradução em alemão, para a página do Instituto Latino americano de Universidade Livre de Berlim (Freie Universität Berlin) foi depois publicada numa versão sem cortes. Agora retomo aqui o texto completo em português, mas novamente adaptando-o ao novo veículo, a revista Literatura e Sociedade, do Departamento de Teoria Literária e Literatura Comparada, porque algumas notas mais factuais, com informações que interessavam ao projeto deste número, foram acrescentadas, a pedido da sua comissão editorial. Isso pode explicar o caráter dual do texto que aqui se publica, entre meio ficcional e informativo. Nele procurei unir boa parte das informações, que me foram solicitadas em 12 perguntas, com a tentativa de entender e expressar a figura do Mestre como uma combinação indissolúvel de alta intelectualidade, simplicidade e profunda riqueza humana, com pouco açúcar e muito afeto.
Em tempo, gostaria de agradecer aos colegas responsáveis por este numero de Literatura e Sociedade, por terem concordado com minha proposta deste texto hibrido.View less
Ecological momentary assessment (EMA) involves repeated, real-time assessments of phenomena (eg, cognitions, emotions, behaviours) over a period of time in naturalistic settings. EMA is increasingly used to study both within-person and between-person processes. We will review EMA studies investigating key health behaviours and synthesise: (1) study characteristics (eg, frequency of assessments, adherence, incentives), (2) associations between psychological predictors and behaviours and (3) moderators of adherence to EMA protocols.
Methods and analysis
This review will focus on EMA studies conducted across five public health behaviours in adult, non-clinical populations: movement behaviour (including physical activity and sedentary behaviour), dietary behaviour, alcohol consumption, tobacco smoking and preventive sexual health behaviours. Studies need to have assessed at least one psychological or contextual predictor of these behaviours. Studies reporting exclusively on physiological outcomes (eg, cortisol) or those not conducted under free-living conditions will be excluded. We will search OVID MEDLINE, Embase, PsycINFO and Web of Science using terms relevant to EMA and the selected health behaviours. Reference lists of existing systematic reviews of EMA studies will be hand searched. Identified articles will be screened by two reviewers. This review is expected to provide a comprehensive summary of EMA studies assessing psychological or contextual predictors of five public health behaviours.
Ethics and dissemination
The results will be disseminated through peer-reviewed publications and presentations. Data from included studies will be made available to other researchers. No ethics are required.View less
Salmonella pathogenicity island (SPI) 2 type three secretion system (T3SS)-mediated effector molecules facilitate bacterial survival in phagocytes but their role in the intestinal epithelium in vivo remains ill-defined. Using our neonatal murine infection model in combination with SPI2 reporter technology and RNA-Seq of sorted primary enterocytes, we demonstrate expression of SPI2 effector molecules by intraepithelial Salmonella Typhimurium (S. Typhimurium). Contrary to expectation, immunostaining revealed that infection with SPI2 T3SS-mutants resulted in significantly enlarged intraepithelial Salmonella-containing vacuoles (SCV) with altered cellular positioning, suggesting impaired apical to basolateral transmigration. Also, infection with isogenic tagged S. Typhimurium strains revealed a reduced spread of intraepithelial SPI2 T3SS mutant S. Typhimurium to systemic body sites. These results suggest that SPI2 T3SS effector molecules contribute to enterocyte apical to basolateral transmigration of the SCV during the early stage of the infection.View less
Viruses evolve extremely quickly, so reliable methods for viral host prediction are necessary to safeguard biosecurity and biosafety alike. Novel human-infecting viruses are difficult to detect with standard bioinformatics workflows. Here, we predict whether a virus can infect humans directly from next-generation sequencing reads. We show that deep neural architectures significantly outperform both shallow machine learning and standard, homology-based algorithms, cutting the error rates in half and generalizing to taxonomic units distant from those presented during training. Further, we develop a suite of interpretability tools and show that it can be applied also to other models beyond the host prediction task. We propose a new approach for convolutional filter visualization to disentangle the information content of each nucleotide from its contribution to the final classification decision. Nucleotide-resolution maps of the learned associations between pathogen genomes and the infectious phenotype can be used to detect regions of interest in novel agents, for example, the SARS-CoV-2 coronavirus, unknown before it caused a COVID-19 pandemic in 2020. All methods presented here are implemented as easy-to-install packages not only enabling analysis of NGS datasets without requiring any deep learning skills, but also allowing advanced users to easily train and explain new models for genomics.View less
