Bumble bees (Bombus) are unusually important pollinators, with approximately 260 wild species native to all biogeographic regions except Africa, Australia, and New Zealand. As they are vitally important in natural ecosystems and to agricultural food production globally, the increase in reports of declining distribution and abundance over the past decade has led to an explosion of interest in bumble bee population decline. We summarize data on the threat status of wild bumble bee species across biogeographic regions, underscoring regions lacking assessment data. Focusing on data-rich studies, we also synthesize recent research on potential causes of population declines. There is evidence that habitat loss, changing climate, pathogen transmission, invasion of nonnative species, and pesticides, operating individually and in combination, negatively impact bumble bee health, and that effects may depend on species and locality. We distinguish between correlational and causal results, underscoring the importance of expanding experimental research beyond the study of two commercially available species to identify causal factors affecting the diversity of wild species. Expected final online publication date for the Annual Review of Entomology, Volume 65 is January 7, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND

Autologous lipotransfer is seen as an ideal filler for soft tissue reconstruction. The main limitation of this procedure is the unpredictable resorption and volume loss of the fat graft. In the recent decade, an increasing amount of research has focused on the use of adipose tissue-derived stromal cells (ASCs) to enrich the fat graft, a procedure termed cell-assisted lipotransfer (CAL). The aim of this review was to systematically review the current preclinical and clinical evidence for the efficacy of CAL compared with conventional lipotransfer.

METHODS

A systematic search was performed on PubMed and other databases to identify all preclinical and clinical studies where CAL with ASCs was compared with conventional lipotransfer. A total of 20 preclinical studies and seven clinical studies were included in the review.

RESULTS

The preclinical studies consisted of 15 studies using immunodeficient animal models and five studies using immunocompetent studies. Seventeen studies examined weight/volume retention of which 15 studies favored CAL over conventional lipotransfer. One clinical study did not find any efficacy of CAL and the remaining six studies favored CAL.

CONCLUSIONS

The present evidence suggests that there is a big potential for CAL in reconstructive surgery; however, the present studies are so far still of low quality with inherent weaknesses. Several aspects regarding CAL still remain unknown such as the optimal degree of cell enrichment and also its safety. Further high-quality studies are needed to establish if CAL can live up to its potential.

METHODS

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

The evolutionary origins of the three major families of chemoreceptors in arthropods-the odorant receptor (OR), gustatory receptor (GR), and ionotropic receptor (IR) families-occurred at the base of the Insecta, Animalia, and Protostomia, respectively. Comparison of receptor family sizes across arthropods reveals a generally positive correlation with their widely disparate complexity of chemical ecology. Closely related species reveal the ongoing processes of gene family evolution, including gene duplication, divergence, pseudogenization, and loss, that mediate these larger patterns. Sets of paralogous receptors within species reveal positive selection on amino acids in regions likely to contribute to ligand binding and specificity. Ligands of many ORs and some GRs and IRs have been identified; however, ligand identification for many more chemoreceptors is needed, as are structures for the OR/GR superfamily, to improve our understanding of the molecular evolution of these ecologically important receptors in arthropods Expected final online publication date for the Annual Review of Entomology Volume 64 is January 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The assumption that early stress leads to dysregulation and impairment is widespread in developmental science and informs prevailing models (e.g., toxic stress). An alternative evolutionary-developmental approach, which complements the standard emphasis on dysregulation, proposes that early stress may prompt the development of costly but adaptive strategies that promote survival and reproduction under adverse conditions. In this review, we survey this growing theoretical and empirical literature, highlighting recent developments and outstanding questions. We review concepts of adaptive plasticity and conditional adaptation, introduce the life history framework and the adaptive calibration model, and consider how physiological stress response systems and related neuroendocrine processes may function as plasticity mechanisms. We then address the evolution of individual differences in susceptibility to the environment, which engenders systematic person-environment interactions in the effects of stress on development. Finally, we discuss stress-mediated regulation of pubertal development as a case study of how an evolutionary-developmental approach can foster theoretical integration. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Dogs are second only to humans in medical surveillance and preventative health care, leading to a recent perception of increased cancer incidence. Scientific priorities in veterinary oncology have thus shifted, with a demand for cancer genetic screens, better diagnostics, and more effective therapies. Most dog breeds came into existence within the last 300 years, and many are derived from small numbers of founders. Each has undergone strong artificial selection, in which dog fanciers selected for many traits, including body size, fur type, color, skull shape, and behavior, to create novel breeds. The adoption of the breed barrier rule-no dog may become a registered member of a breed unless both its dam and its sire are registered members-ensures a relatively closed genetic pool within each breed. As a result, there is strong phenotypic homogeneity within breeds but extraordinary phenotypic variation between breeds. One consequence of this is the high level of breed-associated genetic disease. We and others have taken advantage of this to identify genes for a large number of canine maladies for which mouse models do not exist, particularly with regard to cancer. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND

