A Sample-Centric and Knowledge-Driven Computational Framework for Natural Products Drug Discovery.

The ENPKG framework organizes large heterogeneous metabolomics data sets as a knowledge graph, offering exciting opportunities for drug discovery and chemodiversity characterization.

Comprehensive mass spectrometric metabolomic profiling of a chemically diverse collection of plants of the Celastraceae family.

Natural products exhibit interesting structural features and significant biological activities. The discovery of new bioactive molecules is a complex process that requires high-quality metabolite profiling data to properly target the isolation of compounds of interest and enable their complete structural characterization. The same metabolite profiling data can also be used to better understand chemotaxonomic links between species. This Data Descriptor details a dataset resulting from the untargeted liquid chromatography-mass spectrometry metabolite profiling of 76 natural extracts of the Celastraceae family. The spectral annotation results and related chemical and taxonomic metadata are shared, along with proposed examples of data reuse. This data can be further studied by researchers exploring the chemical diversity of natural products. This can serve as a reference sample set for deep metabolome investigation of this chemically rich plant family.

Integration of Wnt-inhibitory activity and structural novelty scoring results to uncover novel bioactive natural products: new Bicyclo[3.3.1]non-3-ene-2,9-diones from the leaves of Hymenocardia punctata.

In natural products (NPs) research, methods for the efficient prioritization of natural extracts (NEs) are key for discovering novel bioactive NPs. In this study a biodiverse collection of 1,600 NEs, previously analyzed by UHPLC-HRMS2 metabolite profiling was screened for Wnt pathway regulation. The results of the biological screening drove the selection of a subset of 30 non-toxic NEs with an inhibitory IC50 ≤ 5 µg/mL. To increase the chance of finding structurally novel bioactive NPs, Inventa, a computational tool for automated scoring of NEs based on structural novelty was used to mine the HRMS2 analysis and dereplication results. After this, four out of the 30 bioactive NEs were shortlisted by this approach. The most promising sample was the ethyl acetate extract of the leaves of Hymenocardia punctata (Phyllanthaceae). Further phytochemical investigations of this species resulted in the isolation of three known prenylated flavones (3, 5, 7) and ten novel bicyclo[3.3.1]non-3-ene-2,9-diones (1, 2, 4, 6, 8-13), named Hymenotamayonins. Assessment of the Wnt inhibitory activity of these compounds revealed that two prenylated flavones and three novel bicyclic compounds showed interesting activity without apparent cytotoxicity. This study highlights the potential of combining Inventa's structural novelty scores with biological screening results to effectively discover novel bioactive NPs in large NE collections.

TICI: a taxon-independent community index for eDNA-based ecological health assessment.

Global biodiversity is declining at an ever-increasing rate. Yet effective policies to mitigate or reverse these declines require ecosystem condition data that are rarely available. Morphology-based bioassessment methods are difficult to scale, limited in scope, suffer prohibitive costs, require skilled taxonomists, and can be applied inconsistently between practitioners. Environmental DNA (eDNA) metabarcoding offers a powerful, reproducible and scalable solution that can survey across the tree-of-life with relatively low cost and minimal expertise for sample collection. However, there remains a need to condense the complex, multidimensional community information into simple, interpretable metrics of ecological health for environmental management purposes. We developed a riverine taxon-independent community index (TICI) that objectively assigns indicator values to amplicon sequence variants (ASVs), and significantly improves the statistical power and utility of eDNA-based bioassessments. The TICI model training step uses the Chessman iterative learning algorithm to assign health indicator scores to a large number of ASVs that are commonly encountered across a wide geographic range. New sites can then be evaluated for ecological health by averaging the indicator value of the ASVs present at the site. We trained a TICI model on an eDNA dataset from 53 well-studied riverine monitoring sites across New Zealand, each sampled with a high level of biological replication (n = 16). Eight short-amplicon metabarcoding assays were used to generate data from a broad taxonomic range, including bacteria, microeukaryotes, fungi, plants, and animals. Site-specific TICI scores were strongly correlated with historical stream condition scores from macroinvertebrate assessments (macroinvertebrate community index or MCI; R2 = 0.82), and TICI variation between sample replicates was minimal (CV = 0.013). Taken together, this demonstrates the potential for taxon-independent eDNA analysis to provide a reliable, robust and low-cost assessment of ecological health that is accessible to environmental managers, decision makers, and the wider community.