The use of coarse-grained (CG) models is a popular approach to study complex biomolecular systems. By reducing the number of degrees of freedom, a CG model can explore long time- and length-scales inaccessible to computational models at higher resolution. If a CG model is designed by formally integrating out some of the system’s degrees of freedom, one expects multi-body interactions to emerge in the effective CG model’s energy function. In practice, it has been shown that the inclusion of multi-body terms indeed improves the accuracy of a CG model. However, no general approach has been proposed to systematically construct a CG effective energy that includes arbitrary orders of multi-body terms. In this work, we propose a neural network based approach to address this point and construct a CG model as a multi-body expansion. By applying this approach to a small protein, we evaluate the relative importance of the different multi-body terms in the definition of an accurate model. We observe a slow convergence in the multi-body expansion, where up to five-body interactions are needed to reproduce the free energy of an atomistic model.View less
Beneficial plant root-associated microorganisms carry out a range of functions that are essential for plant performance. Establishment of a bacterium on plant roots, however, requires overcoming several challenges, including competition with neighboring microorganisms and host immunity. Forward and reverse genetics have led to the identification of mechanisms that are used by beneficial microorganisms to overcome these challenges, such as the production of iron-chelating compounds, the formation of strong biofilms, or the concealment of characteristic microbial molecular patterns that trigger the host immune system. However, how such mechanisms arose from an evolutionary perspective is much less understood. To study bacterial adaptation in the rhizosphere, we employed experimental evolution to track the physiological and genetic dynamics of root-dwelling Pseudomonas protegens in the Arabidopsis thaliana rhizosphere under axenic conditions. This simplified binary one plant/one bacterium system allows for the amplification of key adaptive mechanisms for bacterial rhizosphere colonization. We identified 35 mutations, including single-nucleotide polymorphisms, insertions, and deletions, distributed over 28 genes. We found that mutations in genes encoding global regulators and in genes for siderophore production, cell surface decoration, attachment, and motility accumulated in parallel, underlining the finding that bacterial adaptation to the rhizosphere follows multiple strategies. Notably, we observed that motility increased in parallel across multiple independent evolutionary lines. All together, these results underscore the strength of experimental evolution in identifying key genes, pathways, and processes for bacterial rhizosphere colonization and a methodology for the development of elite beneficial microorganisms with enhanced root-colonizing capacities that can support sustainable agriculture in the future.
Beneficial root-associated microorganisms carry out many functions that are essential for plant performance. Establishment of a bacterium on plant roots, however, requires overcoming many challenges. Previously, diverse mechanisms that are used by beneficial microorganisms to overcome these challenges were identified. However, how such mechanisms have developed from an evolutionary perspective is much less understood. Here, we employed experimental evolution to track the evolutionary dynamics of a root-dwelling pseudomonad on the root of Arabidopsis. We found that mutations in global regulators, as well as in genes for siderophore production, cell surface decoration, attachment, and motility, accumulate in parallel, emphasizing these strategies for bacterial adaptation to the rhizosphere. We identified 35 mutations distributed over 28 genes. All together, our results demonstrate the power of experimental evolution in identifying key pathways for rhizosphere colonization and a methodology for the development of elite beneficial microorganisms that can support sustainable agriculture.View less
Este artículo explora la relación entre la experiencia viajera femenina y el género epistolar mediante una lectura de Cartas a Ricardo, de Rosario Castellanos como relato de viajes. El objetivo es analizar la naturaleza híbrida de la carta como género que permite ensayar ideas y confesar o revelar afectos durante procesos particulares de construcción de subjetividades femeninas. A diferencia de las crónicas de viajes tradicionales, se argumenta que los relatos de viaje transmitidos a través del género epistolar femenino dan cuenta del desplazamiento físico y emocional, pero también del trabajo intelectual y creativo de las mujeres en circunstancias de (auto)censura o represión. Se concluye que para Castellanos tanto el viaje como la escritura son actos conscientes de libertad intelectual y de género.View less
Understanding fine-grain diversity patterns across large spatial extents is fundamental for macroecological research and biodiversity conservation. Using the GrassPlot database, we provide benchmarks of fine-grain richness values of Palaearctic open habitats for vascular plants, bryophytes, lichens and complete vegetation (i.e., the sum of the former three groups).
Palaearctic biogeographic realm.
We used 126,524 plots of eight standard grain sizes from the GrassPlot database: 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 and 1,000 m2 and calculated the mean richness and standard deviations, as well as maximum, minimum, median, and first and third quartiles for each combination of grain size, taxonomic group, biome, region, vegetation type and phytosociological class.
Patterns of plant diversity in vegetation types and biomes differ across grain sizes and taxonomic groups. Overall, secondary (mostly semi-natural) grasslands and natural grasslands are the richest vegetation type. The open-access file ”GrassPlot Diversity Benchmarks” and the web tool “GrassPlot Diversity Explorer” are now available online (https://edgg.org/databases/GrasslandDiversityExplorer) and provide more insights into species richness patterns in the Palaearctic open habitats.