15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies.

RESULTS

To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing >160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action.

CONCLUSIONS

Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways.

BACKGROUND

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Evolved mate preferences comprise a central causal process in Darwin's theory of sexual selection. Their powerful influences have been documented in all sexually reproducing species, including in sexual strategies in humans. This article reviews the science of human mate preferences and their myriad behavioral manifestations. We discuss sex differences and sex similarities in human sexual psychology, which vary according to short-term and long-term mating contexts. We review context-specific shifts in mating strategy depending on individual, social, and ecological qualities such as mate value, life history strategy, sex ratio, gender economic inequality, and cultural norms. We review the empirical evidence for the impact of mate preferences on actual mating decisions. Mate preferences also dramatically influence tactics of mate attraction, tactics of mate retention, patterns of deception, causes of sexual regret, attraction to cues to sexual exploitability, attraction to cues to fertility, attraction to cues to resources and protection, derogation of competitors, causes of breakups, and patterns of remarriage. We conclude by articulating unresolved issues and offer a future agenda for the science of human mating, including how humans invent novel cultural technologies to better implement ancient sexual strategies and how cultural evolution may be dramatically influencing our evolved mating psychology. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Numerous myths and legends across the world have suggested that corvids are intelligent. However, it is only in the last two decades that their cognition has become the subject of serious scientific investigation. Here I review what we currently know about the temporal, social, and physical cognition of this group. I argue that, while the work to date establishes corvids as one of the most intelligent groups of animals on the planet, the real scientific potential of the Corvidae has yet to be realized. However, a novel 'signature-testing' experimental approach is required if we want to unlock this group's promise and gain insights into the evolution of human and animal minds. For further resources related to this article, please visit the WIREs website.

BACKGROUND

The authors have declared no conflicts of interest for this article.

BACKGROUND

Breast cancer is the most common cancer in women worldwide, affecting one in eight women. Breast-conserving surgery (BCS) has become a well-established alternative to mastectomy in the treatment of breast cancer, providing a less invasive treatment. Just as life expectancy after breast cancer has improved, so has morbidity increased. One of the most relevant and debilitating consequences of oncological breast surgery is postmastectomy pain syndrome (PMPS). Our results published in 2011 on the treatment of PMPS in patients who had undergone mastectomy and radiotherapy and our experience in scar treatment with fat grafts were the theoretical bases for this prospective study.

METHODS

From April 2011 to April 2012 a total of 96 patients, who had undergone lumpectomy and radiation therapy, with the diagnosis of PMPS were considered for fat grafts. We performed autologous fat grafting in 59 patients (study group), whereas 37 patients did not receive any further surgical procedure (control group). Pain assessment was performed using the visual analog scale (VAS) before and after treatment in the treated group and in the control group at the first visit and the control visit, with a mean follow-up of 10 months. Results were analyzed using the Wilcoxon rank sum test.

RESULTS

Four patients were lost to follow-up (two patients in the control group and two patients in the treated group). A significant VAS pain decrease was detected in patients treated with autologous fat grafting (3.1 point reduction, p ≤ 0.005).

CONCLUSIONS

Because of the safety, efficacy, and optimal tolerability of the procedure, we believe that fat grafting can be considered useful in treating PMPS in patients who have undergone BCS and radiotherapy.

