Primary Atopic Disorders.

Primary atopic disorders describes a series of monogenic diseases that have allergy- or atopic effector-related symptoms as a substantial feature. The underlying pathogenic genetic lesions help illustrate fundamental pathways in atopy, opening up diagnostic and therapeutic options for further study in those patients, but ultimately for common allergic diseases as well. Key pathways affected in these disorders include T cell receptor and B cell receptor signaling, cytokine signaling, skin barrier function, and mast cell function, as well as pathways that have not yet been elucidated. While comorbidities such as classically syndromic presentation or immune deficiency are often present, in some cases allergy alone is the presenting symptom, suggesting that commonly encountered allergic diseases exist on a spectrum of monogenic and complex genetic etiologies that are impacted by environmental risk factors.

Timing is everything: How plants optimize reproduction in a variable environment.

Organisms experience a constantly changing environment and must adjust their development to maximize fitness. These "life histories" are fantastically diverse and have fascinated biologists for decades. Recent work published in Cell reveals the complex genetic mechanisms that drive life-history variation within and among species in the Brassicaceae plant family.

Tissue-specific immunity for a changing world.

Our immune system has evolved to protect us from pathogens and maintain homeostasis through localization in diverse tissue sites throughout the body. Immune responses are orchestrated by T cells, which direct pathogen clearance at the infection site and establish tissue-resident memory T cells (TRMs) for protection immunity. Here, we discuss how tissue immune responses are influenced by various stressors (e.g., metabolic, environmental, aging) that are rapidly changing due to climate fluctuations and globalization. We propose potential strategies for targeting tissue immunity to mitigate future pathogenic and environmental challenges and areas of investigation that can elucidate mechanisms for adapting and restoring homeostasis.

Emerging Pandemic Diseases: How We Got to COVID-19.

Infectious diseases prevalent in humans and animals are caused by pathogens that once emerged from other animal hosts. In addition to these established infections, new infectious diseases periodically emerge. In extreme cases they may cause pandemics such as COVID-19; in other cases, dead-end infections or smaller epidemics result. Established diseases may also re-emerge, for example by extending geographically or by becoming more transmissible or more pathogenic. Disease emergence reflects dynamic balances and imbalances, within complex globally distributed ecosystems comprising humans, animals, pathogens, and the environment. Understanding these variables is a necessary step in controlling future devastating disease emergences.

Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.

Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.

Atoms to Phenotypes: Molecular Design Principles of Cellular Energy Metabolism.

We report a 100-million atom-scale model of an entire cell organelle, a photosynthetic chromatophore vesicle from a purple bacterium, that reveals the cascade of energy conversion steps culminating in the generation of ATP from sunlight. Molecular dynamics simulations of this vesicle elucidate how the integral membrane complexes influence local curvature to tune photoexcitation of pigments. Brownian dynamics of small molecules within the chromatophore probe the mechanisms of directional charge transport under various pH and salinity conditions. Reproducing phenotypic properties from atomistic details, a kinetic model evinces that low-light adaptations of the bacterium emerge as a spontaneous outcome of optimizing the balance between the chromatophore's structural integrity and robust energy conversion. Parallels are drawn with the more universal mitochondrial bioenergetic machinery, from whence molecular-scale insights into the mechanism of cellular aging are inferred. Together, our integrative method and spectroscopic experiments pave the way to first-principles modeling of whole living cells.

Cellular, Molecular, and Physiological Adaptations of Hibernation: The Solution to Environmental Challenges.

Thriving in times of resource scarcity requires an incredible flexibility of behavioral, physiological, cellular, and molecular functions that must change within a relatively short time. Hibernation is a collection of physiological strategies that allows animals to inhabit inhospitable environments, where they experience extreme thermal challenges and scarcity of food and water. Many different kinds of animals employ hibernation, and there is a spectrum of hibernation phenotypes. Here, we focus on obligatory mammalian hibernators to identify the unique challenges they face and the adaptations that allow hibernators to overcome them. This includes the cellular and molecular strategies used to combat low environmental and body temperatures and lack of food and water. We discuss metabolic, neuronal, and hormonal cues that regulate hibernation and how they are thought to be coordinated by internal clocks. Last, we touch on questions that are left to be addressed in the field of hibernation research. Studies from the last century and more recent work reveal that hibernation is not simply a passive reduction in body temperature and vital parameters but rather an active process seasonally regulated at the molecular, cellular, and organismal levels.