Leaf metabolic traits reveal hidden dimensions of plant form and function.

The metabolome is the biochemical basis of plant form and function, but we know little about its macroecological variation across the plant kingdom. Here, we used the plant functional trait concept to interpret leaf metabolome variation among 457 tropical and 339 temperate plant species. Distilling metabolite chemistry into five metabolic functional traits reveals that plants vary on two major axes of leaf metabolic specialization-a leaf chemical defense spectrum and an expression of leaf longevity. Axes are similar for tropical and temperate species, with many trait combinations being viable. However, metabolic traits vary orthogonally to life-history strategies described by widely used functional traits. The metabolome thus expands the functional trait concept by providing additional axes of metabolic specialization for examining plant form and function.

Assessment, regionalization, and modeling rainfall erosivity over Brazil: Findings from a large national database.

In this study, we used a large national database to assess the rainfall erosivity (RE) patterns in time and space over the Brazilian territory. Thereby, RE and erosivity density (ED) values were obtained for 5166 rainfall gauges. Also, the concentration of the RE throughout the year and the RE's gravity center locations were analyzed. Finally, homogeneous regions regarding RE values were delimited and estimative regression models were established. The results show that Brazil's mean annual RE value is 5620 MJ mm ha-1 h-1 year-1, with considerable spatial variation over the country. The highest RE magnitudes were found for the north region, while the northeast region shows the lowest values. Regarding the RE's distribution throughout the year, in the southern region of Brazil, it is more equitable, while in some spots of the northeastern region, it is irregularly concentrated in specific months. Further analyses revealed that for most of the months, the RE's gravity centers for Brazil are in the Goiás State and that they present a north-south migration pattern throughout the year. Complementarily, the ED magnitudes allowed the identification of high-intensity rainfall spots. Additionally, the Brazilian territory was divided into eleven homogeneous regions regarding the RE patterns and for each defined region, a regression model was established and validated. These models' statistical metrics were considered satisfactory and, thus, can be used to estimate RE values for the whole country using monthly rainfall depths. Finally, all database produced are available for download. Therefore, the values and maps shown in this study are relevant for improving the accuracy of soil loss estimates in Brazil and for the establishment of soil and water conservation planning on a national scale.

Inventa: A computational tool to discover structural novelty in natural extracts libraries.

Collections of natural extracts hold potential for the discovery of novel natural products with original modes of action. The prioritization of extracts from collections remains challenging due to the lack of a workflow that combines multiple-source information to facilitate the data interpretation. Results from different analytical techniques and literature reports need to be organized, processed, and interpreted to enable optimal decision-making for extracts prioritization. Here, we introduce Inventa, a computational tool that highlights the structural novelty potential within extracts, considering untargeted mass spectrometry data, spectral annotation, and literature reports. Based on this information, Inventa calculates multiple scores that inform their structural potential. Thus, Inventa has the potential to accelerate new natural products discovery. Inventa was applied to a set of plants from the Celastraceae family as a proof of concept. The Pristimera indica (Willd.) A.C.Sm roots extract was highlighted as a promising source of potentially novel compounds. Its phytochemical investigation resulted in the isolation and de novo characterization of thirteen new dihydro-ß-agarofuran sesquiterpenes, five of them presenting a new 9-oxodihydro-ß-agarofuran base scaffold.

Random forest for spatialization of daily evapotranspiration (ET0) in watersheds in the Atlantic Forest.

The importance of daily data on reference evapotranspiration (ET0) has increased in recent years due to its relevance in planning and decision making regarding irrigated agriculture, water production, and forest restoration. Facing the scarcity of this information measured in loco, the study of interpolation methods capable of representing ET0 becomes important. Therefore, this study aimed to evaluate the adequacy of the Random Forest (RF) method in the spatialization of ET0 in the watersheds of the Mid-South region of the Espírito Santo State, located within the Atlantic Forest biome, Brazil. From this study, it was found that the RF method is the most suitable one for ET0 spatialization when compared to the Angular distance weighting (ADW) and the inverse distance weighting (IDW) techniques. Also, the spatializations carried out by this method were transformed into databases in a grid format and made available online. Furthermore, the RF database was also compared to other ET0 grid databases, and it was concluded that the RF database also carried out a better performance than the other ones.