METHODS

For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, rarely, subtle mutations of SMN1 cause SMA, and the copy number of the nearly identical copy gene SMN2 inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of SMN genes, the disease's phenotype-genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease's pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively. This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 21 is August 31, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Antiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV preexposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

BACKGROUND

Madelung's disease (MD) is an uncommon pathology characterized by the presence of multiple masses of unencapsulated adipose tissue that is symmetrically distributed. The aim of this study was to investigate clinical and epidemiological features of patients diagnosed with MD in our department. Associated diseases and evolution after treatment were also investigated.

METHODS

We reviewed the clinical histories of 22 patients diagnosed with MD from 1990 to 2010 and obtained their epidemiological and clinical characteristics.

RESULTS

We found 21 patients with MD type 1 and one patient with MD type 2 according to Enzi's classification. All patients were male, 95.5% with high alcohol intake, and 59.1% with some hepatic disease. No family antecedents were significant; 40.9% had dyslipidemia, 22.7% arterial hypertension, 22.7% chronic obstructive pulmonary disease (COPD), 13.6% hyperuricemia, 9.1% hypothyroidism, 4.5% diabetes mellitus type 2, and 4.5% carbohydrate intolerance; 40.9% had a body mass index>30, and 27.3% presented gynecomastia/lipomastia. The region most frequently affected by fatty deposits was the neck.

CONCLUSIONS

Madelung's disease affects mainly alcoholic males in their fourth decade of life. Hepatic diseases appear in most patients. Also associated with MD are high lipid blood levels, arterial hypertension, COPD, hyperuricemia, and obesity. MD type 1 is the most frequent phenotype and the neck the most common location for fatty masses. Recurrence after surgery, in the same location or different locations, is a frequent event, even in patients who later abstain from alcohol intake.

METHODS

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266 .

For more than 50 years, psychologists, gerontologists, and, more recently, neuroscientists have considered the possibility of successful aging. How to define successful aging remains debated, but well-preserved age-sensitive cognitive functions, like episodic memory, is an often-suggested criterion. Evidence for successful memory aging comes from cross-sectional and longitudinal studies showing that some older individuals display high and stable levels of performance. Successful memory aging may be accomplished via multiple paths. One path is through brain maintenance, or relative lack of age-related brain pathology. Through another path, successful memory aging can be accomplished despite brain pathology by means of efficient compensatory and strategic processes. Genetic, epigenetic, and lifestyle factors influence memory aging via both paths. Some of these factors can be promoted throughout the life course, which, at the individual as well as the societal level, can positively impact successful memory aging. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The evolution of a mutualism requires reciprocal interactions whereby one species provides a service that the other species cannot perform or performs less efficiently. Services exchanged in insect-fungus mutualisms include nutrition, protection, and dispersal. In ectosymbioses, which are the focus of this review, fungi can be consumed by insects or can degrade plant polymers or defensive compounds, thereby making a substrate available to insects. They can also protect against environmental factors and produce compounds antagonistic to microbial competitors. Insects disperse fungi and can also provide fungal growth substrates and protection. Insect-fungus mutualisms can transition from facultative to obligate, whereby each partner is no longer viable on its own. Obligate dependency has (a) resulted in the evolution of morphological adaptations in insects and fungi, (b) driven the evolution of social behaviors in some groups of insects, and (c) led to the loss of sexuality in some fungal mutualists. Expected final online publication date for the Annual Review of Entomology, Volume 65 is January 7, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Disease surveillance systems are a cornerstone of public health tracking and prevention. This review addresses the use, promise, perils, and ethics of social media- and Internet-based data collection for public health surveillance. Our review highlights untapped opportunities for integrating digital surveillance in public health and current applications that could be improved through better integration, validation, and clarity on rules surrounding ethical considerations. Promising developments include hybrid systems that couple traditional surveillance data with data from search queries, social media posts, and crowdsourcing. In the future, it will be important to identify opportunities for public and private partnerships, train public health experts in data science, reduce biases related to digital data (gathered from Internet use, wearable devices, etc.), and address privacy. We are on the precipice of an unprecedented opportunity to track, predict, and prevent global disease burdens in the population using digital data. Expected final online publication date for the Annual Review of Public Health, Volume 41 is April 1, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The diversity of long non-coding RNAs (lncRNAs) in the human transcriptome is in stark contrast to the sparse exploration of their functions concomitant with their conservation and evolution. The pervasive transcription of the largely non-coding human genome makes the evolutionary age and conservation patterns of lncRNAs to a topic of interest. Yet it is a fairly unexplored field and not that easy to determine as for protein-coding genes. Although there are a few experimentally studied cases, which are conserved at the sequence level, most lncRNAs exhibit weak or untraceable primary sequence conservation. Recent studies shed light on the interspecies conservation of secondary structures among lncRNA homologs by using diverse computational methods. This highlights the importance of structure on functionality of lncRNAs as opposed to the poor impact of primary sequence changes. Further clues in the evolution of lncRNAs are given by selective constraints on non-coding gene structures (e.g., promoters or splice sites) as well as the conservation of prevalent spatio-temporal expression patterns. However, a rapid evolutionary turnover is observable throughout the heterogeneous group of lncRNAs. This still gives rise to questions about its functional meaning. WIREs RNA 2017, 8:e1376. doi: 10.1002/wrna.1376 For further resources related to this article, please visit the WIREs website.

