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"Perry, D."
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PI3K inhibitors are finally coming of age
Overactive phosphoinositide 3-kinase (PI3K) in cancer and immune dysregulation has spurred extensive efforts to develop therapeutic PI3K inhibitors. Although progress has been hampered by issues such as poor drug tolerance and drug resistance, several PI3K inhibitors have now received regulatory approval — the PI3Kα isoform-selective inhibitor alpelisib for the treatment of breast cancer and inhibitors mainly aimed at the leukocyte-enriched PI3Kδ in B cell malignancies. In addition to targeting cancer cell-intrinsic PI3K activity, emerging evidence highlights the potential of PI3K inhibitors in cancer immunotherapy. This Review summarizes key discoveries that aid the clinical translation of PI3Kα and PI3Kδ inhibitors, highlighting lessons learnt and future opportunitiesPI3K signalling is one of the most frequently aberrantly activated pathways in cancer. However, the development of therapeutic PI3K pathway inhibitors has faced challenges including poor drug tolerance and drug resistance. Here, Vanhaesebroeck et al. review efforts to understand and therapeutically exploit the biology of PI3Kα and PI3Kδ — the key targets of currently approved PI3K inhibitors, highlighting lessons learned and future opportunities.
Journal Article
The Little Rock crisis : what desegregation politics says about us
\"The Little Rock Crisis describes the power of direct and learned memories of the 1957 desegregation crisis in Little Rock, Arkansas. Personal, dramatic experiences of Little Rockians - known and unknown - reflect on the impact of the crisis on their lives in the 21st century. Linking individual memories to collective action through the lens of social appropriation, the book explores how the crisis has impacted the political behavior of Little Rockians. Oral histories and survey research show how the events from the tumultuous 1950s in Little Rock school politics, inform and direct the national political engagement and local community involvement of diverse residents. Their commitment to political and social participation is linked to their crisis experience\"-- Provided by publisher.
Book
Using insurance data to quantify the multidimensional impacts of warming temperatures on yield risk
Previous research predicts significant negative yield impacts from warming temperatures, but estimating the effects on yield risk and disentangling the relative causes of these losses remains challenging. Here we present new evidence on these issues by leveraging a unique publicly available dataset consisting of roughly 30,000 county-by-year observations on insurance-based measures of yield risk from 1989–2014 for U.S. corn and soybeans. Our results suggest that yield risk will increase in response to warmer temperatures, with a 1 °C increase associated with yield risk increases of approximately 32% and 11% for corn and soybeans, respectively. Using cause of loss information, we also find that additional losses under warming temperatures primarily result from additional reported occurrences of drought, with reported losses due to heat stress playing a smaller role. An implication of our findings is that the cost of purchasing crop insurance will increase for producers as a result of warming temperatures.
The impacts of climate change on agricultural productivity remain debated. Here, the authors present new evidence for the magnitude and causes of U.S. crop insurance losses, using a database of production risk from 1989–2014 across 1733 counties for corn and 1632 counties for soybeans, and find that crop production risk will increase in response to warmer temperatures.
Journal Article
Current drivers and future directions of global livestock disease dynamics
We review the global dynamics of livestock disease over the last two decades. Our imperfect ability to detect and report disease hinders assessment of trends, but we suggest that, although endemic diseases continue their historic decline in wealthy countries, poor countries experience static or deteriorating animal health and epidemic diseases show both regression and expansion. At a mesolevel, disease is changing in terms of space and host, which is illustrated by bluetongue, Lyme disease, and West Nile virus, and it is also emerging, as illustrated by highly pathogenic avian influenza and others. Major proximate drivers of change in disease dynamics include ecosystem change, ecosystem incursion, and movements of people and animals; underlying these are demographic change and an increasing demand for livestock products. We identify three trajectories of global disease dynamics: (i) the worried well in developed countries (demanding less risk while broadening the circle of moral concern), (ii) the intensifying and market-orientated systems of many developing countries, where highly complex disease patterns create hot spots for disease shifts, and (iii) the neglected cold spots in poor countries, where rapid change in disease dynamics is less likely but smallholders and pastoralists continue to struggle with largely preventable and curable livestock diseases.
Journal Article
Tyler Perry : interviews
A career-spanning collection of interviews with the multimedia phenomenon who has directed groundbreaking films like Diary of a Mad Black Woman that feature mostly African American actors and tell stories about adversity, faith, family, and redemption.
Book
Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Microglia nodules (HLA-DR
+
cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.
Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation.
Journal Article
Timing of Early-Life Stress and the Development of Brain-Related Capacities
Early-life stress (ELS) poses risks for developmental and mental health problems throughout the lifespan. More research is needed regarding how specific ELS experiences influence specific aspects of neurodevelopment. We examined the association between ELS, defined as severe adversity (e.g., domestic violence, caregiver drug use) and severe relational poverty (e.g., caregiver neglect, lack of caregiver attunement), occurring during the first 2 months of life and a variety of brain-related, clinician-rated functions, including self-regulation and relational capacities. Interdisciplinary clinicians using the Neurosequential Model of Therapeutics (NMT), an approach to clinical problem solving, reported on the timing and type of treatment-seeking children's (
= 2,155; 8-10 years) stressful experiences during four developmental periods: Perinatal (0-2 months), Infancy (2-12 months), Early Childhood (13 months to 4 years), and Childhood (4-11 years). They also reported on children's current functioning in 32 brain-related domains (e.g., sleep, arousal, impulsivity, empathy, concrete cognition). Non-negative matrix factorization (NMF) was conducted on the 32 brain-related domains to identify latent factors, yielding four factors comprising Sensory Integration, Self-Regulation, Relational, and Cognitive functioning. Regularized hierarchical models were then used to identify associations between ELS and each latent factor while controlling for stress occurring during subsequent developmental periods, and children's current degree of relational health. ELS (stress occurring during the first 2 months of life), specifically a severe lack of positive relational experiences (e.g., caregiver neglect, lack of caregiver attunement), was associated with the Sensory Integration and Self-Regulation factors. The Relational factor was better explained by stress occurring during childhood, and the Cognitive factor by stress occurring during infancy and childhood. Implications for how the timing and type of stress experiences may influence brain-related outcomes that are observed in clinical settings are discussed. Future directions include longitudinal follow-ups and greater specification of environmental variables, such as types of interventions received and when they were received, that may interact with ELS experiences to influence brain-related outcomes.
Journal Article