Future directions for the discovery of natural product-derived immunomodulating drugs: an IUPHAR positional review.

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.

Open and reusable annotated mass spectrometry dataset of a chemodiverse collection of 1,600 plant extracts.

As privileged structures, natural products often display potent biological activities. However, the discovery of novel bioactive scaffolds is often hampered by the chemical complexity of the biological matrices they are found in. Large natural extract collections are thus extremely valuable for their chemical novelty potential but also complicated to exploit in the frame of drug-discovery projects. In the end, it is the pure chemical substances that are desired for structural determination purposes and bioactivity evaluation. Researchers interested in the exploration of large and chemodiverse extract collections should thus establish strategies aiming to efficiently tackle such chemical complexity and access these structures. Establishing carefully crafted digital layers documenting the spectral and chemical complexity as well as bioactivity results of natural extracts collections can help prioritize time-consuming but mandatory isolation efforts. In this note, we report the results of our initial exploration of a collection of 1,600 plant extracts in the frame of a drug-discovery effort. After describing the taxonomic coverage of this collection, we present the results of its liquid chromatography high-resolution mass spectrometric profiling and the exploitation of these profiles using computational solutions. The resulting annotated mass spectral dataset and associated chemical and taxonomic metadata are made available to the community, and data reuse cases are proposed. We are currently continuing our exploration of this plant extract collection for drug-discovery purposes (notably looking for novel antitrypanosomatids, anti-infective and prometabolic compounds) and ecometabolomics insights. We believe that such a dataset can be exploited and reused by researchers interested in computational natural products exploration.

Genotoxicity of Marijuana in Mono-Users.

Marijuana (Cannabis sp.) is among the most recurred controlled substances in the world, and there is a growing tendency to legalize its possession and use; however, the genotoxic effects of marijuana remain under debate. A clear definition of marijuana's genotoxic effects remains obscure by the simultaneous consumption of tobacco and other recreational substances. In order to assess the genotoxic effects of marijuana and to prevent the bias caused by the use of substances other than cannabis, we recruited marijuana users that were sub-divided into three categories: (1) users of marijuana-only (M), (2) users of marijuana and tobacco (M+T), and (3) users of marijuana plus other recreative substances or illicit drugs (M+O), all the groups were compared against a non-user control group. We quantified DNA damage by detection of γH2AX levels and quantification of micronuclei (MN), one of the best-established methods for measuring chromosomal DNA damage. We found increased levels of γH2AX in peripheral blood lymphocytes from the M and M+T groups, and increased levels of MNs in cultures from M+T group. Our results suggest a DNA damage increment for M and M+T groups but the extent of chromosomal damage (revealed here by the presence of MNs and NBuds) might be related to the compounds found in tobacco. We also observed an elevated nuclear division index in all marijuana users in comparison to the control group suggesting a cytostatic dysregulation caused by cannabis use. Our study is the first in Mexico to assess the genotoxicity of marijuana in mono-users and in combination with other illicit drugs.

Spectro-temporal analysis of the Paraopeba River water after the tailings dam burst of the Córrego do Feijão mine, in Brumadinho, Brazil.

Remote sensing is an important tool for environmental assessment, especially in the event of disasters such as the tailings dam burst at the Córrego do Feijão mine, located in the Paraopeba River basin, Brazil. Thus, this study aimed to carry out a spectro-temporal analysis of the Paraopeba River water given the dam burst, using multispectral images from the MSI sensor onboard Sentinel-2 satellites. For this analysis, sections along the river were defined by the creation of buffers, with 10-km intervals each, starting from the origin of the burst. For each section, the average visible to near-infrared (NIR) reflectance values per band and the Normalized Difference Water Index (NDWI) were obtained. We found that the red edge and NIR bands (B5, B6, B7, B8, and B8A) showed higher reflectance values when compared to the visible bands in the months immediately after the disaster, especially in the first 20 km. In these months, negative NDWI values were also found for almost all sections downstream, demonstrating the large volume of mining tailings in the Paraopeba River. The seasonal variation of the observed values indicates the resuspension of the material deposited at the river bottom with the beginning of the rainy season. Finally, we highlight the usefulness of the MSI/Sentinel-2 red edge and NIR bands for further studies on the monitoring from space of water bodies subjected to contamination by large amounts of mud with iron ore tailings and contaminants, as occurred in the state of Minas Gerais, southeastern Brazil.