The GrassPlot Diversity Benchmarks provide high-quality data on species richness in open habitat types across the Palaearctic. These benchmark data can be used in vegetation ecology, macroecology, biodiversity conservation and data quality checking. While the amount of data in the underlying GrassPlot database and their spatial coverage are smaller than in other extensive vegetation-plot databases, species recordings in GrassPlot are on average more complete, making it a valuable complementary data source in macroecology.View less
This introductory contribution examines the ‘Global South’ as a meta category in the study of world politics. Against the backdrop of a steep rise in references to the ‘Global South’ across academic publications, we ask whether and how the North–South binary in general, and the ‘(Global) South’ in particular, can be put to use analytically. Building on meta categories as tools for the classification of global space, we discuss the increasing prominence of the ‘Global South’ and then outline different understandings attached to it, notably socio-economic marginality, multilateral alliance-building and resistance against global hegemonic power. Following an overview of individual contributions to this volume, we reflect on the analytical implications for using the ‘Global South’ category in academic research. Insights from China, the Caribbean, international negotiations or academic knowledge production itself not only point to patterns of shared experiences but also highlight the heterogeneity of ‘Southern’ realities and increasing levels of complexity that cut across the North–South divide. Overall, we argue for an issue-based and field-specific use of the ‘Global South’ as part of a broader commitment to a more deliberate, explicit and differentiated engagement with taken-for-granted categories.View less
A comprehensive treatment of the N African genus Heteromera Pomel (Compositae, Anthemideae) is presented. Morphological, anatomical and karyological features as well as distribution maps are reported. The analysis of nrDNA and cpDNA sequence variation reveals the close relationship of the two species, with H. philaenorum exhibiting little variation and being well separated from a more diverse H. fuscata. The chromosome numbers of H. fuscata and H. philaenorum are reported for the first time. Heteromera philaenorum Maire & Weiller, Chrysanthemum fuscatum f. pubescens Trotter and Chrysanthemum fuscatum f. subcanescens Trotter are lectotypified and H. philaenorum is reported as new for the flora of Algeria and Tunisia.View less
Given that houses have become a key signifier of an orientation towards the future, several villagers in Pliya can be regarded or regard themselves as pioneers of the construction of a new type of house. I will suggest here that the construction of new concrete houses is not to be understood merely as an adoption of lowland styles but as a self-conscious and selective use of a style of building. Those who are pioneering these houses also discuss their efforts in terms of pioneering acts, emphasising the self-taught nature of their appropriation of new aspects of craftsmanship. Drawing on long-term fieldwork among the Khmu of Pliya, and especially on more recent fieldwork in 2019 and 2020, I wish to argue that the way in which new houses have entered the local cosmos and are materialised by pioneering builders highlights a pioneering ethos that infuses local attempts at future-making, from wet rice cultivation to concrete villas.View less
Drawing on various ethnographic case studies from upland Southeast Asia, this special issue explores uplanders’ pioneering agency and challenges the stereotype of the remote and marginal uplander. We consider upland areas as dynamic sites of future-making and change – initiated by pioneering individuals or local elites who seek out and explore different potential sources of (economic and spiritual) potency. By using the figure of the pioneer as heuristic device, we realign our ethnographic gaze on uplanders by giving particular emphasis to: (1) agents of sociopolitical dynamics in Zomia, (2) questions of remoteness and pioneering mobility, (3) old and new sources of potency, from ‘the state’ to the religious domain, (4) aspirations and future-making and (5) pioneers of change and emergent elites.View less
Scholars generally assume that consumer ratings reflect consumer satisfaction, but ratings can be influenced by the design of the rating system. We examine two rating designs—single-dimensional rating systems, which elicit overall ratings only, and multidimensional (MD) rating systems, which elicit both dimensional and overall ratings—and how they impact overall ratings. Drawing on the accessibility–diagnosticity framework, we argue that dimensional ratings in MD systems influence overall ratings based on how the dimensions have been rated. We support this explanation with seven experiments. Our results suggest that across various experimental settings, rating objects, dimensions, and numbers of dimensions, overall ratings are systematically influenced by the design of the rating system.View less