The physiological significance of innate immune signaling lies primarily in its role in host defense against invading pathogens. It is becoming increasingly clear that innate immune signaling also modulates the development of metabolic diseases, especially nonalcoholic fatty liver disease and cardiovascular diseases, which are characterized by chronic, low-grade inflammation due to a disarrangement of innate immune signaling. Notably, recent studies indicate that in addition to regulating canonical innate immune-mediated inflammatory responses (or immune-dependent signaling-induced responses), molecules of the innate immune system regulate pathophysiological responses in multiple organs during metabolic disturbances (termed immune-independent signaling-induced responses), including the disruption of metabolic homeostasis, tissue repair, and cell survival. In addition, emerging evidence from the study of immunometabolism indicates that the systemic metabolic status may have profound effects on cellular immune function and phenotypes through the alteration of cell-intrinsic metabolism. We summarize how the innate immune system interacts with metabolic disturbances to trigger immune-dependent and immune-independent pathogenesis in the context of nonalcoholic fatty liver disease, as representative of metabolic diseases, and cardiovascular diseases. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cell-type- and condition-specific profiles of gene expression require coordination between protein-coding gene promoters and cis-regulatory sequences called enhancers. Enhancers can stimulate gene activity at great genomic distances from their targets, raising questions about how enhancers communicate with specific gene promoters and what molecular mechanisms underlie enhancer function. Characterization of enhancer loci has identified the molecular features of active enhancers that accompany the binding of transcription factors and local opening of chromatin. These characteristics include coactivator recruitment, histone modifications, and noncoding RNA transcription. However, it remains unclear which of these features functionally contribute to enhancer activity. Here, we discuss what is known about how enhancers regulate their target genes and how enhancers and promoters communicate. Further, we describe recent data demonstrating many similarities between enhancers and the gene promoters they control, and we highlight unanswered questions in the field, such as the potential roles of transcription at enhancers. Expected final online publication date for the Annual Review of Biochemistry, Volume 89 is June 22, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Making decisions in environments with few choice options is easy. We select the action that results in the most valued outcome. Making decisions in more complex environments, where the same action can produce different outcomes in different conditions, is much harder. In such circumstances, we propose that accurate action selection relies on top-down control from the prelimbic and orbitofrontal cortices over striatal activity through distinct thalamostriatal circuits. We suggest that the prelimbic cortex exerts direct influence over medium spiny neurons in the dorsomedial striatum to represent the state space relevant to the current environment. Conversely, the orbitofrontal cortex is argued to track a subject's position within that state space, likely through modulation of cholinergic interneurons. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND

Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico.

RESULTS

A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24-26, 27-29, and 30-33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24-26, 27-29, and 30-33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses.

CONCLUSIONS

Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis. Please see later in the article for the Editors' Summary.

People worldwide are living longer, and it is estimated that by 2050, the proportion of the world's population over 60 years of age will nearly double. Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. As the aging population rapidly grows, it is essential to examine how alterations in cellular function and cell-to-cell interactions of pulmonary resident cells and systemic immune cells contribute to a higher risk of increased susceptibility to infection and development of chronic diseases, such as chronic obstructive pulmonary disease and interstitial pulmonary fibrosis. This review provides an overview of physiological, structural, and cellular changes in the aging lung and immune system that facilitate the development and progression of disease. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.