Sensitization of renal carcinoma cells to TRAIL-induced apoptosis by rocaglamide and analogs

Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells. Rocaglamide alone induced cell cycle arrest, but not apoptosis. Rocaglates averaged 4–5-fold higher potency as TRAIL sensitizers than as protein synthesis inhibitors suggesting a potential window for maximizing TRAIL sensitization while minimizing effects of general protein synthesis inhibition. A wide range of other rocaglate effects (e.g. on JNK or RAF-MEK-ERK signaling, death receptor levels, ROS, ER stress, eIF4E phosphorylation) were assessed, but did not contribute to TRAIL sensitization. Other than a rapid loss of MCL-1, rocaglates had minimal effects on mitochondrial apoptotic pathway proteins. The identification of structurally diverse/mechanistically similar TRAIL sensitizing rocaglates provides insights into both rocaglate structure and function and potential further development for use in RCC-directed combination therapy.This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research. Research performed at Boston University was supported in part by NIH R35 GM118173. Work at the BU-CMD is supported by R24 GM111625. (HHSN261200800001E - National Cancer Institute, National Institutes of Health; Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research; R35 GM118173 - NIH; R24 GM111625)Published versio

Multiple dimensions of functional diversity affect stream fish taxonomic β-diversity

1. When investigating metacommunity dynamics, functional differences amongspecies are often assumed to be as important as environmental differences be-tween sites in determining β-diversity. However, few studies have examined theinfluence of functional diversity on β-diversity. We examine the relative importance of regional functional diversity partitioned by niche dimensions and environmental variation in structuring taxonomic β-diversity of stream fishes using a large dataset of stream fish assemblages (hereafter, simply β-diversity). We predicted that both functional diversity and environmental variation play a rolein determining β-diversity.2. We tested this prediction by modelling the patterns of stream fish β-diversity asa function of environmental variation, functional diversity and γ- richness across10,220 sites for 329 fish species using a series of conceptual path models.3. Environmental variation consistently affected β-diversity across all models,whereas functional diversity and γ- richness influenced β-diversity only in somemodels. We show that including relevant trait differences among species in pathmodels can improve their ability to explain β-diversity, suggesting that functional traits influence β-diversity.4. The ability of path models to explain β-diversity varied depending on the traitgrouping included in the model, demonstrating that specific path models representing different niche dimensions can improve the ability of a model to explain β-diversity. In addition, parsing traits into different niche dimensions revealed alternative patterns of functional diversity–β-diversity relationships that other-wise would have been missed.5. The selection of relevant traits and linked niche dimensions is critical for detecting relationships between functional diversity and β-diversity. Using traitsassociated with different niche dimensions allows for the identification of nichedimensions most strongly associated with species sorting and the detection ofpatterns missed by focusing on a single niche dimension. Determining the niche dimensions that influence β-diversity could provide insights into the processesdriving biodiversity and metacommunity dynamics, improving our ability to con-serve or restore aquatic communities

Multiregional origins of the domesticated tetraploid wheats

We used genotyping-by-sequencing (GBS) to investigate the evolutionary history of domesticated tetraploid wheats. With a panel of 189 wild and domesticated wheats, we identified 1,172,469 single nucleotide polymorphisms (SNPs) with a read depth ≥3. Principal component analyses (PCAs) separated the Triticum turgidum and Triticum timopheevii accessions, as well as wild T. turgidum from the domesticated emmers and the naked wheats, showing that SNP typing by GBS is capable of providing robust information on the genetic relationships between wheat species and subspecies. The PCAs and a neighbour-joining analysis suggested that domesticated tetraploid wheats have closest affinity with wild emmers from the northern Fertile Crescent, consistent with the results of previous genetic studies on the origins of domesticated wheat. However, a more detailed examination of admixture and allele sharing between domesticates and different wild populations, along with genome-wide association studies (GWAS), showed that the domesticated tetraploid wheats have also received a substantial genetic input from wild emmers from the southern Levant. Taking account of archaeological evidence that tetraploid wheats were first cultivated in the southern Levant, we suggest that a pre-domesticated crop spread from this region to southeast Turkey and became mixed with a wild emmer population from the northern Fertile Crescent. Fixation of the domestication traits in this mixed population would account for the allele sharing and GWAS results that we report. We also propose that feralization of the component of the pre-domesticated population that did not acquire domestication traits has resulted in the modern wild population from southeast Turkey displaying features of both the domesticates and wild emmer from the southern Levant, and hence appearing to be the sole progenitor of domesticated tetraploids when the phylogenetic relationships are studied by methods that assume a treelike pattern of evolution.This work was supported by: TAB, 339941, European Research Council; TAB, NE/M010805/1, Natural Environment Research Councilinfo:eu-repo/semantics/publishedVersio

