Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer.

Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, and prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 inhibition, but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer.

Mycorrhizal effects on crop yield and soil ecosystem functions in a long-term tillage and fertilization experiment.

It is well understood that agricultural management influences arbuscular mycorrhizal (AM) fungi, but there is controversy about whether farmers should manage for AM symbiosis. We assessed AM fungal communities colonizing wheat roots for three consecutive years in a long-term (> 14 yr) tillage and fertilization experiment. Relationships among mycorrhizas, crop performance, and soil ecosystem functions were quantified. Tillage, fertilizers and continuous monoculture all reduced AM fungal richness and shifted community composition toward dominance of a few ruderal taxa. Rhizophagus and Dominikia were depressed by tillage and/or fertilization, and their abundances as well as AM fungal richness correlated positively with soil aggregate stability and nutrient cycling functions across all or no-tilled samples. In the field, wheat yield was unrelated to AM fungal abundance and correlated negatively with AM fungal richness. In a complementary glasshouse study, wheat biomass was enhanced by soil inoculum from unfertilized, no-till plots while neutral to depressed growth was observed in wheat inoculated with soils from fertilized and conventionally tilled plots. This study demonstrates contrasting impacts of low-input and conventional agricultural practices on AM symbiosis and highlights the importance of considering both crop yield and soil ecosystem functions when managing mycorrhizas for more sustainable agroecosystems.

Enhancing agency and empowerment in agricultural development projects: A synthesis of mixed methods impact evaluations from the Gender, Agriculture, and Assets Project, Phase 2 (GAAP2).

Development interventions increasingly include women's empowerment and gender equality among their objectives, but evaluating their impact has been stymied by the lack of measures that are comparable across interventions. This paper synthesizes the findings of 11 mixed-methods impact evaluations of agricultural development projects from South Asia and sub-Saharan Africa that were part of the Gender, Agriculture, and Assets Project, Phase 2 (GAAP2). As part of GAAP2, qualitative and quantitative data were used to develop and validate the multidimensional project-level Women's Empowerment in Agriculture Index (pro-WEAI), which was used to assess the impact of GAAP2 projects on women's empowerment. This paper assesses the extent to which: (1) a two- to three-year agricultural development project can contribute to women's empowerment; and (2) a suite of methods comprising a standardized quantitative measure of women's empowerment and a set of qualitative protocols, can evaluate such impacts. Our synthesis finds that the most common positive significant impacts were on the instrumental and collective agency indicators that comprise pro-WEAI, owing to the group-based approaches used. We found few projects significantly improved intrinsic agency, even among those with explicitly stated objectives to change gender norms. Unsurprisingly, we find mixed, and mostly null impacts on aggregate pro-WEAI, with positive impacts more likely in the South Asian, rather than African, cases. Our results highlight the need for projects to design their strategies specifically for empowerment, rather than assume that projects aiming to reach and benefit women automatically empower them. Our study also shows the value of a suite of methods containing a common metric to compare empowerment impacts and qualitative protocols to understand and contextualize these impacts.

Sympatric soil biota mitigate a warmer-drier climate for Bouteloua gracilis.

Climate change is altering temperature and precipitation, resulting in widespread plant mortality and shifts in plant distributions. Plants growing in soil types with low water holding capacity may experience intensified effects of reduced water availability as a result of climate change. Furthermore, complex biotic interactions between plants and soil organisms may mitigate or exacerbate the effects of climate change. This 3-year field experiment observed the performance of Bouteloua gracilis ecotypes that were transplanted across an environmental gradient with either sympatric soil from the seed source location or allopatric soil from the location that plants were transplanted into. We also inoculated plants with either sympatric or allopatric soil biotic communities to test: (1) how changes in climate alone influence plant growth, (2) how soil types interact with climate to influence plant growth, and (3) the role of soil biota in mitigating plant migration to novel environments. As expected, plants moved to cooler-wetter sites exhibited enhanced growth; however, plants moved to warmer-drier sites responded variably depending on the provenance of their soil and inoculum. Soil and inoculum provenance had little influence on the performance of plants moved to cooler-wetter sites, but at warmer-drier sites they were important predictors of plant biomass, seed set, and specific leaf area. Specifically, transplants inoculated with their sympatric soil biota and grown in their sympatric soil were as large as or larger than reference plants grown at the seed source locations; however, individuals inoculated with allopatric soil biota were smaller than reference site individuals at warmer, drier sites. These findings demonstrate complicated plant responses to various aspects of environmental novelty where communities of soil organisms may help ameliorate stress. The belowground microbiome of plants should be considered to predict the responses of vegetation more accurately to climate change.

