Search

Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro in mouse TNBC xenografts and in patient-derived estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single-agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol-trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. Significance: Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple-negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.

The following is based on a qualitative study conducted with two not-for-profit organizations based in Hamilton, Ontario: A Rocha and Good Shepherd Centres. Guided by grounded theory and participatory action research (PAR) methodologies, my research examined Operation Wild, A Rocha's environmental education (EE) program for adults with disabilities. In this article, I draw on participant voices from that research to respond to and extend Mitchell Thomashow's (1996) work on ecological identity by suggesting that his conceptualization of the ecological self is theorized as a solely individualistic, anthropocentric concept. With guidance from literature by Indigenous and disability studies scholars, I outline a theory of relational ecological identity, which encourages the interdependent, intergenerational, and interactive components of ecological identity-building. The concept is explored by foregrounding the stories and perspectives that emerged from Operation Wild's participants.

Plant transpiration links physiological responses of vegetation to water supply and demand with hydrological, energy, and carbon budgets at the land-atmosphere interface. However, despite being the main land evaporative flux at the global scale, transpiration and its response to environmental drivers are currently not well constrained by observations. Here we introduce the first global compilation of whole-plant transpiration data from sap flow measurements (SAPFLUXNET, https://sapfluxnet.creaf.cat/, last access: 8 June 2021). We harmonized and quality-controlled individual datasets supplied by contributors worldwide in a semi-automatic data workflow implemented in the R programming language. Datasets include sub-daily time series of sap flow and hydrometeorological drivers for one or more growing seasons, as well as metadata on the stand characteristics, plant attributes, and technical details of the measurements. SAPFLUXNET contains 202 globally distributed datasets with sap flow time series for 2714 plants, mostly trees, of 174 species. SAPFLUXNET has a broad bioclimatic coverage, with woodland/shrubland and temperate forest biomes especially well represented (80% of the datasets). The measurements cover a wide variety of stand structural characteristics and plant sizes. The datasets encompass the period between 1995 and 2018, with 50% of the datasets being at least 3 years long. Accompanying radiation and vapour pressure deficit data are available for most of the datasets, while on-site soil water content is available for 56% of the datasets. Many datasets contain data for species that make up 90% or more of the total stand basal area, allowing the estimation of stand transpiration in diverse ecological settings. SAPFLUXNET adds to existing plant trait datasets, ecosystem flux networks, and remote sensing products to help increase our understanding of plant water use, plant responses to drought, and ecohydrological processes. SAPFLUXNET version 0.1.5 is freely available from the Zenodo repository (10.5281/zenodo.3971689; Poyatos et al., 2020a). The "sapfluxnetr"R package-designed to access, visualize, and process SAPFLUXNET data-is available from CRAN.

Objective: Informed by the contextual behavioral science (CBS) model of behavioral health, the present cross-sectional study examined whether mindful awareness moderated the associations between psychological inflexibility and four distress variables. Participants: Cross-sectional data were collected from 402 ethnically diverse undergraduate college students from September 2015 to October 2015. Methods: Participants competed an online self-report survey. Results: Mindful awareness moderated the associations between psychological inflexibility and distress variables, with stronger associations for somatization and anxiety, and weaker associations for general distress and depression. Specifically, the strength of the positive associations between psychological inflexibility and these distress variables were substantially greater among those low in mindful awareness. Conclusion: These findings suggest that a greater degree of mindful awareness may buffer the effects of psychological inflexibility on distress variables, particularly somatization and anxiety. Theoretical and applied implications as well as limitations of the study are discussed.

Author(s): Timothy J. Martin [sup.1] [sup.2] , Samuel D. Spencer [sup.1] , Akihiko Masuda [sup.1] Author Affiliations: (1) grid.410445.0, 0000 0001 2188 0957, Department of Psychology, University of Hawai'i at [...], The proposed cross-sectional survey of a non-clinical college sample investigated (1) whether two forms of mental health self-stigma (i.e., mental illness self-stigma and psychological distress self-stigma) were positively associated with psychological distress and (2) whether mindfulness mediated the association between mental health self-stigma and psychological distress. University students participated in an online survey. The results of the study revealed that both mental illness self-stigma and psychological distress self-stigma were positively associated with psychological distress, and that mindfulness partially mediated these associations. Additional analyses revealed that mindfulness moderated the association between psychological distress self-stigma and psychological distress. Mindfulness is an important variable for understanding mental health self-stigma and its association with psychological distress. Future studies should investigate the role of mindfulness in this association further.