Naturalizing mouse models for immunology.

Laboratory mice have provided invaluable insight into mammalian immune systems. Yet the immune phenotypes of mice bred and maintained in conventional laboratory conditions often differ from the immune phenotypes of wild mammals. Recent work to naturalize the environmental experience of inbred laboratory mice-to take them where the wild things are (to borrow a phrase from Maurice Sendak), via approaches such as construction of exposure histories, provision of fecal transplants or surrogate mothering by wild mice, and rewilding-is poised to expand understanding, complementing genetic and phylogenetic research on how natural selection has shaped mammalian immune systems while improving the translational potential of mouse research.

Regulatory T cell adaptation in the intestine and skin.

The intestine and skin are distinct microenvironments with unique physiological functions and are continually exposed to diverse environmental challenges. Host adaptation at these sites is an active process that involves interaction between immune cells and tissue cells. Regulatory T cells (Treg cells) play a pivotal role in enforcing homeostasis at barrier surfaces, illustrated by the development of intestinal and skin inflammation in diseases caused by primary deficiency in Treg cells. Treg cells at barrier sites are phenotypically distinct from their lymphoid-organ counterparts, and these 'tissue' signatures often reflect their tissue-adapted function. We discuss current understanding of Treg cell adaptation in the intestine and skin, including unique phenotypes, functions and metabolic demands, and how increased knowledge of Treg cells at barrier sites might guide precision medicine therapies.

The Human Functional Genomics Project: Understanding Generation of Diversity.

Generation of biologic diversity is a cornerstone of immunity, yet the tools to investigate the causal influence of genetic and environmental factors have been greatly limited. Studies from the Human Functional Genomics Project, presented in Cell and other Cell Press journals, integrate environmental and genetic factors with the direction and magnitude of immune responses to decipher inflammatory disease pathogenesis.

Microbial Skin Inhabitants: Friends Forever.

To gain insight into the stability of the microbial communities that inhabit our skin, Oh et al., in a tour-de-force effort, map the human skin metagenomes over time. Remarkably, their data indicate that the individual, not the environment, primarily drives the composition of skin microbial communities.

Information Integration and Communication in Plant Growth Regulation.

Plants are equipped with the capacity to respond to a large number of diverse signals, both internal ones and those emanating from the environment, that are critical to their survival and adaption as sessile organisms. These signals need to be integrated through highly structured intracellular networks to ensure coherent cellular responses, and in addition, spatiotemporal actions of hormones and peptides both orchestrate local cell differentiation and coordinate growth and physiology over long distances. Further, signal interactions and signaling outputs vary significantly with developmental context. This review discusses our current understanding of the integrated intracellular and intercellular signaling networks that control plant growth.

A Corticostriatal Path Targeting Striosomes Controls Decision-Making under Conflict.

A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions, including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival.

Subicular neurons encode concave and convex geometries.

Animals in the natural world constantly encounter geometrically complex landscapes. Successful navigation requires that they understand geometric features of these landscapes, including boundaries, landmarks, corners and curved areas, all of which collectively define the geometry of the environment1-12. Crucial to the reconstruction of the geometric layout of natural environments are concave and convex features, such as corners and protrusions. However, the neural substrates that could underlie the perception of concavity and convexity in the environment remain elusive. Here we show that the dorsal subiculum contains neurons that encode corners across environmental geometries in an allocentric reference frame. Using longitudinal calcium imaging in freely behaving mice, we find that corner cells tune their activity to reflect the geometric properties of corners, including corner angles, wall height and the degree of wall intersection. A separate population of subicular neurons encode convex corners of both larger environments and discrete objects. Both corner cells are non-overlapping with the population of subicular neurons that encode environmental boundaries. Furthermore, corner cells that encode concave or convex corners generalize their activity such that they respond, respectively, to concave or convex curvatures within an environment. Together, our findings suggest that the subiculum contains the geometric information needed to reconstruct the shape and layout of naturalistic spatial environments.

Molecular mechanisms of environmental exposures and human disease.

A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome - the cumulative measure of environmental influences over the lifespan - and its integration into future environmental health research.

The dynamics of pattern matching in camouflaging cuttlefish.

