Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes

It’s not all about autism: The emerging landscape of anti-vaccination sentiment on Facebook

Background: Due in part to declining vaccination rates, in 2018 over 20 states reported at least one case of measles, and over 40,000 cases have been confirmed in Europe. Anti-vaccine posts on social media may be facilitating anti-vaccination behaviour. This study aimed to systematically characterize (1) individuals known to publicly post anti-vaccination content on Facebook, (2) the information they convey, and (3) the spread of this content. Methods: Our data set consisted of 197 individuals who posted anti-vaccination comments in response to a message promoting vaccination. We systematically analysed publicly-available content using quantitative coding, descriptive analysis, social network analysis, and an in-depth qualitative assessment. The final codebook consisted of 26 codes; Cohen’s κ ranged 0.71-1.0 after double-coding. Results: The majority (89%) of individuals identified as female. Among 136 individuals who divulged their location, 36 states and 8 other countries were represented. In a 2-mode network of individuals and topics, modularity analysis revealed 4 distinct sub-groups labelled as “trust,” “alternatives,” “safety,” and “conspiracy.” For example, a comment representative of “conspiracy” is that poliovirus does not exist and that pesticides caused clinical symptoms of polio. An example from the “alternatives” sub-group is that eating yogurt cures human papillomavirus. Deeper qualitative analysis of all 197 individuals’ profiles found that these individuals also tended to post material against other health-related practices such as water fluoridation and circumcision. Conclusions: Social media outlets may facilitate anti-vaccination connections and organization by facilitating the diffusion of centuries old arguments and techniques. Arguments against vaccination are diverse but remain consistent within sub-groups of individuals. It would be valuable for health professionals to leverage social networks to deliver more effective, targeted messages to different constituencies

The Association between Social Media Use and Eating Concerns among US Young Adults

Background. Although the etiology of eating concerns is multi-factorial, exposure to media messages is considered to be a contributor. While traditional media, such as television and magazines, have been examined extensively in relation to risk for eating concerns, the influence of social media has received relatively less attention. Objective. To examine the association between social media use and eating concerns in a large, nationally representative sample of young adults. Design. Cross-sectional survey. Participants/setting. Participants were 1765 young adults ages 19-32, who were randomly selected from a national probability-based online non-volunteer panel. Outcome measures. An eating concerns scale was adapted from two validated measures: the SCOFF Questionnaire and the Eating Disorder Screen for Primary Care (ESP). Social media use was assessed using both volume (time per day) and frequency (visits per week). Statistical analyses. To examine associations between eating concerns and social media use, ordered logistic regression was used, controlling for all covariates. Results. Compared to those in the lowest quartile, participants in the highest quartiles of time per day and visits per week had significantly greater odds of having eating concerns (AOR = 2.18, 95% CI = 1.50 - 3.17 and AOR = 2.55, 95% CI = 1.72 - 3.78, respectively). There were significant overall linear associations between the social media use variables and eating concerns (P < 0.001). Conclusions. The results from this study indicate a strong and consistent association between social media use and eating concerns in a nationally-representative sample of young adults ages 19 to 32. This association was apparent whether social media use was measured using time per day or visits per week. Further research should assess the temporality of these associations. It would also be useful to examine more closely the influence of specific characteristics of social media use—including content-related and contextual features

Intraspecific variation in male mating strategies in an African ground squirrel (Xerus inauris)

DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding author upon reasonable request. All data are associated with tables and figures: Dryad https://doi.org/10.5061/dryad.jsxksn0cv.Male mating strategies respond to female availability such that variation in resources that affect spatial distribution can also alter cost–benefit tradeoffs within a population. In arid-adapted species, rainfall alters reproduction, behavior, morphology, and population density such that populations differing in resource availability may also differ in successful reproductive strategies. Here, we compare two populations of Cape ground squirrels (Xerus inauris), a sub-Saharan species with year-round breeding and intense mating competition. Unlike most mammals where males resort to aggressive interactions over females, male X. inauris are tolerant of one another, relying instead on other nonaggressive pre-and postcopulatory strategies to determine reproductive success. Our findings suggest that differences in resource availability affect female distribution, which ultimately leads to intraspecific variation in male reproductive tactics and sexual morphology. Sperm competition, assessed by reproductive morphometrics, was more pronounced in our high resource site where females were distributed evenly across the landscape, whereas dominance seemed to be an important determinant of success in our low resource site where females were more aggregated. Both sites had similar mating intensities, and most males did not sire any offspring. However, our low resource site had a higher variance in fertilization success with fewer males siring multiple offspring compared with our high resource site where more individuals were successful. Our results lend support to resource models where variations in female spatial distribution attributed to environmental resources ultimately impact male reproductive behaviors and morphology.National Science Foundation and Natural Sciences and Engineering Research Council of Canada.http://www.ecolevol.orgam2023Zoology and Entomolog

A One-Dimensional Model for Many-Electron Atoms in Extremely Strong Magnetic Fields: Maximum Negative Ionization

We consider a one-dimensional model for many-electron atoms in strong magnetic fields in which the Coulomb potential and interactions are replaced by one-dimensional regularizations associated with the lowest Landau level. For this model we show that the maximum number of electrons is bounded above by 2Z+1 + c sqrt{B}. We follow Lieb's strategy in which convexity plays a critical role. For the case of two electrons and fractional nuclear charge, we also discuss the critical value at which the nuclear charge becomes too weak to bind two electrons.Comment: 23 pages, 5 figures. J. Phys. A: Math and General (in press) 199

Pennsylvania policymakers’ knowledge, attitudes and likelihood for action regarding waterpipe tobacco smoking and electronic nicotine delivery systems

INTRODUCTION Use of waterpipe tobacco smoking (WTS, or hookah smoking) and electronic nicotine delivery systems (ENDS, such as e-cigarettes) is rapidly increasing. However, legislatures have been slow to update policy measures related to them. Therefore, we aimed to assess knowledge, attitudes and likelihood to take future action regarding WTS and ENDS among Pennsylvania legislators. METHODS We approached all Standing Members of key Pennsylvania House and Senate health and welfare committees to complete a survey about substances of abuse, including WTS and ENDS. Closed-ended knowledge, attitude and action items used a 100-point scale. Responses to open-ended items were assessed using thematic analysis by three independently working researchers. RESULTS We received responses from 13 of 27 eligible policymakers (48%). Participants answered a mean of only 27% (SD=20%) of knowledge items correctly. When asked to rank by priority eight issues in substance abuse, WTS ranked eighth (least urgent) and ENDS ranked fifth. Participants reported low likelihood to introduce legislation on WTS (mean=29, median=25) and/or ENDS (mean=28, median=10). Thematic analysis revealed that participants readily acknowledged lack of understanding of WTS and ENDS, and were eager for additional information. CONCLUSIONS Policymakers exhibit a lack of knowledge concerning newer forms of tobacco and nicotine delivery systems and consider them to be relatively low legislative priorities. However, respondents expressed a desire for more information, suggesting the potential for public health entities to promote effective policy development via improved dissemination of information

For Better or for Worse? A Systematic Review of the Evidence on Social Media Use and Depression Among Lesbian, Gay, and Bisexual Minorities