A call to action: Community pharmacists to address COVID-19-related behavioral health concerns.

Owing to the extended nature and worldwide exposure of the coronavirus disease (COVID-19) pandemic, it is likely that the presence and impact of behavioral health conditions will increase. For example, it is anticipated that individuals living with a major depressive disorder could reach as high as 60% of the population owing to the ongoing disruption from COVID-19. In 2017, the annual rate of individuals experiencing a major depressive episode was only 7.1%. Pharmacists, specifically community pharmacists, are well positioned to provide needed intervention and triage services to individuals living with, and struggling with, a mental health condition. Pharmacists, therefore, need additional training and support to be effective in serving the community in this way.

Resistance of soil biota and plant growth to disturbance increases with plant diversity.

Plant diversity is critical to the functioning of ecosystems, potentially mediated in part by interactions with soil biota. Here, we characterised multiple groups of soil biota across a plant diversity gradient in a long-term experiment. We then subjected soil samples taken along this gradient to drought, freezing and a mechanical disturbance to test how plant diversity affects the responses of soil biota and growth of a focal plant to these disturbances. High plant diversity resulted in soils that were dominated by fungi and associated soil biota, including increased arbuscular mycorrhizal fungi and reduced plant-feeding nematodes. Disturbance effects on the soil biota were reduced when plant diversity was high, resulting in higher growth of the focal plant in all but the frozen soils. These results highlight the importance of plant diversity for soil communities and their resistance to disturbance, with potential feedback effects on plant productivity.

Arbuscular mycorrhizal fungi in roots and soil respond differently to biotic and abiotic factors in the Serengeti.

This study explores the relationships of AM fungal abundance and diversity with biotic (host plant, ungulate grazing) and abiotic (soil properties, precipitation) factors in the Serengeti National Park, Tanzania. Soil and root samples were collected from grazed and ungrazed plots at seven sites across steep soil fertility and precipitation gradients. AM fungal abundance in the soil was estimated from the density of spores and the concentration of a fatty acid biomarker. Diversity of AM fungi in roots and soils was measured using DNA sequencing and spore identification. AM fungal abundance in soil decreased with grazing and precipitation and increased with soil phosphorus. The community composition of AM fungal DNA in roots and soils differed. Root samples had more AM fungal indicator species associated with biotic factors (host plant species and grazing), and soil samples had more indicator species associated with particular sample sites. These findings suggest that regional edaphic conditions shape the site-level species pool from which plant species actively select root-colonizing fungal assemblages modified by grazing. Combining multiple measurements of AM fungal abundance and community composition provides the most informed assessment of the structure of mycorrhizal fungal communities in natural ecosystems.

Dynamics of arbuscular mycorrhizal fungal community structure and functioning along a nitrogen enrichment gradient in an alpine meadow ecosystem.

Nitrogen (N) availability is increasing dramatically in many ecosystems, but the influence of elevated N on the functioning of arbuscular mycorrhizal (AM) fungi in natural ecosystems is not well understood. We measured AM fungal community structure and mycorrhizal function simultaneously across an experimental N addition gradient in an alpine meadow that is limited by N but not by phosphorus (P). AM fungal communities at both whole-plant-community (mixed roots) and single-plant-species (Elymus nutans roots) scales were described using pyro-sequencing, and the mycorrhizal functioning was quantified using a mycorrhizal-suppression treatment in the field (whole-plant-community scale) and a glasshouse inoculation experiment (single-plant-species scale). Nitrogen enrichment progressively reduced AM fungal abundance, changed AM fungal community composition, and shifted mycorrhizal functioning towards parasitism at both whole-plant-community and E. nutans scales. N-induced shifts in AM fungal community composition were tightly linked to soil N availability and/or plant species richness, whereas the shifts in mycorrhizal function were associated with the communities of specific AM fungal lineages. The observed changes in both AM fungal community structure and functioning across an N enrichment gradient highlight that N enrichment of ecosystems that are not P-limited can induce parasitic mycorrhizal functioning and influence plant community structure and ecosystem sustainability.

