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\"What we eat, where it is from, and how it is produced are vital questions in today's America. We think seriously about food because it is freighted with the hopes, fears, and anxieties of modern life. Yet critiques of food and food systems all too often sprawl into jeremiads against modernity itself, while supporters of the status quo refuse to acknowledge the problems with today's methods of food production and distribution. Food Fights sheds new light on these crucial debates, using a historical lens. Its essays take strong positions, even arguing with one another, as they explore the many themes and tensions that define how we understand our food--from the promises and failures of agricultural technology to the politics of taste\"-- Provided by publisher.

Strictly controlled production of ethylene gas lies upstream of the signaling activities of this crucial regulator throughout the plant life cycle. Although the biosynthetic pathway is enzymatically simple, the regulatory circuits that modulate signal production are fine tuned to allow integration of responses to environmental and intrinsic cues. Recently identified posttranslational mechanisms that control ethylene production converge on one family of biosynthetic enzymes and overlay several independent reversible phosphorylation events and distinct mediators of ubiquitin-dependent protein degradation. Although the core pathway is conserved throughout seed plants, these posttranslational regulatory mechanisms may represent evolutionarily recent innovations. The evolutionary origins of the pathway and its regulators are not yet clear; outside the seed plants, numerous biochemical and phylogenetic questions remain to be addressed.

Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG–independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1 ) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition. Enhancer of zeste homolog 2 (EZH2) has been implicated as a driver of disease progression and resistance to hormonal therapies. Here, the authors focus on EZH2 in two subtypes of advanced prostate cancer and report how it modulates the bivalent genes thereby leading to forward differentiation after being targeted in neuroendocrine prostate cancer.

Protein phosphatase 2A (PP2A) presents unique opportunities for analyzing molecular mechanisms of functional divergence between gene family members. The canonical PP2A holoenzyme regulates multiple eukaryotic signaling pathways by dephosphorylating target proteins and contains a catalytic (C) subunit, a structural/scaffolding (A) subunit, and a regulatory (B) subunit. Genes encoding PP2A subunits have expanded into multigene families in both flowering plants and mammals, and the extent to which different isoform functions may overlap is not clearly understood. To gain insight into the diversification of PP2A subunits, we used phylogenetic analyses to reconstruct the evolutionary histories of PP2A gene families in Arabidopsis (Arabidopsis thaliana). Genes encoding PP2A subunits in mammals represent ancient lineages that expanded early in vertebrate evolution, while flowering plant PP2A subunit lineages evolved much more recently. Despite this temporal difference, our data indicate that the expansion of PP2A subunit gene families in both flowering plants and animals was driven by whole-genome duplications followed by nonrandom gene loss. Selection analysis suggests that the expansion of one B subunit gene family (B56/PPP2R5) was driven by functional diversification rather than by the maintenance of gene dosage. We also observed reduced expansion rates in three distinct B subunit subclades. One of these subclades plays a highly conserved role in cell division, while the distribution of a second subclade suggests a specialized function in supporting beneficial microbial associations. Thus, while whole-genome duplications have driven the expansion and diversification of most PP2A gene families, members of functionally specialized subclades quickly revert to singleton status after duplication events.

ObjectiveEmergency ambulance use for problems that could be managed in primary care continues to rise owing to complex reasons that are poorly understood. The objective of this systematic review is to draw together published evidence across a variety of study methodologies and settings to gain a better understanding of why patients seek help from ambulance services for these problems.DesignSystematic searches were undertaken across the MEDLINE, EMBASE, PsychINFO, CINAHL, Health Management Information Consortium and Health Management Information Service publication databases. Google Scholar, Web of Science, OpenSigle, EThOS and DART databases were also systematically searched for reports, proceedings, book chapters and theses, along with hand-searching of grey literature sources. Studies were included if they reported on findings examining patient, carer, health professional or service management interactions with ambulance services for primary care problems. All study methodologies and perspectives were of interest. Data were extracted, quality assessed and systematically mapped according to key findings through generation of an iterative framework.ResultsA total of 31 studies met inclusion criteria. Findings were summarised across 5 broad categories: factors associated with individual patients; actions of care-givers and bystanders; population-level factors; health infrastructure factors; challenges faced by health professionals. A number of subcategories were developed to explore these factors in more detail.ConclusionsThis review reports important factors that may impact on ambulance use for primary care problems across a global setting, including demographic measures associated with deprivation, minority status and individual social circumstances. Categorising ambulance calls for primary care problems as ‘inappropriate’ is context dependant and may be unhelpful. Potential implications for triage and risk management strategies are discussed.

Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35–40% of human SCLCs. Duplaquet, Li et al. identify and characterize KDM6A as an epigenetic regulator that impacts chromatin accessibility to modulate ASCL1-to-NEUROD1 subtype switching in small cell lung cancer.

Humans have relied on sourdough starter microbial communities to make leavened bread for thousands of years, but only a small fraction of global sourdough biodiversity has been characterized. Working with a community-scientist network of bread bakers, we determined the microbial diversity of 500 sourdough starters from four continents. In sharp contrast with widespread assumptions, we found little evidence for biogeographic patterns in starter communities. Strong co-occurrence patterns observed in situ and recreated in vitro demonstrate that microbial interactions shape sourdough community structure. Variation in dough rise rates and aromas were largely explained by acetic acid bacteria, a mostly overlooked group of sourdough microbes. Our study reveals the extent of microbial diversity in an ancient fermented food across diverse cultural and geographic backgrounds. Sourdough bread is an ancient fermented food that has sustained humans around the world for thousands of years. It is made from a sourdough ‘starter culture’ which is maintained, portioned, and shared among bread bakers around the world. The starter culture contains a community of microbes made up of yeasts and bacteria, which ferment the carbohydrates in flour and produce the carbon dioxide gas that makes the bread dough rise before baking. The different acids and enzymes produced by the microbial culture affect the bread’s flavor, texture and shelf life. However, for such a dependable staple, sourdough bread cultures and the mixture of microbes they contain have scarcely been characterized. Previous studies have looked at the composition of starter cultures from regions within Europe. But there has never been a comprehensive study of how the microbial diversity of sourdough starters varies across and between continents. To investigate this, Landis, Oliverio et al. used genetic sequencing to characterize the microbial communities of sourdough starters from the homes of 500 bread bakers in North America, Europe and Australasia. Bread makers often think their bread’s unique qualities are due to the local environment of where the sourdough starter was made. However, Landis, Oliverio et al. found that geographical location did not correlate with the diversity of the starter cultures studied. The data revealed that a group of microbes called acetic acid bacteria, which had been overlooked in past research, were relatively common in starter cultures. Moreover, starters with a greater abundance of this group of bacteria produced bread with a strong vinegar aroma and caused dough to rise at a slower rate. This research demonstrates which species of bacteria and yeast are most commonly found in sourdough starters, and suggests geographical location has little influence on the microbial diversity of these cultures. Instead, the diversity of microbes likely depends more on how the starter culture was made and how it is maintained over time.

ObjectivesTo understand the reasons behind, and experience of, seeking and receiving emergency ambulance treatment for a ‘primary care sensitive’ condition.DesignA comprehensive, qualitative systematic review. Medline, Embase, PsychInfo, Cumulative Index of Nursing and Allied Health, Health Management Information Systems, Healthcare Management Information Consortium, OpenSigle, EThOS and Digital Archive of Research Theses databases were systematically searched for studies exploring patient, carer or healthcare professional interactions with ambulance services for ‘primary care sensitive’ problems. Studies using wholly qualitative approaches or mixed-methods studies with substantial use of qualitative techniques in both the methods and analysis sections were included. An analytical thematic synthesis was undertaken, using a line-by-line qualitative coding method and a hierarchical inductive approach.ResultsOf 1458 initial results, 33 studies met the first level (relevance) inclusion criteria, and six studies met the second level (methodology and quality) criteria. The analysis suggests that patients define situations worthy of ‘emergency’ ambulance use according to complex socioemotional factors, as well as experienced physical symptoms. There can be a mismatch between how patients and professionals define ‘emergency’ situations. Deciding to call an ambulance is a process shaped by practical considerations and a strong emotional component, which can be influenced by the views of caregivers. Sometimes the value of a contact with the ambulance service is principally in managing this emotional component. Patients often wish to hand over responsibility for decisions when experiencing a perceived emergency. Feeling empowered to take control of a situation is a highly valued aspect of ambulance care.ConclusionsWhen responding to a request for ‘emergency’ help for a low-acuity condition, urgent-care services need to be sensitive to how the patient's emotional and practical perception of the situation may have shaped their decision-making and the influence that carers may have had on the process. There may be novel ways to deliver some of the valued aspects of urgent care, more geared to the resource-limited environment.

San Francisco Bay is the largest and most productive estuary on the Pacific Coast of North America. It is also home to the oldest and densest urban settlements in the American West. Focusing on human inhabitation of the Bay since Ohlone times, Down by the Bay reveals the ongoing role of nature in shaping that history. From birds to oyster pirates, from gold miners to farmers, from salt ponds to ports, this is the first history of the San Francisco Bay and Delta as both a human and natural landscape. It offers invaluable context for current discussions over the best management and use of the Bay in the face of sea level rise.