Multivariate statistics for spatial and seasonal quality assessment of water in the Doce River basin, Southeastern Brazil.

This study employed multivariate statistical techniques in one of the main river basins in Brazil, the Doce River basin, to select and evaluate the most representative parameters of the current water quality aspects, and to group the stations according to the similarity of the selected parameters, for both dry and rainy seasons. Data from 63 qualitative monitoring stations, belonging to the Minas Gerais Water Management Institute network were used, considering 38 parameters for the hydrological year 2017/2018. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were used to reduce the total number of variables and to group stations with similar characteristics, respectively. Using PCA, four principal components were selected as indicators of water quality, explaining the cumulative variance of 68% in the rainy season and 65% in the dry season. The HCA grouped the stations into four groups in the rainy season and three groups in the dry season, showing the influence of seasonality on the grouping of stations. Moreover, the HCA made it possible to differentiate water quality stations located in the headwaters of the basin, in the main river channel, and near urban centers. The results obtained through multivariate statistics proved to be important in understanding the current water quality situation in the basin and can be used to improve the management of water resources because the collection and analysis of all parameters in all monitoring stations require greater availability of financial resources.

Quinolizidine Alkaloids from Cylicomorpha solmsii.

Five new quinolizidine alkaloids were isolated from the leaves of Cylicomorpha solmstii (Urb.) Urb. (Caricaceae) and named cylicomorphins A-E (1-5). They all are ester derivatives of the same basic quinolizidine skeleton bearing hydroxy, methyl, and ethanoic acid substituents. Their structures were mainly established by NMR spectroscopy, and the absolute configuration is proposed on the basis of VCD data and Mosher ester derivatization. Compound 5 displayed cytotoxicity in the 10 µM range against an HCT-116 cell line.

A cozinha do Centro de Referência da Assistência Social como espaço de acolhimento e construção de vínculo: relato de experiência de um grupo de mulheres / Kitchen of the Reference Center for Social Assistance as welcoming and bond-building space: an experience report of a group of women

Introdução: A realização de práticas de Educação Alimentar e Nutricional (EAN) nos serviços públicos e comunidades ainda permanece como um desafio aos profissionais de saúde e educadores, sendo necessários relatos de experiência que motivem e auxiliem a construção práticas de EAN em diferentes cenários. Objetivo: Relatar a experiência do processo de criação e desenvolvimento de um grupo de mulheres no âmbito do Centro de Referência da Assistência Social (CRAS), como parte das atividades curriculares do Curso de Nutrição da Universidade Federal de Campina Grande. Método: Foram descritas 17 atividades realizadas no período letivo de 2019-1 e 2019-2 e durante o recesso acadêmico. Como estratégia de EAN, foi utilizada a oficina culinária. Resultados: A metodologia dos encontros estava organizada em três momentos articulados: acolhimento, oficina culinária e roda de conversa. As atividades promoveram a troca de experiência, priorizando um diálogo ampliado, para além de temas relacionados especificamente com alimentação e nutrição. Foram desenvolvidas estratégias para criação de vínculo entre mulheres, estudantes, professora e profissionais do CRAS. Regada por desafios, a roda de conversa demandou a aplicação de metodologias para oportunizar a democratização da fala e da escuta, e a reflexão sobre si. Conclusão: Para além da abordagem nutricional e técnica, a oficina culinária foi uma estratégia que promoveu a criação de vínculo entre as mulheres e os profissionais do serviço, contribuindo também para potencializar o espaço do CRAS com a oferta de ações de promoção de saúde e EAN.

Introduction: Food and Nutrition Education (FNE) practices in public services and communities are challenging for health professionals and educators, requiring experience reports to motivate and assist FNE practices in different scenarios. Objective: Report the experience of creating and developing a group of women at the Reference Center for Social Assistance (CRAS) as part of curricular activities of the Department of Nutrition at the Federal University of Campina Grande. Methods: We described 17 activities held in the first and second academic semesters of 2019 and during the academic break. Culinary workshop was used as FNE strategy. Results: Meetings were organized in three articulated moments: welcoming, culinary workshop, and conversation circles. Activities promoted exchange of experience, prioritizing an open dialogue that addressed topics beyond those related to food and nutrition. Strategies were developed to build bonds between women, students, the professor, and CRAS professionals. Conversation circles were challenging and demanded methodologies to democratize speech, listening, and self-reflection. Conclusion: Culinary workshop was a strategy that promoted nutritional and technical approach and bond formation between women and CRAS professionals and potentiated CRAS space by offering health promotion and FNE actions.