Beyond ICOM8: perspectives on advances in mycorrhizal research from 2015 to 2017.

This report reviews important advances in mycorrhizal research that occurred during the past 2 years. We highlight major advancements both within and across levels of biological organization and describe areas where greater integration has led to unique insights. Particularly active areas of research include exploration of the mechanisms underpinning the development of the mycorrhizal symbiosis, the mycorrhizal microbiome, comparisons among types of mycorrhizas from molecular to ecosystem scales, the extent and function of mycorrhizal networks and enhanced understanding of the role of mycorrhizas in carbon dynamics from local to global scales. The top-tier scientific journals have acknowledged mycorrhizas to be complex adaptive systems that play key roles in the development of communities and ecosystem processes. Understanding the mechanisms driving these large-scale effects requires integration of knowledge across scales of biological organization.

Evolution of microbial markets.

Biological market theory has been used successfully to explain cooperative behavior in many animal species. Microbes also engage in cooperative behaviors, both with hosts and other microbes, that can be described in economic terms. However, a market approach is not traditionally used to analyze these interactions. Here, we extend the biological market framework to ask whether this theory is of use to evolutionary biologists studying microbes. We consider six economic strategies used by microbes to optimize their success in markets. We argue that an economic market framework is a useful tool to generate specific and interesting predictions about microbial interactions, including the evolution of partner discrimination, hoarding strategies, specialized versus diversified mutualistic services, and the role of spatial structures, such as flocks and consortia. There is untapped potential for studying the evolutionary dynamics of microbial systems. Market theory can help structure this potential by characterizing strategic investment of microbes across a diversity of conditions.

Gender, Assets, and Agricultural Development: Lessons from Eight Projects.

Ownership of assets is important for poverty reduction, and women's control of assets is associated with positive development outcomes at the household and individual levels. This research was undertaken to provide guidance for agricultural development programs on how to incorporate gender and assets in the design, implementation, and evaluation of interventions. This paper synthesizes the findings of eight mixed-method evaluations of the impacts of agricultural development projects on individual and household assets in seven countries in Africa and South Asia. The results show that assets both affect and are affected by projects, indicating that it is both feasible and important to consider assets in the design, implementation, and evaluation of projects. All projects were associated with increases in asset levels and other benefits at the household level; however, only four projects documented significant, positive impacts on women's ownership or control of some types of assets relative to a control group, and of those only one project provided evidence of a reduction in the gender asset gap. The quantitative and qualitative findings suggest ways that greater attention to gender and assets by researchers and development implementers could improve outcomes for women in future projects.

Mycorrhizal phenotypes and the Law of the Minimum.

Mycorrhizal phenotypes arise from interactions among plant and fungal genotypes and the environment. Differences in the stoichiometry and uptake capacity of fungi and plants make arbuscular mycorrhizal (AM) fungi inherently more nitrogen (N) limited and less phosphorus (P) limited than their host plants. Mutualistic phenotypes are most likely in P-limited systems and commensal or parasitic phenotypes in N-limited systems. Carbon (C) limitation is expected to cause phenotypes to shift from mutualism to commensalism and even parasitism. Two experiments compared the influence of fertilizer and shade on mycorrhizas in Andropogon gerardii across three naturally N-limited or P-limited grasslands. A third experiment examined the interactive effects of N and P enrichment and shade on A. gerardii mycorrhizas. Our experiments generated the full spectrum of mycorrhizal phenotypes. These findings support the hypothesis that mutualism is likely in P-limited systems and commensalism or parasitism is likely in N-limited systems. Furthermore, shade decreased C-assimilation and generated less mutualistic mycorrhizal phenotypes with reduced plant and fungal biomass. Soil fertility is a key controller of mycorrhizal costs and benefits and the Law of the Minimum is a useful predictor of mycorrhizal phenotype. In our experimental grasslands arbuscular mycorrhizas can ameliorate P-limitation but not N-limitation.

Development of the Primary Care Quality-Homeless (PCQ-H) instrument: a practical survey of homeless patients' experiences in primary care.

