ALBERT

Description: Dysregulations in hepatic lipid synthesis are often associated with obesity and type 2 diabetes, and therefore a perfect understanding of the regulation of this metabolic pathway appears essential to identify potential therapeutic targets. Recently, the transcription factor ChREBP (carbohydrate-responsive element-binding protein) has emerged as a major mediator of glucose action on lipogenic gene expression and as a key determinant of lipid synthesis in vivo. Indeed, liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in obese ob/ob mice. Since ChREBP cellular localization is a determinant of its functional activity, a better knowledge of the mechanisms involved in regulating its nucleo-cytoplasmic shuttling and/or its post-translational activation is crucial in both physiology and physiopathology. Here, we review some of the studies that have begun to elucidate the regulation and function of this key transcription factor in liver.

Description: In many epileptic patients, anticonvulsant drugs either fail adequately to control seizures or they cause serious side effects. An important adjunct to pharmacologic therapy is the ketogenic diet, which often improves seizure control, even in patients who respond poorly to medications. The mechanisms that explain the therapeutic effect are incompletely understood. Evidence points to an effect on brain handling of amino acids, especially glutamic acid, the major excitatory neurotransmitter of the central nervous system. The diet may limit the availability of oxaloacetate to the aspartate aminotransferase reaction, an important route of brain glutamate handling. As a result, more glutamate becomes accessible to the glutamate decarboxylase reaction to yield gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter and an important antiseizure agent. In addition, the ketogenic diet appears to favor the synthesis of glutamine, an essential precursor to GABA. This occurs both because ketone body carbon is metabolized to glutamine and because in ketosis there is increased consumption of acetate, which astrocytes in the brain quickly convert to glutamine. The ketogenic diet also may facilitate mechanisms by which the brain exports to blood compounds such as glutamine and alanine, in the process favoring the removal of glutamate carbon and nitrogen.

Description: ▪ Abstract  This review summarizes the research advances of the past decade regarding the role of human genetic differences in energy and nutrient intake as well as in eating behavior phenotypes and selected eating disorders. The evidence for familial aggregation and heritability based on twin and nuclear family study designs is summarized. Genome-wide linkage scans and quantitative trait loci identified to date are discussed. DNA sequence variants in candidate genes are reviewed. Single genes associated with classical eating disorders are also incorporated. Epigenetic events will need to be incorporated in future studies designed to investigate the effects of DNA variants on dietary phenotypes. Understanding the relative contribution of global genetic variation and of DNA sequence variants in specific genes is important in the effort to influence dietary habits in a healthier direction.

Description: ▪ Abstract  Type 1 diabetes is an autoimmune disease in which the patient's immune system destroys the insulin-secreting β-cells in the pancreatic islets of Langerhans. A majority of cases is thought to occur as a result of gene-environment interactions. The identity of the environmental factors remains unknown mainly because of the difficulty in linking past exposures with later disease development. Overall, the data suggest a model in which individuals develop diabetes by several different pathways, each influenced by numerous genetic and environmental variables. The most investigated environmental factors are diet and viruses. In this review, we examine the evidence that the source of dietary proteins can modify diabetes outcome, describe new approaches to identify candidate diabetes-related dietary agents, examine possible links with gut dysfunction, discuss some of the limitations, and propose a multifactorial model for dietary modification of diabetes. The key to diabetes pathogenesis, its prevention, and the ultimate success of β-cell replacement therapies lies in understanding how the environment controls disease expression. Dietary proteins could be one of these keys.

Description: ▪ Abstract  The strongest evidence that cow's milk stimulates linear growth comes from observational and intervention studies in developing countries that show considerable effects. Additionally, many observational studies from well-nourished populations also show an association between milk intake and growth. These results suggest that milk has a growth-stimulating effect even in situations where the nutrient intake is adequate. This effect is supported by studies that show milk intake stimulates circulating insulin-like growth factor (IGF)-I, which suggests that at least part of the growth-stimulating effects of milk occur through the stimulation of IGFs. Given that the biological purpose of milk is to support the newborn during a period of high growth velocity, such an effect seems plausible. Adding cow's milk to the diet of stunted children is likely to improve linear growth and thereby reduce morbidity. In well-nourished children, the long-term consequences of an increased consumption of cow's milk, which may lead to higher levels of IGF-I in circulation or an increase in the velocity of linear growth, are likely to be both positive and negative. Based on emerging data that suggest both growth and diet during early life program the IGF axis, the association between milk intake and later health is likely to be complex. [ Notice ]