In the spirit of the well-known odd-number limitation, we study the failure of Pyragas control of periodic orbits and equilibria. Addressing the periodic orbits first, we derive a fundamental observation on the invariance of the geometric multiplicity of the trivial Floquet multiplier. This observation leads to a clear and unifying understanding of the odd-number limitation, both in the autonomous and the non-autonomous setting. Since the presence of the trivial Floquet multiplier governs the possibility of successful stabilization, we refer to this multiplier as the determining center. The geometric invariance of the determining center also leads to a necessary condition on the gain matrix for the control to be successful. In particular, we exclude scalar gains. The application of Pyragas control on equilibria does not only imply a geometric invariance of the determining center but surprisingly also on centers that resonate with the time delay. Consequently, we formulate odd- and any-number limitations both for real eigenvalues together with an arbitrary time delay as well as for complex conjugated eigenvalue pairs together with a resonating time delay. The very general nature of our results allows for various applications.View less
Through controlled biomineralization, organisms yield complicated structures with specific functions. Here, Jania sp., an articulated coralline red alga that secretes high-Mg calcite as part of its skeleton, is in focus. It is shown that Jania sp. exhibits a remarkable structure, which is highly porous (with porosity as high as 64 vol%) and reveals several hierarchical orders from the nano to the macroscale. It is shown that the structure is helical, and proven that its helical configuration provides the alga with superior compliance that allows it to adapt to stresses in its natural environment. Thus, the combination of high porosity and a helical configuration result in a sophisticated, light-weight, compliant structure. It is anticipated that the findings on the advantages of such a structure are likely to be of value in the design or improvement of lightweight structures with superior mechanical properties.View less
Michauxia campanuloides (Campanulaceae) is a biennial to short-lived perennial characterized by white to purple-suffused, deeply lobed corollas with narrow and strongly reflexed corolla lobes. It occurs widely on the eastern fringe of the Mediterranean area in Turkey, Syria, Lebanon and Israel. First collected by Leonhard Rauwolf as early as 1575, it was made known by him through the publication of a description and an illustration. His herbarium specimen, among the first collected in the Near East, survives in Leiden. More than two centuries had to pass until André Michaux and, independently, Jean Jacques Houtou de Labillardière collected M. campanuloides again and made specimens and seeds available to the botanical community in Paris. On the basis of living material, but including references to herbarium specimens, Charles-Louis L'Héritier de Brutelle was the first to provide a binomial for this striking plant. This paper focuses on the widely unappreciated record of herbarium specimens and printed illustrations, and lists and comments on early specimens collected in the wild as well as those cultivated in botanical gardens up to 1800. In addition, the name M. campanuloides is properly lectotypified.View less
Tephroseris is generally considered a difficult genus. Based on the examination of extensive herbarium material and considering the existing literature, we recognize seven species in Europe outside Russia. These are T. palustris, T. integrifolia with subsp. integrifolia, subsp. aurantiaca, subsp. capitata, subsp. maritima, subsp. serpentini and subsp. “tundricola”, T. balbisiana, T. crispa, T. helenitis, T. longifolia and T. papposa. Phylogenetic analysis of ITS and ETS sequences showed that these species fall into three lineages. These are: (1) T. palustris, clearly related to Arctic species of the genus; (2) T. integrifolia; and (3) the remaining species. Molecular dating of the T. integrifolia lineage resulted in a crown group age of 1.76 (0.85–2.87) million years. Possible reasons for taxonomic difficulties in the genus in Europe outside Russia may include its young phylogenetic age and extensive migration and genetic admixture in the Quaternary. The decline of the genus in Europe outside Russia is documented and discussed. We consider it possible that its decline is related to rising global temperatures.View less
The traditional use of plants and their preparations in the treatment of diseases as a first medication in the past centuries indicates the presence of active components for specific targets in the natural material. Many of the tested plants in this study have been traditionally used in the treatment of Diabetes mellitus type 2 and associated symptoms in different cultural areas. Additionally, hypoglycemic effects, such as a decrease in blood glucose concentration, have been demonstrated in vivo for these plants. In order to determine the mode of action, the plants were prepared as methanolic and aqueous extracts and tested for their effects on intestinal glucose and fructose absorption in Caco2 cells. The results of this screening showed significant and reproducible inhibition of glucose uptake between 40 and 80% by methanolic extracts made from the fruits of Aronia melanocarpa, Cornus officinalis, Crataegus pinnatifida, Lycium chinense, and Vaccinium myrtillus; the leaves of Brassica oleracea, Juglans regia, and Peumus boldus; and the roots of Adenophora triphylla. Furthermore, glucose uptake was inhibited between 50 and 70% by aqueous extracts made from the bark of Eucommia ulmoides and the fruit skin of Malus domestica. The methanolic extracts of Juglans regia and Peumus boldus inhibited the fructose transport between 30 and 40% in Caco2 cells as well. These findings can be considered as fundamental work for further research regarding the treatment of obesity-correlated diseases, such as Diabetes mellitus type 2.View less