Explore the vast range of titles available.

\"Emily Dickinson is revered as one of America's greatest and most original poets. Quiet Fire presents the life and art of Dickinson through the poet's own letters and poems\"-- Provided by publisher.

The accuracy of five docking programs at reproducing crystallographic structures of complexes of 8 macrolides and 12 related macrocyclic structures, all with their corresponding receptors, was evaluated. Self-docking calculations indicated excellent performance in all cases (mean RMSD values ≤ 1.0) and confirmed the speed of AutoDock Vina. Afterwards, the lowest-energy conformer of each molecule and all the conformers lying 0–10 kcal/mol above it (as given by Macrocycle, from MacroModel 10.0) were subjected to standard docking calculations. While each docking method has its own merits, the observed speed of the programs was as follows: Glide 6.6 > AutoDock Vina 1.1.2 > DOCK 6.5 >> AutoDock 4.2.6 > AutoDock 3.0.5. For most of the complexes, the five methods predicted quite correct poses of ligands at the binding sites, but the lower RMSD values for the poses of highest affinity were in the order: Glide 6.6 ≈ AutoDock Vina ≈ DOCK 6.5 > AutoDock 4.2.6 >> AutoDock 3.0.5. By choosing the poses closest to the crystal structure the order was: AutoDock Vina > Glide 6.6 ≈ DOCK 6.5 ≥ AutoDock 4.2.6 >> AutoDock 3.0.5. Re-scoring (AutoDock 4.2.6//AutoDock Vina, Amber Score and MM-GBSA) improved the agreement between the calculated and experimental data. For all intents and purposes, these three methods are equally reliable.

Multiagent Reinforcement Learning (RL) solves complex tasks that require coordination with other agents through autonomous exploration of the environment. However, learning a complex task from scratch is impractical due to the huge sample complexity of RL algorithms. For this reason, reusing knowledge that can come from previous experience or other agents is indispensable to scale up multiagent RL algorithms. This survey provides a unifying view of the literature on knowledge reuse in multiagent RL. We define a taxonomy of solutions for the general knowledge reuse problem, providing a comprehensive discussion of recent progress on knowledge reuse in Multiagent Systems (MAS) and of techniques for knowledge reuse across agents (that may be actuating in a shared environment or not). We aim at encouraging the community to work towards reusing all the knowledge sources available in a MAS. For that, we provide an in-depth discussion of current lines of research and open questions.

Amphidinolides are a family of more than forty macrolides of varying sizes and complex structures isolated from dinoflagellates of the genus Amphidinium. Although all of them display potent-to-moderate cytotoxicity, their full bioactivity profile and mode of action have not been fully investigated. Access to enough material is needed for these studies, but samples of these compounds are limited due to the minute amounts that can only be obtained by either large-scale cultivation of the organism that produces them or by total synthesis. Of all the amphidinolides known to date, only the targets of five of them (B1, H1, J, K, and X) have been examined and all have been found to interact with actin, a crucial cytoskeletal protein. This paper reviews what is currently known about actin-interacting amphidinolides, with a focus on the research of our group. Amphidinolides J and X are F-actin destabilizers, whereas Amphidinolides H1 and K stabilize actin filaments, likely via different mechanisms. More precise details of the interaction between amphidinolides and actin are missing.

While recent work in reinforcement learning (RL) has led to agents capable of solving increasingly complex tasks, the issue of high sample complexity is still a major concern. This issue has motivated the development of additional techniques that augment RL methods in an attempt to increase task learning speed. In particular, inter-agent teaching—endowing agents with the ability to respond to instructions from others—has been responsible for many of these developments. RL agents that can leverage instruction from a more competent teacher have been shown to be able to learn tasks significantly faster than agents that cannot take advantage of such instruction. That said, the inter-agent teaching paradigm presents many new challenges due to, among other factors, differences between the agents involved in the teaching interaction. As a result, many inter-agent teaching methods work only in restricted settings and have proven difficult to generalize to new domains or scenarios. In this article, we propose two frameworks that provide a comprehensive view of the challenges associated with inter-agent teaching. We highlight state-of-the-art solutions, open problems, prospective applications, and argue that new research in this area should be developed in the context of the proposed frameworks.