Description: ▪ Abstract  In 1992, asymmetrical dimethylarginine (ADMA) was first described as an endogenous inhibitor of the arginine-nitric oxide (NO) pathway. From then, its role in regulating NO production has attracted increasing attention. Nowadays, ADMA is regarded as a novel cardiovascular risk factor. The role of the kidney and the liver in the metabolism of ADMA has been extensively studied and both organs have proven to play a key role in the elimination of ADMA. Although the liver removes ADMA exclusively via degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), the kidney uses both metabolic degradation via DDAH and urinary excretion to eliminate ADMA. Modulating activity and/or expression of DDAH is still under research and may be a potential therapeutic approach to influence ADMA plasma levels. Interestingly, next to its association with cardiovascular disease, ADMA also seems to play a role in other clinical conditions, such as critical illness, hepatic failure, and preeclampsia. To elucidate the clinical significance of ADMA in these conditions, the field of research must be enlarged.

Description: ▪ Abstract  Critically ill patients who depend on intensive care for more than a few days reveal profound erosion of lean body mass, which is thought to contribute to high morbidity and mortality. Despite a shortfall of evidence that supplemental feeding actually alters clinical outcome of these life-threatening disease states, this observation evoked an almost universal, albeit often inappropriate, use of nutritional support (NS) in the critically ill, administered via the parenteral or the enteral route. Lack of knowledge and overenthusiasm subsequently resulted in complications associated with both parenteral nutrition (PN) and enteral nutrition (EN), which led to the standing controversy over which should be preferred. With time, however, it became clear that EN and PN are not mutually exclusive and that critically ill patients requiring NS should be fed according to the functional status of the gastrointestinal tract. In addition, tight blood glucose control with insulin is advised in fed critically ill patients because overall metabolic control appears to surpass any outcome benefit attributed to the route of feeding. Recently, various special nutritional formulas have been suggested to prevent or treat multiorgan failure in the critically ill, among other pathways via modulation of immune function. Although special nutritional formulas may be promising in a variety of clinical settings, based on currently available data, these cannot be recommended for routine use in critically ill patients.

Description: ▪ Abstract  Multiple peptide hormones produced within the gastrointestinal system aid in the regulation of energy homeostasis and metabolism. Among these is the intestinotrophic peptide glucagon-like peptide-2 (GLP-2), which is released following food intake and plays a significant role in the adaptive regulation of bowel mass and mucosal integrity. The discovery of GLP-2's potent growth-promoting and cytoprotective effects in the gastrointestinal (GI) tract stimulated interest in its use as a therapeutic agent for the treatment of GI diseases involving malabsorption, inflammation, and/or mucosal damage. Current research has focused on determining the physiological mechanisms contributing to the effects of GLP-2 and factors regulating its biological mechanisms of action. This chapter provides an overview of the biology of GLP-2 with a focus on the most recent findings on the role of this peptide hormone in the normal and diseased GI tract.

Description: Anorexia nervosa is a perplexing illness marked by low body weight and persistent fear of weight gain. Anorexia nervosa has the highest mortality rate of any psychiatric disease. Historically, anorexia nervosa was viewed as a disorder primarily influenced by sociocultural factors; however, over the past decade, this perception has been challenged. Family studies have consistently demonstrated that anorexia nervosa runs in families. Twin studies have underscored the contribution of additive genetic factors to the observed familial aggregation. With these bodies of literature as a starting point, we evaluate critically the current state of research on molecular genetic studies of anorexia nervosa and provide guidance for future research.

Description: The evolution of large human brain size has had important implications for the nutritional biology of our species. Large brains are energetically expensive, and humans expend a larger proportion of their energy budget on brain metabolism than other primates. The high costs of large human brains are supported, in part, by our energy- and nutrient-rich diets. Among primates, relative brain size is positively correlated with dietary quality, and humans fall at the positive end of this relationship. Consistent with an adaptation to a high-quality diet, humans have relatively small gastrointestinal tracts. In addition, humans are relatively “undermuscled” and “over fat” compared with other primates, features that help to offset the high energy demands of our brains. Paleontological evidence indicates that rapid brain evolution occurred with the emergence of Homo erectus 1.8 million years ago and was associated with important changes in diet, body size, and foraging behavior.