2000 Year-old Bogong moth (Agrotis infusa) Aboriginal food remains, Australia.

Insects form an important source of food for many people around the world, but little is known of the deep-time history of insect harvesting from the archaeological record. In Australia, early settler writings from the 1830s to mid-1800s reported congregations of Aboriginal groups from multiple clans and language groups taking advantage of the annual migration of Bogong moths (Agrotis infusa) in and near the Australian Alps, the continent's highest mountain range. The moths were targeted as a food item for their large numbers and high fat contents. Within 30 years of initial colonial contact, however, the Bogong moth festivals had ceased until their recent revival. No reliable archaeological evidence of Bogong moth exploitation or processing has ever been discovered, signalling a major gap in the archaeological history of Aboriginal groups. Here we report on microscopic remains of ground and cooked Bogong moths on a recently excavated grindstone from Cloggs Cave, in the southern foothills of the Australian Alps. These findings represent the first conclusive archaeological evidence of insect foods in Australia, and, as far as we know, of their remains on stone artefacts in the world. They provide insights into the antiquity of important Aboriginal dietary practices that have until now remained archaeologically invisible.

Comparison of the Phytochemical Composition of Serenoa repens Extracts by a Multiplexed Metabolomic Approach.

Phytochemical extracts are highly complex chemical mixtures. In the context of an increasing demand for phytopharmaceuticals, assessment of the phytochemical equivalence of extraction procedures is of utmost importance. Compared to routine analytical methods, comprehensive metabolite profiling has pushed forward the concept of phytochemical equivalence. In this study, an untargeted metabolomic approach was used to cross-compare four marketed extracts from Serenoa repens obtained with three different extraction processes: ethanolic, hexanic and sCO2 (supercritical carbon dioxide). Our approach involved a biphasic extraction of native compounds followed by liquid chromatography coupled to a high-resolution mass spectrometry based metabolomic workflow. Our results showed significant differences in the contents of major and minor compounds according to the extraction solvent used. The analyses showed that ethanolic extracts were supplemented in phosphoglycerides and polyphenols, hexanic extracts had higher amounts of free fatty acids and minor compounds, and sCO2 samples contained more glycerides. The discriminant model in this study could predict the extraction solvent used in commercial samples and highlighted the specific biomarkers of each process. This metabolomic survey allowed the authors to assess the phytochemical content of extracts and finished products of S. repens and unequivocally established that sCO2, hexanic and ethanolic extracts are not chemically equivalent and are therefore unlikely to be pharmacologically equivalent.

Genetic structure and demographic inference of the regular sea urchin Sterechinus neumayeri (Meissner, 1900) in the Southern Ocean: The role of the last glaciation.

One of the most relevant characteristics of the extant Southern Ocean fauna is its resiliency to survive glacial processes of the Quaternary. These climatic events produced catastrophic habitat reductions and forced some marine benthic species to move, adapt or go extinct. The marine benthic species inhabiting the Antarctic upper continental shelf faced the Quaternary glaciations with different strategies that drastically modified population sizes and thus affected the amount and distribution of intraspecific genetic variation. Here we present new genetic information for the most conspicuous regular sea urchin of the Antarctic continental shelf, Sterechinus neumayeri. We studied the patterns of genetic diversity and structure in this broadcast-spawner across three Antarctic regions: Antarctic Peninsula, the Weddell Sea and Adélie Land in East Antarctica. Genetic analyses based on mitochondrial and nuclear markers suggested that S. neumayeri is a single genetic unit around the Antarctic continent. The species is characterized by low levels of genetic diversity and exhibits a typical star-like haplotype genealogy that supports the hypothesis of a single in situ refugium. Based on two mutation rates standardized for this genus, the Bayesian Skyline plot analyses detected a rapid demographic expansion after the Last Glacial Maximum. We propose a scenario of rapid postglacial expansion and recolonization of Antarctic shallow areas from a less ice-impacted refugium where the species survived the LGM. Considering the patterns of genetic diversity and structure recorded in the species, this refugium was probably located in East Antarctica.