Nutritional immunity describes the host-driven manipulation of essential micronutrients, including iron, zinc and manganese. To withstand nutritional immunity and proliferate within their hosts, pathogenic microbes must express efficient micronutrient uptake and homeostatic systems. Here we have elucidated the pathway of cellular zinc assimilation in the major human fungal pathogen Candida albicans. Bioinformatics analysis identified nine putative zinc transporters: four cytoplasmic-import Zip proteins (Zrt1, Zrt2, Zrt3 and orf19.5428) and five cytoplasmic-export ZnT proteins (orf19.1536/Zrc1, orf19.3874, orf19.3769, orf19.3132 and orf19.52). Only Zrt1 and Zrt2 are predicted to localise to the plasma membrane and here we demonstrate that Zrt2 is essential for C. albicans zinc uptake and growth at acidic pH. In contrast, ZRT1 expression was found to be highly pH-dependent and could support growth of the ZRT2-null strain at pH 7 and above. This regulatory paradigm is analogous to the distantly related pathogenic mould, Aspergillus fumigatus, suggesting that pH-adaptation of zinc transport may be conserved in fungi and we propose that environmental pH has shaped the evolution of zinc import systems in fungi. Deletion of C. albicans ZRT2 reduced kidney fungal burden in wild type, but not in mice lacking the zinc-chelating antimicrobial protein calprotectin. Inhibition of zrt2Δ growth by neutrophil extracellular traps was calprotectin-dependent. This suggests that, within the kidney, C. albicans growth is determined by pathogen-Zrt2 and host-calprotectin. As well as serving as an essential micronutrient, zinc can also be highly toxic and we show that C. albicans deals with this potential threat by rapidly compartmentalising zinc within vesicular stores called zincosomes. In order to understand mechanistically how this process occurs, we created deletion mutants of all five ZnT-type transporters in C. albicans. Here we show that, unlike in Saccharomyces cerevisiae, C. albicans Zrc1 mediates zinc tolerance via zincosomal zinc compartmentalisation. This novel transporter was also essential for virulence and liver colonisation in vivo. In summary, we show that zinc homeostasis in a major human fungal pathogen is a multi-stage process initiated by Zrt1/Zrt2-cellular import, followed by Zrc1-dependent intracellular compartmentalisation.

Toxicity evaluation of engineered nanomaterials is challenging due to the ever increasing number of materials and because nanomaterials (NMs) frequently interfere with commonly used assays. Hence, there is a need for robust, high-throughput assays with which to assess their hazard potential. The present study aimed at evaluating the applicability of a genotoxicity assay based on the immunostaining and foci counting of the DNA repair protein 53BP1 (p53-binding protein 1), in a high-throughput format, for NM genotoxicity assessment. For benchmarking purposes, we first applied the assay to a set of eight known genotoxic agents, as well as X-ray irradiation (1 Gy). Then, a panel of NMs and nanobiomaterials (NBMs) was evaluated with respect to their impact on cell viability and genotoxicity, and to their potential to induce reactive oxygen species (ROS) production. The genotoxicity recorded using the 53BP1 assay was confirmed using the micronucleus assay, also scored via automated (high-throughput) microscopy. The 53BP1 assay successfully identified genotoxic compounds on the HCT116 human intestinal cell line. None of the tested NMs showed any genotoxicity using the 53BP1 assay, except the positive control consisting in (CoO)(NiO) NMs, while only TiO 2 NMs showed positive outcome in the micronucleus assay. Only Fe 3 O 4 NMs caused significant elevation of ROS, not correlated to DNA damage. Therefore, owing to its adequate predictivity of the genotoxicity of most of the tested benchmark substance and its ease of implementation in a high throughput format, the 53BP1 assay could be proposed as a complementary high-throughput screening genotoxicity assay, in the context of the development of New Approach Methodologies.