Description: ▪ Abstract  The kidney plays a central role in our ability to maintain an appropriate sodium balance, which is critical for the determination of blood pressure. The kidney's capacity for salt conservation may not be widely appreciated, and in general we consume vastly more salt than we need. Here we consider the socioeconomics of salt consumption, outline current knowledge of renal salt handling at the molecular level, describe some of the disease entities associated with abnormal sodium handling, give an overview of some of the animal models and their relevance to human disease, and examine the evidence that lowering our salt intake can help combat hypertension and cardiovascular disease.

Description: The mammary gland has a remarkable capacity to adapt to maternal deficiency or excess of iron, copper, and zinc and to homeostatically control milk concentrations of these essential nutrients. Similarly, it can regulate changes in concentrations of iron, copper, and zinc change during lactation. For iron, this regulation is achieved by transferrin receptor, DMT1, and ferroportin, whereas mammary gland copper metabolism is regulated by Ctr1, ATP7A, and ATP7B. Zinc homeostasis is complex, involving both zinc importers (Zip3) and zinc exporters (ZnT-1, ZnT-2, and ZnT-4). Both transcriptional and post-translational regulation can affect protein abundance and cellular localization of these transporters, finely orchestrating uptake, intracellular trafficking, and secretion of iron, copper, and zinc. The control of mammary gland uptake and milk secretion of iron, copper, and zinc protects both the mammary gland and the breast-fed infant against deficiency and excess of these nutrients.

Description: ▪ Abstract  A significant proportion of the population is either affected by or concerned about food allergy. Our knowledge about food allergens and how they stimulate the immune system has increased dramatically over the past decade. However, reasons for the increased prevalence of food allergy are not clear. The diagnosis of food allergy requires that the patient and caregivers examine all foods for the presence of potential allergens in order to prevent inadvertent ingestion and further reactions. Fortunately, many children develop tolerance to allergenic foods after a period of dietary elimination. Various immunotherapy approaches are under investigation to alleviate or prevent food-induced reactions in those who have persistent food allergies.

Description: Abstract  The soybean cyst nematode, Heterodera glycines, adversely affects the production of soybean, Glycine max, in many areas of the world, particularly in the United States, where it is the most economically important soybean pathogen. Despite the availability of hundreds of H. glycines–resistant soybean cultivars, the nematode continues to be a major limiting factor in soybean production. The use of nonhost rotation and resistance are the primary means of reducing losses caused by the nematode, but each of these options has disadvantages. As a subject for study of nematode parasitism and virulence, H. glycines provides a useful model despite its obligately parasitic nature. Its obligately sexual reproduction and ready adaptation to resistant cultivars, formerly referred to as “race shift,” presents an excellent opportunity for the study of virulence in nematodes. Recent advances in H. glycines genomics have helped identify putative nematode parasitism genes, which, in turn, will aid in the understanding of nematode pathogenicity and virulence and may provide new targets for engineering nematode resistance.

Description: Abstract  This review considers factors affecting the coexistence of closely related pathogen species on arable crops, with particular reference to data available at Rothamsted for Septoria tritici/Stagonospora nodorum (Mycosphaerella graminicola/Phaeosphaeria nodorum) (septoria leaf blotch diseases on winter wheat), Oculimacula yallundae/O. acuformis (eyespot disease of winter cereals), and Leptosphaeria maculans/L. biglobosa (phoma stem canker on winter oilseed rape). Factors affecting the short-term, medium-term, and long-term coexistence of such related pathogen species are reviewed, and their evolution from common ancestors considered. Small niche differences between the related pathogen species enable them to coexist on the same host. The niche differences result from small differences in their biology/epidemiology, leading to separation in space, time, or resource use. Changes in both natural (e.g., fluctuating temperature) and man-made (e.g., agronomic practices, pollution) factors influence the coexistence. Such factors may result in coexistence between the related species in some parts of the world, whereas in other parts only one species occurs. These principles illustrated with pathogens of arable crops are generic to other host-pathogen systems.