Many cephalopods escape detection using camouflage1. This behaviour relies on a visual assessment of the surroundings, on an interpretation of visual-texture statistics2-4 and on matching these statistics using millions of skin chromatophores that are controlled by motoneurons located in the brain5-7. Analysis of cuttlefish images proposed that camouflage patterns are low dimensional and categorizable into three pattern classes, built from a small repertoire of components8-11. Behavioural experiments also indicated that, although camouflage requires vision, its execution does not require feedback5,12,13, suggesting that motion within skin-pattern space is stereotyped and lacks the possibility of correction. Here, using quantitative methods14, we studied camouflage in the cuttlefish Sepia officinalis as behavioural motion towards background matching in skin-pattern space. An analysis of hundreds of thousands of images over natural and artificial backgrounds revealed that the space of skin patterns is high-dimensional and that pattern matching is not stereotyped-each search meanders through skin-pattern space, decelerating and accelerating repeatedly before stabilizing. Chromatophores could be grouped into pattern components on the basis of their covariation during camouflaging. These components varied in shapes and sizes, and overlay one another. However, their identities varied even across transitions between identical skin-pattern pairs, indicating flexibility of implementation and absence of stereotypy. Components could also be differentiated by their sensitivity to spatial frequency. Finally, we compared camouflage to blanching, a skin-lightening reaction to threatening stimuli. Pattern motion during blanching was direct and fast, consistent with open-loop motion in low-dimensional pattern space, in contrast to that observed during camouflage.

Native diversity buffers against severity of non-native tree invasions.

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species1,2. Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies3,4. Here, leveraging global tree databases5-7, we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions.

Crop switching can enhance environmental sustainability and farmer incomes in China.

Achieving food-system sustainability is a multidimensional challenge. In China, a doubling of crop production since 1990 has compromised other dimensions of sustainability1,2. Although the country is promoting various interventions to enhance production efficiency and reduce environmental impacts3, there is little understanding of whether crop switching can achieve more sustainable cropping systems and whether coordinated action is needed to avoid tradeoffs. Here we combine high-resolution data on crop-specific yields, harvested areas, environmental footprints and farmer incomes to first quantify the current state of crop-production sustainability. Under varying levels of inter-ministerial and central coordination, we perform spatial optimizations that redistribute crops to meet a suite of agricultural sustainable development targets. With a siloed approach-in which each government ministry seeks to improve a single sustainability outcome in isolation-crop switching could realize large individual benefits but produce tradeoffs for other dimensions and between regions. In cases of central coordination-in which tradeoffs are prevented-we find marked co-benefits for environmental-impact reductions (blue water (-4.5% to -18.5%), green water (-4.4% to -9.5%), greenhouse gases (GHGs) (-1.7% to -7.7%), fertilizers (-5.2% to -10.9%), pesticides (-4.3% to -10.8%)) and increased farmer incomes (+2.9% to +7.5%). These outcomes of centrally coordinated crop switching can contribute substantially (23-40% across dimensions) towards China's 2030 agricultural sustainable development targets and potentially produce global resource savings. This integrated approach can inform feasible targeted agricultural interventions that achieve sustainability co-benefits across several dimensions.

Four ways blue foods can help achieve food system ambitions across nations.

Blue foods, sourced in aquatic environments, are important for the economies, livelihoods, nutritional security and cultures of people in many nations. They are often nutrient rich1, generate lower emissions and impacts on land and water than many terrestrial meats2, and contribute to the health3, wellbeing and livelihoods of many rural communities4. The Blue Food Assessment recently evaluated nutritional, environmental, economic and justice dimensions of blue foods globally. Here we integrate these findings and translate them into four policy objectives to help realize the contributions that blue foods can make to national food systems around the world: ensuring supplies of critical nutrients, providing healthy alternatives to terrestrial meat, reducing dietary environmental footprints and safeguarding blue food contributions to nutrition, just economies and livelihoods under a changing climate. To account for how context-specific environmental, socio-economic and cultural aspects affect this contribution, we assess the relevance of each policy objective for individual countries, and examine associated co-benefits and trade-offs at national and international scales. We find that in many African and South American nations, facilitating consumption of culturally relevant blue food, especially among nutritionally vulnerable population segments, could address vitamin B12 and omega-3 deficiencies. Meanwhile, in many global North nations, cardiovascular disease rates and large greenhouse gas footprints from ruminant meat intake could be lowered through moderate consumption of seafood with low environmental impact. The analytical framework we provide also identifies countries with high future risk, for whom climate adaptation of blue food systems will be particularly important. Overall the framework helps decision makers to assess the blue food policy objectives most relevant to their geographies, and to compare and contrast the benefits and trade-offs associated with pursuing these objectives.