A selective p53 activator and anticancer agent to improve colorectal cancer therapy

Impairment of the p53 pathway is a critical event in cancer. Therefore, reestablishing p53 activity has become one of the most appealing anticancer therapeutic strategies. Here, we disclose the p53-activating anticancer drug (3S)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole (MANIO). MANIO demonstrates a notable selectivity to the p53 pathway, activating wild-type (WT)p53 and restoring WT-like function to mutant (mut)p53 in human cancer cells. MANIO directly binds to the WT/mutp53 DNA-binding domain, enhancing the protein thermal stability, DNA-binding ability, and transcriptional activity. The high efficacy of MANIO as an anticancer agent toward cancers harboring WT/mutp53 is further demonstrated in patient-derived cells and xenograft mouse models of colorectal cancer (CRC), with no signs of undesirable side effects. MANIO synergizes with conventional chemotherapeutic drugs, and in vitro and in vivo studies predict its adequate drug-likeness and pharmacokinetic properties for a clinical candidate. As a single agent or in combination, MANIO will advance anticancer-targeted therapy, particularly benefiting CRC patients harboring distinct p53 status.We thank PT national funds (FCT/MCTES , Fundação para a Ciência e a Tecnologia , and Ministério da Ciência, Tecnologia e Ensino Superior ) through grants UIDB/50006/2020 , UID/BIO/04469/2019 , UIDB/04539/2020 , and UIDP/04539/2020 ( CIBB ); BioTecNorte operation ( NORTE-01-0145-FEDER-000004 ) and Porto Neurosciences and Neurologic Disease Research Initiative at I3S ( Norte-01-0145-FEDER-000008 ) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte ; Masaryk University ( Project MUNI/A/1127/2019 ) and Ministry of Education, Youth and Sports of the Czech Republic (project nos. LQ1605 and LM2018125 ); FCT financial support through the fellowships SFRH/BD/119144/2016 (H.R.) and SFRH/BD/117949/2016 (L.R.); Fondazione AIRC ( IG#18985 , A.I.); and the Programa Operacional Potencial Humano (POCH), specifically the BiotechHealth Programme (Doctoral Programme on Cellular and Molecular Biotechnology Applied to Health Sciences , PD/00016/2012 ). We thank Dario Rizzotto for assistance in preparing the libraries for RNA sequencing. Funding: This work was supported by PT National Funds (FCT/MCTES, Fundação para a Ciência e Tecnologia , and Ministério da Ciência, Tecnologia e Ensino Superior ) via the projects UIDB/50006/2020 ( LAQV/REQUIMTE ), UIDB/00313/2020 , and UIDP/00313/2020 , co-funded by COMPETE2020-UE

Updating known distribution models for forecasting climate change impact on endangered species

To plan endangered species conservation and to design adequate management programmes, it is necessary to predict their distributional response to climate change, especially under the current situation of rapid change. However, these predictions are customarily done by relating de novo the distribution of the species with climatic conditions with no regard of previously available knowledge about the factors affecting the species distribution. We propose to take advantage of known species distribution models, but proceeding to update them with the variables yielded by climatic models before projecting them to the future. To exemplify our proposal, the availability of suitable habitat across Spain for the endangered Bonelli’s Eagle (Aquila fasciata) was modelled by updating a pre-existing model based on current climate and topography to a combination of different general circulation models and Special Report on Emissions Scenarios. Our results suggested that the main threat for this endangered species would not be climate change, since all forecasting models show that its distribution will be maintained and increased in mainland Spain for all the XXI century. We remark on the importance of linking conservation biology with distribution modelling by updating existing models, frequently available for endangered species, considering all the known factors conditioning the species’ distribution, instead of building new models that are based on climate change variables only.Ministerio de Ciencia e Innovación and FEDER (project CGL2009-11316/BOS

Dung removal increases under higher dung beetle functional diversity regardless of grazing intensification