Description: Abstract  Inducible defense-related proteins have been described in many plant species upon infection with oomycetes, fungi, bacteria, or viruses, or insect attack. Several types of proteins are common and have been classified into 17 families of pathogenesis-related proteins (PRs). Others have so far been found to occur more specifically in some plant species. Most PRs and related proteins are induced through the action of the signaling compounds salicylic acid, jasmonic acid, or ethylene, and possess antimicrobial activities in vitro through hydrolytic activities on cell walls, contact toxicity, and perhaps an involvement in defense signaling. However, when expressed in transgenic plants, they reduce only a limited number of diseases, depending on the nature of the protein, plant species, and pathogen involved. As exemplified by the PR-1 proteins in Arabidopsis and rice, many homologous proteins belonging to the same family are regulated developmentally and may serve different functions in specific organs or tissues. Several defense-related proteins are induced during senescence, wounding or cold stress, and some possess antifreeze activity. Many defense-related proteins are present constitutively in floral tissues and a substantial number of PR-like proteins in pollen, fruits, and vegetables can provoke allergy in humans. The evolutionary conservation of similar defense-related proteins in monocots and dicots, but also their divergent occurrence in other conditions, suggest that these proteins serve essential functions in plant life, whether in defense or not.

Description: Abstract  The bacterial family Enterobacteriaceae contains some of the most devastating human and animal pathogens, including Escherichia coli, Salmonella enterica and species of Yersinia and Shigella. These are among the best-studied of any organisms, yet there is much to be learned about the nature and evolution of interactions with their hosts and with the wider environment. Comparative and functional genomics have fundamentally improved our understanding of their modes of adaptation to different ecological niches and the genes that determine their pathogenicity. In addition to animal pathogens, Enterobacteriaceae include important plant pathogens, such as Erwinia carotovora subsp. atroseptica (Eca), the first plant-pathogenic enterobacterium to be sequenced ( 20 ). This review focuses on genomic comparisons between Eca and other enterobacteria, with particular emphasis on the differences that exemplify or explain the plant-associated lifestyle(s) of Eca. Horizontal gene transfer in Eca may directly have led to the acquisition of a number of determinants that mediate its interactions, pathogenic or otherwise, with plants, offering a glimpse into its evolutionary divergence from animal-pathogenic enterobacteria.

Description: Abstract  The oomycetes form a phylogenetically distinct group of eukaryotic microorganisms that includes some of the most notorious pathogens of plants. Oomycetes accomplish parasitic colonization of plants by modulating host cell defenses through an array of disease effector proteins. The biology of effectors is poorly understood but tremendous progress has been made in recent years. This review classifies and catalogues the effector secretome of oomycetes. Two classes of effectors target distinct sites in the host plant: Apoplastic effectors are secreted into the plant extracellular space, and cytoplasmic effectors are translocated inside the plant cell, where they target different subcellular compartments. Considering that five species are undergoing genome sequencing and annotation, we are rapidly moving toward genome-wide catalogues of oomycete effectors. Already, it is evident that the effector secretome of pathogenic oomycetes is more complex than expected, with perhaps several hundred proteins dedicated to manipulating host cell structure and function.

Description: Virus infections are the cause of numerous plant disease syndromes that are generally characterized by the induction of disease symptoms such as developmental abnormalities, chlorosis, and necrosis. How viruses induce these disease symptoms represents a long-standing question in plant pathology. Recent studies indicate that symptoms are derived from specific interactions between virus and host components. Many of these interactions have been found to contribute to the successful completion of the virus life-cycle, although the role of other interactions in the infection process is not yet known. However, all share the potential to disrupt host physiology. From this information we are beginning to decipher the progression of events that lead from specific virus-host interactions to the establishment of disease symptoms. This review highlights our progress in understanding the mechanisms through which virus-host interactions affect host physiology. The emerging picture is one of complexity involving the individual effects of multiple virus-host interactions.

Description: Abstract  Among the multitude of soil-inhabiting, saprophytic Streptomyces species are a growing number of plant pathogens that cause economically important diseases, including potato scab. Streptomyces scabies is the dominant pathogenic species worldwide, but is only one of many that cause very similar disease symptoms on plants. Molecular genetic analysis is beginning to identify the mechanisms used by plant pathogenic species to manipulate their hosts. The nitrated dipeptide phytotoxin, thaxtomin, inhibits cellulose biosynthesis in expanding plant tissues, stimulates Ca2+ spiking, and causes cell death. A secreted necrogenic protein, Nec1, contributes to virulence on diverse plant species. The thaxtomin biosynthetic genes and nec1 lie on a large mobilizable PAI, along with other putative virulence genes including a cytokinin biosynthetic pathway and a saponinase homolog. The PAI is mobilized during conjugation and site-specifically inserts in the linear chromosome of recipient species, accounting for the emergence of new pathogens in agricultural systems. The recently available genome sequence of S. scabies will accelerate research on host-pathogen interactions.