Colletotrichum is a globally significant genus of plant pathogens known for causing anthracnose across a diverse array of hosts. Notably, Colletotrichum graminicola is a pathogen affecting maize. Annually, the global economic impact of this pathogen reaches billions of US dollars. C. graminicola produces conidia that have a characteristic falcate shape and are dispersed by rain. Upon attachment to maize leaves, these conidia develop melanized appressoria to penetrate the leaf surface to initiate disease. Recent findings have emphasized the existence of an adhesive strip on only one side of C. graminicola conidia. This strip colocalizes with an actin array, playing a crucial role in facilitating attachment and germination. This asymmetrical adhesive was postulated to enhance spore dispersal by assuring that some conidia do not attach to their initial deposition site. The extent of this asymmetric adhesive phenotype in other Colletotrichum species remains unknown, raising questions about its conservation within the genus. This study reveals the ubiquitous presence of an asymmetric adhesive on the conidia across nine isolates of Colletotrichum , representing eight species. Morphological differences in conidium shape and adhesive distribution were observed. Significantly, Colletotrichum truncatum is unique from other observed species by exhibiting an adhesive strip on both sides of its conidium. Furthermore, in C. graminicola , we noted a simultaneous development of the actin array and detachment from its mother cell after spore development. We posit that the study of other Colletotrichum members holds promise in elucidating the evolutionary trajectory of this phenotype. Furthermore, these insights may prove instrumental in understanding spore dispersal dynamics across diverse hosts, shedding light on the intricate web of host specificity within the genus. [ABSTRACT FROM AUTHOR]

Aerodynamic canopy height (ha) is the effective height of vegetation canopy for its influence on atmospheric fluxes and is a key parameter of surface-atmosphere coupling. However, methods to estimate ha from data are limited. This synthesis evaluates the applicability and robustness of the calculation of ha from eddy covariance momentum-flux data. At 69 forest sites, annual ha robustly predicted site-to-site and year-to-year differences in canopy heights (R2 = 0.88, 111 site-years). At 23 cropland/grassland sites, weekly ha successfully captured the dynamics of vegetation canopies over growing seasons (R2 > 0.70 in 74 site-years). Our results demonstrate the potential of flux-derived ha determination for tracking the seasonal, interannual, and/or decadal dynamics of vegetation canopies including growth, harvest, land use change, and disturbance. The large-scale and time-varying ha derived from flux networks worldwide provides a new benchmark for regional and global Earth system models and satellite remote sensing of canopy structure.

Background and Objectives: This educational review outlines the current landscape of pediatric anesthesia training, care delivery, and challenges across Canada, Barbados, and the United States. Descriptions and Conclusions: Approximately 5% of Canadian children undergo general anesthesia annually, administered by fellowship‐trained pediatric anesthesiologists in children's hospitals, general anesthesiologists in community hospitals, or family practice anesthesiologists in underserved regions. In Canada, the focus is on national‐level evaluation and accreditation of pediatric anesthesia fellowship training, addressing challenges arising from workforce shortages, particularly in remote areas. Barbados, a Caribbean nation, lacks dedicated pediatric hospitals but has provided pediatric anesthesia since 1972 through anesthetists with additional training. Challenges in its development, common to low‐middle‐income countries, include inadequate infrastructure and workforce shortages. Increased awareness of pediatric anesthesia as a sub‐specialty could enhance perioperative care for Barbadian children. Pediatric anesthesia encompasses various specialties in the United States, with pediatric anesthesiologists playing a foundational role. Challenges faced include recruitment and retention difficulties, supply‐chain shortages, and the proliferation of anesthesia sites, all impacting the delivery of modern, high‐quality, and cost‐effective patient care. Collaborative efforts at national and organizational levels strive to improve the quality and safety of pediatric anesthesia care in the United States. [ABSTRACT FROM AUTHOR]

Rimsulfuron is a sulfonylurea herbicide that controls grass and broadleaf weeds in maize, potatoes, fruits, nuts, and other crops. It can also be used as a burndown herbicide to clear invasive weed species along roadsides and other nonagricultural land. Rimsulfuron acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. As is common practice, rimsulfuron has been subject to periodic reviews by regulatory agencies for reregistration since its introduction into the market in the early 1990s. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this reregistration process for rimsulfuron, a new confined rotational crop study was required to address a data gap requested by the European Food Safety Authority (EFSA). Consequently, the corresponding pyridine and pyrimidine radiolabeled [14C]rimsulfuron and [M + 3] stable isotopes of rimsulfuron were synthesized for this study to support the reregistration process. [ABSTRACT FROM AUTHOR]