Titanium dioxide (TiO2) nanofibres are a novel fibrous nanomaterial with increasing applications in a variety of fields. While the biological effects of TiO2 nanoparticles have been extensively studied, the toxicological characterization of TiO2 nanofibres is far from being complete. In this study, we evaluated the toxicity of commercially available anatase TiO2 nanofibres using TiO2 nanoparticles (NP) and crocidolite asbestos as non-fibrous or fibrous benchmark materials. The evaluated endpoints were cell viability, haemolysis, macrophage activation, trans-epithelial electrical resistance (an indicator of the epithelial barrier competence), ROS production and oxidative stress as well as the morphology of exposed cells. The results showed that TiO2 nanofibres caused a cell-specific, dose-dependent decrease of cell viability, with larger effects on alveolar epithelial cells than on macrophages. The observed effects were comparable to those of crocidolite, while TiO2 NP did not decrease cell viability. TiO2 nanofibres were also found endowed with a marked haemolytic activity, at levels significantly higher than those observed with TiO2 nanoparticles or crocidolite. Moreover, TiO2 nanofibres and crocidolite, but not TiO2 nanoparticles, caused a significant decrease of the trans-epithelial electrical resistance of airway cell monolayers. SEM images demonstrated that the interaction with nanofibres and crocidolite caused cell shape perturbation with the longest fibres incompletely or not phagocytosed. The expression of several pro-inflammatory markers, such as NO production and the induction of Nos2 and Ptgs2, was significantly increased by TiO2 nanofibres, as well as by TiO2 nanoparticles and crocidolite. This study indicates that TiO2 nanofibres had significant toxic effects and, for most endpoints with the exception of pro-inflammatory changes, are more bio-active than TiO2 nanoparticles, showing the relevance of shape in determining the toxicity of nanomaterials. Given that several toxic effects of TiO2 nanofibres appear comparable to those observed with crocidolite, the possibility that they exert length dependent toxicity in vivo seems worthy of further investigation.

Background Adverse outcome pathways (AOPs) are conceptual frameworks that organize knowledge about biological interactions and toxicity mechanisms. They present a sequence of events commencing with initial interaction(s) of a stressor, which defines the perturbation in a biological system (molecular initiating event, MIE), and a dependent series of key events (KEs), ending with an adverse outcome (AO). AOPs have recently become the subject of intense studies in a view to better understand the mechanisms of nanomaterial (NM) toxicity. Silver nanoparticles (Ag NPs) are one of the most explored nanostructures and are extensively used in various application. This, in turn, has increased the potential for interactions of Ag NPs with environments, and toxicity to human health. The aim of this study was to construct a putative AOPs (pAOP) related to reproductive toxicity of Ag NPs, in order to lay the groundwork for a better comprehension of mechanisms affecting both undesired toxicity (against human cell) and expected toxicity (against microorganisms). Methods PubMed and Scopus were systematically searched for peer-reviewed studies examining reproductive toxicity potential of Ag NPs. The quality of selected studies was assessed through ToxRTool. Eventually, forty-eight studies published between 2005 and 2022 were selected to identify the mechanisms of Ag NPs impact on reproductive function in human male. The biological endpoints, measurements, and results were extracted from these studies. Where possible, endpoints were assigned to a potential KE and an AO using expert judgment. Then, KEs were classified at each major level of biological organization. Results We identified the impairment of intracellular SH-containing biomolecules, which are major cellular antioxidants, as a putative MIE, with subsequent KEs defined as ROS accumulation, mitochondrial damage, DNA damage and lipid peroxidation, apoptosis, reduced production of reproductive hormones and reduced quality of sperm. These successive KEs may result in impaired male fertility (AO). Conclusion This research recapitulates and schematically represents complex literature data gathered from different biological levels and propose a pAOP related to the reproductive toxicity induced by AgNPs. The development of AOPs specific to NMs should be encouraged in order to provide new insights to gain a better understanding of NP toxicity.