BACKGROUND: Homeless patients face unique challenges in obtaining primary care responsive to their needs and context. Patient experience questionnaires could permit assessment of patient-centered medical homes for this population, but standard instruments may not reflect homeless patients' priorities and concerns. OBJECTIVES: This report describes (a) the content and psychometric properties of a new primary care questionnaire for homeless patients; and (b) the methods utilized in its development. METHODS: Starting with quality-related constructs from the Institute of Medicine, we identified relevant themes by interviewing homeless patients and experts in their care. A multidisciplinary team drafted a preliminary set of 78 items. This was administered to homeless-experienced clients (n=563) across 3 VA facilities and 1 non-VA Health Care for the Homeless Program. Using Item Response Theory, we examined Test Information Function (TIF) curves to eliminate less informative items and devise plausibly distinct subscales. RESULTS: The resulting 33-item instrument (Primary Care Quality-Homeless) has 4 subscales: Patient-Clinician Relationship (15 items), Cooperation among Clinicians (3 items), Access/Coordination (11 items), and Homeless-specific Needs (4 items). Evidence for divergent and convergent validity is provided. TIF graphs showed adequate informational value to permit inferences about groups for 3 subscales (Relationship, Cooperation, and Access/Coordination). The 3-item Cooperation subscale had lower informational value (TIF<5) but had good internal consistency (α=0.75) and patients frequently reported problems in this aspect of care. CONCLUSIONS: Systematic application of qualitative and quantitative methods supported the development of a brief patient-reported questionnaire focused on the primary care of homeless patients and offers guidance for future population-specific instrument development.

"Everyone should be able to choose how they get around": how Topeka, Kansas, passed a complete streets resolution.

BACKGROUND: Regular physical activity can help prevent chronic diseases, yet only half of US adults meet national physical activity guidelines. One barrier to physical activity is a lack of safe places to be active, such as bike paths and sidewalks. Complete Streets, streets designed to enable safe access for all users, can help provide safe places for activity. COMMUNITY CONTEXT: This community case study presents results from interviews with residents and policymakers of Topeka, Kansas, who played an integral role in the passage of a Complete Streets resolution in 2009. It describes community engagement processes used to include stakeholders, assess existing roads and sidewalks, and communicate with the public and decision-makers. METHODS: Key informant interviews were conducted with city council members and members of Heartland Healthy Neighborhoods in Topeka to learn how they introduced a Complete Streets resolution and the steps they took to ensure its successful passage in the City Council. Interviews were recorded, transcribed, and analyzed by using focused-coding qualitative analysis. OUTCOME: Results included lessons learned from the process of passing the Complete Streets resolution and advice from participants for other communities interested in creating Complete Streets in their communities. INTERPRETATION: Lessons learned can apply to other communities pursuing Complete Streets. Examples include clearly defining Complete Streets; educating the public, advocates, and decision-makers about Complete Streets and how this program enhances a community; building a strong and diverse network of supporters; and using stories and examples from other communities with Complete Streets to build a convincing case.

It takes a village: a community partnership model in caring for the homeless.

Population health management calls for hospitals and health care entities to better align their strategies in order to deliver quality care more efficiently. Although these efforts tend to be addressed with insured populations, the homeless demand a very intentional focus. The issue of homelessness has adverse effects on the health care system, resulting in the inefficient use of resources. Community-wide efforts must be mobilized to address this inefficiency and need for preventative care and self-management education for this population. Carondelet Health Network, in partnership with El Rio Community Health Center, a federally qualified health center, along with other health care and social service providers, has established the Southern Arizona Health Village for the Homeless, providing a health care delivery system to ensure the best functional and clinical outcomes. This system includes a van (the Van of Hope), licensed as a health center, and staffed with an El Rio Community Health Center nurse practitioner and a medical assistant partnering with a Carondelet Health Network behavioral health specialist and a community outreach worker. Clinical patient information is managed via an electronic health record inclusive of clinical data, number of visits, referrals, self-management education, hospitalizations, and follow-up care. A post-hospital program with shelters and an Emergency Room Navigation Program are additional components of the village that provide a comprehensive pre-acute and post-acute effort to support the homeless. Financial impact is measured by reductions in hospitalizations and average length of stay.

Controlled breathing with or without peppermint aromatherapy for postoperative nausea and/or vomiting symptom relief: a randomized controlled trial.