Description: The plant virus family Flexiviridae includes the definitive genera Potexvirus, Mandarivirus, Allexivirus, Carlavirus, Foveavirus, Capillovirus, Vitivirus, Trichovirus, the putative genus Citrivirus, and some unassigned species. Its establishment was based on similarities in virion morphology, common features in genome type and organization, and strong phylogenetic relationships between replicational and structural proteins. In this review, we provide a brief account of the main biological and molecular properties of the members of the family, with special emphasis on the relationships within and among the genera. In phylogenetic analyses the potexvirus-like replicases were more closely related to tymoviruses than to carlaviruses. We postulate a common evolutionary ancestor for the family Tymoviridae and the two distinct evolutionary clusters of the Flexiviridae, i.e., a plant virus with a polyadenylated genome, filamentous virions, and a triple gene block of movement proteins. Subsequent recombination and gene loss would then have generated a very diverse group of plant and fungal viruses.

Description: Abstract  The continuous rise in the number of outbreaks of foodborne illness linked to fresh fruit and vegetables challenges the notion that enteric pathogens are defined mostly by their ability to colonize the intestinal habitat. This review describes the epidemiology of produce-associated outbreaks of foodborne disease and presents recently acquired knowledge about the behavior of enteric pathogens on plants, with an emphasis on Salmonella enterica, Escherichia coli O157:H7, and Listeria monocytogenes. The growth and survival of enteric pathogens on plants are discussed in the light of knowledge and concepts in plant microbial ecology, including epiphytic fitness, the physicochemical nature of plant surfaces, biofilm formation, and microbe-microbe and plant-microbe interactions. Information regarding the various stresses that affect the survival of enteric pathogens and the molecular events that underlie their interactions in the plant environment provides a good foundation for assessing their role in the infectious dose of the pathogens when contaminated fresh produce is the vehicle of illness.

Description: Abstract  The phytohormone ethylene is a principal modulator in many aspects of plant life, including various mechanisms by which plants react to pathogen attack. Induced ethylene biosynthesis and subsequent intracellular signaling through a single conserved pathway have been well characterized. This leads to a cascade of transcription factors consisting of primary EIN3-like regulators and downstream ERF-like transcription factors. The latter control the expression of various effector genes involved in various aspects of systemic induced defense responses. Moreover, at this level significant cross-talk occurs with other defense response pathways controlled by salicylic acid and jasmonate, eventually resulting in a differentiated disease response.

Description: Abstract  The majority of positive-strand RNA viruses of plants replicate and selectively encapsidate their progeny genomes into stable virions in cytoplasmic compartments of the cell where the opportunity to copackage cellular RNA also exists. Remarkably, highly purified infectious virions contain almost exclusively viral RNA, suggesting that mechanisms exist to regulate preferential packaging of viral genomes. The general principle that governs RNA packaging is an interaction between the structural CP and a specific RNA signal. Mechanisms that enhance selective packaging of viral genomes and formation of infectious virions may involve factors other than CP and nucleic acid sequences. The possible involvement of replicase proteins is an example. Our knowledge concerning genome packaging among spherical plant RNA viruses is still maturing. The main focus of this review is to discuss factors that have limited progress and to evaluate recent technical breakthroughs likely to help unravel the mechanism of RNA packaging among viruses of agronomic importance. A key breakthrough is the development of in vivo systems and comparisons with results obtained in vitro.

Description: Abstract  The ability to infect host flowers offers important ecological benefits to plant-parasitic fungi; not surprisingly, therefore, numerous fungal species from a wide range of taxonomic groups have adopted a life style that involves flower infection. Although flower-infecting fungi are very diverse, they can be classified readily into three major groups: opportunistic, unspecialized pathogens causing necrotic symptoms such as blossom blights (group 1), and specialist flower pathogens which infect inflorescences either through the gynoecium (group 2) or systemically through the apical meristem (group 3). This three-tier system is supported by life history attributes such as host range, mode of spore transmission, degree of host sterilization as a result of infection, and whether or not the fungus undergoes an obligate sexual cycle, produces resting spores in affected inflorescences, and is r- or K-selected. Across the three groups, the flower as an infection court poses important challenges for disease management. Ecologically and evolutionarily, terms and concepts borrowed from the study of venereal (sexually transmitted) diseases of animals do not adequately capture the range of strategies employed by fungi that infect flowers.