Aim Human land‐use and climate change are two of the main threats affecting biodiversity, especially in arid/semiarid regions. The most effective way to protect the species in these ecosystems against these threats is through the delimitation of protected areas (PAs). However, such PAs need to be targeted cost‐efficiently and consider future climate change. We identify priority areas to preserve small mammal species in the Caatinga in the present and in a future of climate changes. We also evaluate how well these priority areas are protected by currently PAs and identify ways forward to improve their protection. Location The Caatinga Dry Forest, Northeast Brazil. Methods We use ecological niche models and Zonation spatial prioritisation software to identify the top 30% priority areas to preserve small mammal species under current climate and land use scenarios, besides considering optimistic and pessimistic scenarios of future climate change. We also evaluate how much these priority areas are covered by current PAs, identify ways to further improve their protection using hierarchical mask analysis, and by evaluating species mean distribution coverage. Results The consequences of climate change will not hugely impact the distribution of priority areas for species conservation in the Caatinga. Around 13% of the identified priority areas overlap with current PAs, and planning the expansion of PAs considering integral protection areas increases the coverage of priority areas to more than 18% and captures more than 72% of species suitable area. Main Conclusions Our prioritisations take into account climate change and provide low risk if conducted as a ‘no‐regrets’ conservation action. These priority areas are poorly supported by the Brazilian PA system, and need of further protection. One cost‐effective option could be to upgrade some sustainable use PAs into more restrictive ones. Securing these priority areas helps preserve the long‐term ecosystem functioning and to prevent biodiversity loss in a changing world. Resumo Objetivo Uso do solo e mudanças climáticas antrópicos são duas das principais ameaças para a biodiversidade, especialmente em regiões áridas e semiáridas. A forma mais eficiente de se proteger as espécies contra essas ameaças é através da delimitação de Áreas Protegidas (APs). Entretanto, estas APs precisam ser delimitadas de forma custo‐eficiente e considerar os cenários de mudanças climáticas. Nosso objetivo foi identificar áreas prioritárias para preservar espécies de pequenos mamíferos na Caatinga no presente e sob mudanças climáticas futuras, além de verificar o quanto essas áreas estão sob efetiva proteção de APs, identificando ainda formas de melhorar essa cobertura. Localização Bioma Caatinga, no Nordeste brasileiro. Métodos Usamos Modelos de Nicho Ecológico e o software de priorização espacial Zonation para identificar as 30% mais importantes áreas prioritárias para preservar espécies de pequenos mamíferos com cenários atuais de uso de solo e mudanças climáticas e, em seguida, com cenários otimistas e pessimistas de mudanças climáticas futuras. Também avaliamos o quanto dessas áreas prioritárias são cobertas por APs, identificamos formas de melhorar essa proteção através da análise de máscara hierárquica e da avaliação de cobertura média da distribuição das espécies. Resultados As consequências das mudanças climáticas não vão impactar de forma significativa a distribuição das áreas prioritárias para conservação das espécies de pequenos mamíferos na Caatinga. Cerca de 13% das áreas prioritárias identificadas estão cobertas por APs e planejar a expansão do sistema de APs considerando as áreas de Proteção Integral aumenta a cobertura de áreas prioritárias para mais de 18%, além de capturar mais de 72% das áreas adequadas para ocorrência das espécies. Conclusões Nossas priorizações levam em consideração o future de mudanças climáticas e apresentam baixo risco de implementação como uma ação de conservação de ‘não‐arrependimento’. Estas áreas prioritárias estão pouco suportadas pelo atual Sistema Brasileiro de APs e precisam de proteção adicional. Uma opção custo‐eficiente para ampliar essa proteção seria transformar determinadas áreas de Uso Sustentável em Proteção Integral. Garantir essas áreas prioritárias ajuda a preservar o funcionamento dos ecossistemas a longo prazo e a prevenir a perda de biodiversidade em um mundo de mudanças.