Resilience-Focused HIV Care to Promote Psychological Well-Being During COVID-19 and Other Catastrophes

The COVID-19 pandemic has adversely affected people with HIV due to disruptions in prevention and care services, economic impacts, and social isolation. These stressors have contributed to worse physical health, HIV treatment outcomes, and psychological wellness. Psychological sequelae associated with COVID-19 threaten the overall well-being of people with HIV and efforts to end the HIV epidemic. Resilience is a known mediator of health disparities and can improve psychological wellness and behavioral health outcomes along the HIV Continuum of Care. Though resilience is often organically developed in individuals as a result of overcoming adversity, it may be fostered through multi-level internal and external resourcing (at psychological, interpersonal, spiritual, and community/neighborhood levels). In this Perspective, resilience-focused HIV care is defined as a model of care in which providers promote optimum health for people with HIV by facilitating multi-level resourcing to buffer the effects of adversity and foster well-being. Adoption of resilience-focused HIV care may help providers better promote well-being among people living with HIV during this time of increased psychological stress and help prepare systems of care for future catastrophes. Informed by the literature, we constructed a set of core principles and considerations for successful adoption and sustainability of resilience-focused HIV care. Our definition of resilience-focused HIV care marks a novel contribution to the knowledge base and responds to the call for a multidimensional definition of resilience as part of HIV research

Workforce Characteristics, Perceptions, Stress, and Satisfaction among Staff in Green House and Other Nursing Homes

OBJECTIVE: To compare workforce characteristics and staff perceptions of safety, satisfaction, and stress between Green House (GH) and comparison nursing homes (CNHs). DATA SOURCES/STUDY SETTING: Primary data on staff perceptions of safety, stress, and satisfaction from 13 GHs and 8 comparison NHs in 11 states; secondary data from human resources records on workforce characteristics, turnover, and staffing from 01/01/2011-06/30/2012. STUDY DESIGN: Observational study. DATA COLLECTION METHODS: Workforce data were from human resources offices; staff perceptions were from surveys. PRINCIPAL FINDINGS: Few significant differences were found between GH and CNHs. Exceptions were GH direct caregivers were older, provided twice the normalized hours per week budgeted per resident than CNAs in CNHs or Legacy NHs, and trended toward lower turnover. CONCLUSIONS: GH environment may promote staff longevity and does not negatively affect worker's stress, safety perceptions, or satisfaction. Larger studies are needed to confirm findings

Metapopulation viability of an endangered shorebird depends on dispersal and human-created habitats: piping plovers (\u3ci\u3eCharadrius melodus\u3c/i\u3e) and prairie rivers

Background: Many species are distributed as metapopulations in dynamic landscapes, where habitats change through space and time. Individuals locate habitat through dispersal, and the relationship between a species and landscape characteristics can have profound effects on population persistence. Despite the importance of connectivity in dynamic environments, few empirical studies have examined temporal variability in dispersal or its effect on metapopulation dynamics. In response to this knowledge gap, we studied the dispersal, demography, and viability of a metapopulation of an endangered, disturbance-dependent shorebird. We examined three subpopulations of piping plovers (Charadrius melodus) on the lower Platte and Missouri rivers from 2008–2013. High flow events from an upstream dam on the Missouri River in 2010 and 2011 allowed us to assess the effect of total habitat loss and the subsequent creation of new habitat associated with a large disturbance at one ‘natural’ study location. The other two sites within the metapopulation, which were maintained by anthropogenic activities (e.g., mining, development, habitat restoration), were largely unaffected by this disturbance, resulting in a controlled natural experiment. Results: High flow events were associated with increased emigration, decreased immigration, and decreased survival in the subpopulation that experienced high flows. Following the high flow event, immigration into that subpopulation increased. Dispersal rates among subpopulations were negatively correlated with distance. The metapopulation had a low probability of extinction over 100 years (0 %) under the current disturbance interval and associated dispersal and survival rates. However, persistence depended on relatively stable, human-created habitats, not the dynamic, natural habitat (47.7 % extinction probability for this subpopulation). Conclusions: We found that functional connectivity, as measured by the rate of dispersal among subpopulations, increased as a result of the high flow event in our study metapopulation. Plovers also increased reproductive output following this event. Although the study metapopulation had a low overall probability of extinction, metapopulation persistence depended on anthropogenically created habitats that provided a small but stable source of nesting habitat and dispersers through time. However, all subpopulations remained small, even if persistent, making them individually vulnerable to extinction through stochastic events. Given the highly dynamic nature of habitat availability in this system, maintaining several subpopulations within the metapopulation and stable sources of habitat will be critical, and this species will likely remain conservation-reliant