Description: Using genomic technologies, it is now possible to address research hypotheses in the context of entire developmental or biochemical pathways, gene networks, and chromosomal location of relevant genes and their inferred evolutionary history. Through a range of platforms, researchers can survey an entire transcriptome under a variety of experimental and field conditions. Interpretation of such data has led to new insights and revealed previously undescribed phenomena. In the area of plant-pathogen interactions, transcript profiling has provided unparalleled perception into the mechanisms underlying gene-for-gene resistance and basal defense, host vs nonhost resistance, biotrophy vs necrotrophy, and pathogenicity of vascular vs nonvascular pathogens, among many others. In this way, genomic technologies have facilitated a system-wide approach to unifying themes and unique features in the interactions of hosts and pathogens.

Description: Abstract  The phenazines include upward of 50 pigmented, heterocyclic nitrogen-containing secondary metabolites synthesized by some strains of fluorescent Pseudomonas spp. and a few other bacterial genera. The antibiotic properties of these compounds have been known for over 150 years, but advances within the past two decades have provided significant new insights into the genetics, biochemistry, and regulation of phenazine synthesis, as well as the mode of action and functional roles of these compounds in the environment. This new knowledge reveals conservation of biosynthetic enzymes across genera but raises questions about conserved biosynthetic mechanisms, and sets the stage for improving the performance of phenazine producers used as biological control agents for soilborne plant pathogens.

Description: Although seed production has been moved to semiarid regions to escape seedborne pathogens, seedborne bacterial diseases continue to be problematic and cause significant economic losses worldwide. Infested seeds are responsible for the re-emergence of diseases of the past, movement of pathogens across international borders, or the introduction of diseases into new areas. Considerable attention has been paid to improving the sensitivity and selectivity of seed health assays by using techniques such as flow cytometry and the polymerase chain reaction. There has also been progress in understanding infection thresholds and how they influence seed sample size determination and ultimately the reliability of seed health testing. Disease development and dissemination of pathogens from contaminated seedlots can be predicted using formulas that take into account inoculum density and environmental pressures. In general, seeds infested with bacterial pathogens are distributed within a Poisson distribution. In a subset of contaminated seeds, bacteria are distributed in non-Gaussian distributions, e.g., a lognormal distribution.

Description: A major challenge facing agricultural scientists today is the need to secure food for an increasing world population. This growth occurs predominantly in developing, mostly tropical countries, where the majority of hungry people live. Reducing yield losses caused by pathogens of tropical agricultural crops is one measure that can contribute to increased food production. Although plant-parasitic nematodes are often not as important as some other biotic and nonbiotic constraints on crop production in the tropics, they can nevertheless cause extensive damage and substantial yield losses. The effects of agricultural, environmental, socioeconomic, and policy changes on the occurrence of plant-parasitic nematodes in the tropics and the losses these pathogens cause are largely undocumented. Recent developments pose new challenges to tropical nematology. The increased application of molecular diagnostics may widen the knowledge gap between nematologists working in developed countries and in the tropics. Uncertainties concerning the validity of nematode species will lead to practical problems related to quarantine measures and nematode management. The study of interactions between nematodes and other pathogens in disease complexes provide opportunities for multidisciplinary research with scientists from other disciplines but remain underexploited. Difficulties in recognizing emerging nematode threats prevent the timely implementation of management strategies, thus increasing yield losses. Research is needed to address these challenges. Examples are presented mainly but not exclusively from banana, peanut, and rice nematology.

Description: Gene-for-gene resistance in plants is based on the presence of a resistance (R) gene in the host and a matching Avirulence (Avr) gene in the pathogen. Many R genes have been cloned over the past two decades, mostly from the Solanaceae. The gene products, called R proteins, display modular domain structures. R protein function has recently been shown to require dynamic interactions between the various domains. In addition to these intramolecular interactions, R proteins interact with other proteins to form signaling complexes that are able to activate an innate immune response that arrests proliferation of the invading pathogen, thereby conferring disease resistance. In this review, we summarize current understanding of R protein structure and function, as well as the molecular mechanisms underlying the activation of defense signaling processes. As well as being a rich source for R genes, Solanaceae are a leading model system in which to study inter- and intramolecular interactions of R proteins.