Dung removal by macrofauna such as dung beetles is an important process for nutrient cycling in pasturelands. Intensification of farming practices generally reduces species and functional diversity of terrestrial invertebrates, which may negatively affect ecosystem services. Here, we investigate the effects of cattle-grazing intensification on dung removal by dung beetles in field experiments replicated in 38 pastures around the world. Within each study site, we measured dung removal in pastures managed with low- and high-intensity regimes to assess between-regime differences in dung beetle diversity and dung removal, whilst also considering climate and regional variations. The impacts of intensification were heterogeneous, either diminishing or increasing dung beetle species richness, functional diversity, and dung removal rates. The effects of beetle diversity on dung removal were more variable across sites than within sites. Dung removal increased with species richness across sites, while functional diversity consistently enhanced dung removal within sites, independently of cattle grazing intensity or climate. Our findings indicate that, despite intensified cattle stocking rates, ecosystem services related to decomposition and nutrient cycling can be maintained when a functionally diverse dung beetle community inhabits the human-modified landscape

Evaluating the Psychometric Quality of Social Skills Measures: A Systematic Review

Introduction - Impairments in social functioning are associated with an array of adverse outcomes. Social skills measures are commonly used by health professionals to assess and plan the treatment of social skills difficulties. There is a need to comprehensively evaluate the quality of psychometric properties reported across these measures to guide assessment and treatment planning. Objective - To conduct a systematic review of the literature on the psychometric properties of social skills and behaviours measures for both children and adults. Methods - A systematic search was performed using four electronic databases: CINAHL, PsycINFO, Embase and Pubmed; the Health and Psychosocial Instruments database; and grey literature using PsycExtra and Google Scholar. The psychometric properties of the social skills measures were evaluated against the COSMIN taxonomy of measurement properties using pre-set psychometric criteria. Results - Thirty-Six studies and nine manuals were included to assess the psychometric properties of thirteen social skills measures that met the inclusion criteria. Most measures obtained excellent overall methodological quality scores for internal consistency and reliability. However, eight measures did not report measurement error, nine measures did not report cross-cultural validity and eleven measures did not report criterion validity. Conclusions - The overall quality of the psychometric properties of most measures was satisfactory. The SSBS-2, HCSBS and PKBS-2 were the three measures with the most robust evidence of sound psychometric quality in at least seven of the eight psychometric properties that were appraised. A universal working definition of social functioning as an overarching construct is recommended. There is a need for ongoing research in the area of the psychometric properties of social skills and behaviours instruments

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Native and exotic distributions of siamweed (Chromolaena odorata) modeled using the genetic algorithm for rule-set production

Siamweed is an asteraceous shrub native to the Neotropics that ranks among the world's most widespread and troublesome invasive species. It was introduced in several regions of Africa, Southeast Asia, and the Pacific Islands, where it severely infests natural habitats and plantation crops. Although extensive data document the weed's abundance and distribution throughout the invaded continents, the details of its current range are not fully known, especially within its native region. In this study, we used point-occurrence data and digital maps summarizing relevant environmental parameters to generate predictions for the species' geographic distributional potential-specifically, we modeled the native range of siamweed in the Neotropics using the genetic algorithm for rule-set prediction, an evolutionary computing approach. The native range occurrence data set contained 239 published and herbarium records. Models were trained on a random subset of half the points and tested using the other half. The rule sets of the native-range models were projected onto the invaded continents to predict the weed's potential for invasion, blind to its known occurrences in such regions. Native-range models predicted a wide potential distribution of siamweed throughout tropical America, from southern United States to northern Argentina and southern Brazil. The weed's occurrence has been confirmed on the northern Pacific coast, in southeast Brazil, and in other South American areas, where it was supposed to be absent. Independent model projections to Africa, Asia, and Oceania are supported by known occurrence records. Four regions are predicted to be susceptible to siamweed spread: (1) Central Africa, currently being invaded from Western Africa; (2) Infestations spreading northward from South Africa, which have already reached Swaziland and Mozambique and may extend to East Africa and Madagascar; and (3) northern New Zealand and (4) Australia, which are at risk from uncontrolled infestations on several western Pacific islands.551414