An Observational Analysis of ‘Me Too’ Narratives from YouTube

The ‘me too’ movement originated to help survivors of sexual violence by providing resources and building a community of advocates to exemplify the magnitude of sexual violence victimization. This movement gained momentum via Twitter due to the viral hashtag—#metoo. YouTube is often used as a means of expression in younger generations, thus sexual violence survivors began using the platform as a way to disseminate ‘me too’ narratives. Therefore, this study aimed to examine how sexual violence narratives resulting from the ‘me too’ movement are being told on YouTube and understand the components of the narratives related to self-blaming mindsets. Based on predetermined search criteria, researchers identified and screened YouTube videos of people sharing ‘me too’ narratives, and developed themes and codes (e.g., type of violence, perpetrator characteristics). Descriptive statistics and a logistic regression were conducted using demographic, experience, and attitudinal data to predict self-blaming mindsets. Sixty-two YouTube videos were included, consisting of 96 individual ‘me too’ stories. The sample was mostly female, and perpetrators were predominately strangers. The model explained 19.3% of the variance in self-blaming attitudes. Odds of self-blaming rose 4.589 times for those who experienced sexual harassment, and 6.109 times for those who experienced rape. If the perpetrator was not mentioned in the video, odds of self-blaming dropped by 89.4%. This study suggests self-blaming beliefs are prominent among victims, even when they have the space to share their story. Overall, our findings support the continued need for further education and support for victims

Effects of climate change and anthropogenic modification on a disturbance-dependent species in a large riverine system

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ecosphere 8 (2017): e01653, doi:10.1002/ecs2.1653.Humans have altered nearly every natural disturbance regime on the planet through climate and land-use change, and in many instances, these processes may have interacting effects. For example, projected shifts in temperature and precipitation will likely influence disturbance regimes already affected by anthropogenic fire suppression or river impoundments. Understanding how disturbance-dependent species respond to complex and interacting environmental changes is important for conservation efforts. Using field-based demographic and movement rates, we conducted a metapopulation viability analysis for piping plovers (Charadrius melodus), a threatened disturbance-dependent species, along the Missouri and Platte rivers in the Great Plains of North America. Our aim was to better understand current and projected future metapopulation dynamics given that natural disturbances (flooding or high-flow events) have been greatly reduced by river impoundments and that climate change could further alter the disturbance regime. Although metapopulation abundance has been substantially reduced under the current suppressed disturbance regime (high-flow return interval ~ 20 yr), it could grow if the frequency of high-flow events increases as predicted under likely climate change scenarios. We found that a four-year return interval would maximize metapopulation abundance, and all subpopulations in the metapopulation would act as sources at a return interval of 15 yr or less. Regardless of disturbance frequency, the presence of even a small, stable source subpopulation buffered the metapopulation and sustained a low metapopulation extinction risk. Therefore, climate change could have positive effects in ecosystems where disturbances have been anthropogenically suppressed when climatic shifts move disturbance regimes toward more historical patterns. Furthermore, stable source populations, even if unintentionally maintained through anthropogenic activities, may be critical for the persistence of metapopulations of early-successional species under both suppressed disturbance regimes and disturbance regimes where climate change has further altered disturbance frequency or scope.Nebraska Environmental Trust Nebraska State Wildlife Grant Program; Nebraska Wildlife Conservation Fund; U.S. Army Corps of Engineers; U.S. Fish and Wildlife Service (USFWS); USFWS North Atlantic Landscape Conservation Cooperative; Virginia Tec