PURPOSE: With little scientific evidence to support use of aromatherapy for postoperative nausea and/or vomiting (PONV) symptoms, this study evaluated controlled breathing with peppermint aromatherapy (AR) and controlled breathing alone (CB) for PONV relief. DESIGN: A single blind randomized control trial design was used. METHODS: On initial PONV complaint, symptomatic subjects received either CB (n = 16) or AR (n = 26) intervention based on randomization at enrollment. A second treatment was repeated at 5 minutes if indicated. Final assessment occurred 10 minutes post initial treatment. Rescue medication was offered for persistent symptoms. FINDINGS: Among eligible subjects, PONV incidence was 21.4% (42/196). Gender was the only risk factor contributing to PONV symptoms (P = .0024). Though not statistically significant, CB was more efficacious than AR, 62.5% versus 57.7%, respectively. CONCLUSIONS: CB can be initiated without delay as an alternative to prescribed antiemetics. Data also support use of peppermint AR in conjunction with CB for PONV relief.

Computer vision models enable mixed linear modeling to predict arbuscular mycorrhizal fungal colonization using fungal morphology.

The presence of Arbuscular Mycorrhizal Fungi (AMF) in vascular land plant roots is one of the most ancient of symbioses supporting nitrogen and phosphorus exchange for photosynthetically derived carbon. Here we provide a multi-scale modeling approach to predict AMF colonization of a worldwide crop from a Recombinant Inbred Line (RIL) population derived from Sorghum bicolor and S. propinquum. The high-throughput phenotyping methods of fungal structures here rely on a Mask Region-based Convolutional Neural Network (Mask R-CNN) in computer vision for pixel-wise fungal structure segmentations and mixed linear models to explore the relations of AMF colonization, root niche, and fungal structure allocation. Models proposed capture over 95% of the variation in AMF colonization as a function of root niche and relative abundance of fungal structures in each plant. Arbuscule allocation is a significant predictor of AMF colonization among sibling plants. Arbuscules and extraradical hyphae implicated in nutrient exchange predict highest AMF colonization in the top root section. Our work demonstrates that deep learning can be used by the community for the high-throughput phenotyping of AMF in plant roots. Mixed linear modeling provides a framework for testing hypotheses about AMF colonization phenotypes as a function of root niche and fungal structure allocations.

Predicting community and ecosystem outcomes of mycorrhizal responses to global change.

Mycorrhizal symbioses link the biosphere with the lithosphere by mediating nutrient cycles and energy flow though terrestrial ecosystems. A more mechanistic understanding of these plant-fungal associations may help ameliorate anthropogenic changes to C and N cycles and biotic communities. We explore three interacting principles: (1) optimal allocation, (2) biotic context and (3) fungal adaptability that may help predict mycorrhizal responses to carbon dioxide enrichment, nitrogen eutrophication, invasive species and land-use changes. Plant-microbial feedbacks and thresholds are discussed in light of these principles with the goal of generating testable hypotheses. Ideas to develop large-scale collaborative research efforts are presented. It is our hope that mycorrhizal symbioses can be effectively integrated into global change models and eventually their ecology will be understood well enough so that they can be managed to help offset some of the detrimental effects of anthropogenic environmental change.

Patterns of diversity and adaptation in Glomeromycota from three prairie grasslands.

Arbuscular mycorrhizal (AM) fungi are widespread root symbionts that often improve the fitness of their plant hosts. We tested whether local adaptation in mycorrhizal symbioses would shape the community structure of these root symbionts in a way that maximizes their symbiotic functioning. We grew a native prairie grass (Andropogon gerardii) with all possible combinations of soils and AM fungal inocula from three different prairies that varied in soil characteristics and disturbance history (two native prairie remnants and one recently restored). We identified the AM fungi colonizing A. gerardii roots using PCR amplification and cloning of the small subunit rRNA gene. We observed 13 operational taxonomic units (OTUs) belonging to six genera in three families. Taxonomic richness was higher in the restored than the native prairies with one member of the Gigaspora dominating the roots of plants grown with inocula from native prairies. Inoculum source and the soil environment influenced the composition of AM fungi that colonized plant roots. Correspondingly, host plants and AM fungi responded significantly to the soil-inoculum combinations such that home fungi often had the highest fitness and provided the greatest benefit to A. gerardii. Similar patterns were observed within the soil-inoculum combinations originating from two native prairies, where five sequence types of a single Gigaspora OTU were virtually the only root colonizers. Our results indicate that indigenous assemblages of AM fungi were adapted to the local soil environment and that this process occurred both at a community scale and at the scale of fungal sequence types within a dominant OTU.