Background: Over 90% of adults in the United States have at least one social media account, and lesbian, gay, and bisexual (LGB) persons are more socially active on social media than heterosexuals. Rates of depression among LGB persons are between 1.5- and 2-fold higher than those among their heterosexual counterparts. Social media allows users to connect, interact, and express ideas, emotions, feelings, and thoughts. Thus, social media use might represent both a protective and a risk factor for depression among LGB persons. Studying the nature of the relationship between social media use and depression among LGB individuals is a necessary step to inform public health interventions for this population. Objective: The objective of this systematic review was to synthesize and critique the evidence on social media use and depression among LGB populations. Methods: We conducted a literature search for quantitative and qualitative studies published between January 2003 and June 2017 using 3 electronic databases. Articles were included if they were peer-reviewed, were in English, assessed social media use either quantitatively or qualitatively, measured depression, and focused on LGB populations. A minimum of two authors independently extracted data from each study using an a priori developed abstraction form. We assessed appropriate reporting of studies using the Strengthening the Reporting of Observational Studies in Epidemiology and the Consolidated Criteria for Reporting Qualitative Research for quantitative and qualitative studies, respectively. Results: We included 11 articles in the review; 9 studies were quantitative and cross-sectional and 2 were qualitative. Appropriate reporting of results varied greatly. Across quantitative studies, we found heterogeneity in how social media use was defined and measured. Cyberbullying was the most studied social media experience and was associated with depression and suicidality. Qualitative studies found that while social media provides a space to disclose minority experiences and share ways to cope and get support, constant surveillance of one’s social media profile can become a stressor, potentially leading to depression. In most studies, sexual minority participants were identified inconsistently. Conclusions: This review supports the need for research on the role of social media use on depression outcomes among LBG persons. Using social media may be both a protective and a risk factor for depression among LGB individuals. Support gained via social media may buffer the impact of geographic isolation and loneliness. Negative experiences such as cyberbullying and other patterns of use may be associated with depression. Future research would benefit from more consistent definitions of both social media use and study populations. Moreover, use of larger samples and accounting for patterns of use and individuals’ experiences on social media may help better understand the factors that impact LGB mental health disparities

Seniors, and their food handlers and caregivers, need food safety and nutrition education

Seniors are at greater risk than other adults for foodborne illness, poor nutrition and high rates of nutrition- and lifestyle-related chronic diseases. They also represent a major underserved segment of the UC Cooperative Extension client population. The Make Food Safe for Seniors (MFSFS) initiative assessed food safety and nutrition education needs of fixed-income seniors and food handlers and caregivers serving seniors in 10 California counties. Baseline survey results found unsafe practices by over 50% of the participants in six areas - and by over 65% of participants in three of those areas. After one food safety training, a post-test showed an average knowledge gain of 18.1%; seniors had gained the least knowledge, food handlers had gained some knowledge, and caregivers had gained the most. The unsafe food handling practices of a majority of the study group, as well as poor food behaviors, suggested areas in which education could reinforce or improve food safety, healthy eating and disease prevention practices of seniors, caregivers and food handlers serving seniors

The Community Land Model version 5 : description of new features, benchmarking, and impact of forcing uncertainty

The Community Land Model (CLM) is the land component of the Community Earth System Model (CESM) and is used in several global and regional modeling systems. In this paper, we introduce model developments included in CLM version 5 (CLM5), which is the default land component for CESM2. We assess an ensemble of simulations, including prescribed and prognostic vegetation state, multiple forcing data sets, and CLM4, CLM4.5, and CLM5, against a range of metrics including from the International Land Model Benchmarking (ILAMBv2) package. CLM5 includes new and updated processes and parameterizations: (1) dynamic land units, (2) updated parameterizations and structure for hydrology and snow (spatially explicit soil depth, dry surface layer, revised groundwater scheme, revised canopy interception and canopy snow processes, updated fresh snow density, simple firn model, and Model for Scale Adaptive River Transport), (3) plant hydraulics and hydraulic redistribution, (4) revised nitrogen cycling (flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake), (5) global crop model with six crop types and time‐evolving irrigated areas and fertilization rates, (6) updated urban building energy, (7) carbon isotopes, and (8) updated stomatal physiology. New optional features include demographically structured dynamic vegetation model (Functionally Assembled Terrestrial Ecosystem Simulator), ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Conclusive establishment of improvement or degradation of individual variables or metrics is challenged by forcing uncertainty, parametric uncertainty, and model structural complexity, but the multivariate metrics presented here suggest a general broad improvement from CLM4 to CLM5