Description: My job at Pullman, Washington, starting in 1965, was to control the root diseases of wheat and barley, focusing first on fusarium root and crown rot, then including take-all and pythium and rhizoctonia root rots. In the absence of viable alternatives, the agronomic approaches used were implemented through design of cereal-based cropping systems. Starting in the late 1970s, the mission focused further on cereal-intensive direct-seed (no-till) cropping systems. A team effort demonstrated the role of indigenous antibiotic-producing fluorescent pseudomonads in the widespread decline of take-all in response to monoculture wheat (or barley-wheat sequences). Today, the suppression of take-all by these beneficial rhizobacteria is the centerpiece of an integrated system that augments take-all decline while limiting pythium and rhizoctonia root rots and fusarium root and crown rot in direct-seed systems. In such systems, “crop rotation” takes the form of different sequences of winter and spring wheat, barley and triticale varieties, and market classes, all susceptible to all four root diseases.

Description: Many factors affect the development and application of diagnostic techniques. Plant viruses are an inherently diverse group that, unlike cellular pathogens, possess no nucleotide sequence type (e.g., ribosomal RNA sequences) in common. Detection of plant viruses is becoming more challenging as globalization of trade, particularly in ornamentals, and the potential effects of climate change enhance the movement of viruses and their vectors, transforming the diagnostic landscape. Techniques for assessing seed, other propagation materials and field samples for the presence of specific viruses include biological indexing, electron microscopy, antibody-based detection, including enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and microarray detection. Of these, microarray detection provides the greatest capability for parallel yet specific testing, and can be used to detect individual, or combinations of viruses and, using current approaches, to do so with a sensitivity comparable to ELISA. Methods based on PCR provide the greatest sensitivity among the listed techniques but are limited in parallel detection capability even in “multiplexed” applications. Various aspects of microarray technology, including probe development, array fabrication, assay target preparation, hybridization, washing, scanning, and interpretation are presented and discussed, for both current and developing technology.

Description: Abstract  Most plant viruses are absolutely dependent on a vector for plant-to-plant spread. Although a number of different types of organisms are vectors for different plant viruses, phloem-feeding Hemipterans are the most common and transmit the great majority of plant viruses. The complex and specific interactions between Hemipteran vectors and the viruses they transmit have been studied intensely, and two general strategies, the capsid and helper strategies, are recognized. Both strategies are found for plant viruses that are transmitted by aphids in a nonpersistent manner. Evidence suggests that these strategies are found also for viruses transmitted in a semipersistent manner. Recent applications of molecular and cell biology techniques have helped to elucidate the mechanisms underlying the vector transmission of several plant viruses. This review examines the fundamental contributions and recent developments in this area.

Description: The plant basal immune system can detect broadly present microbe-associated molecular patterns (MAMPs, also called PAMPs) and induce defenses, but adapted microbes express a suite of effector proteins that often act to suppress these defenses. Plants have evolved other receptors (R proteins) that detect these pathogen effectors and activate strong defenses. Pathogens can subsequently alter or delete their recognized effectors to avoid defense elicitation, at risk of a fitness cost associated with loss of those effectors. Significant research progress is revealing, among other things, mechanisms of MAMP perception, the host defense processes and specific host proteins that pathogen effectors target, the mechanisms of R protein activation, and the ways in which pathogen effector suites and R genes evolve. These findings carry practical ramifications for resistance durability and for future resistance engineering. The present review uses numerous questions to help clarify what we know and to identify areas that are ripe for further investigation.

Description: Abstract  An appreciation of the risks caused by emergent plant viruses is critical in tropical areas that rely heavily on agriculture for subsistence and rural livelihood. Molecular ecology, within 10 years, has unraveled the factors responsible for the emergence of several of the economically most important tropical plant viruses: Rice yellow mottle virus (RYMV), Cassava mosaic geminiviruses (CMGs), Maize streak virus (MSV), and Banana streak virus (BSV). A large range of mechanisms—most unsuspected until recently—were involved: recombination and synergism between virus species, new vector biotypes, genome integration of the virus, host adaptation, and long-distance dispersal. A complex chain of molecular and ecological events resulted in novel virus-vector-plant-environment interactions that led to virus emergence. It invariably involved a major agricultural change: crop introduction, cultural intensification, germplasm movement, and new genotypes. A current challenge is now to complement the analysis of the causes by an assessment of the risks of emergence. Recent attempts to assess the risks of emergence of virulent virus strains are described.

Description: Plant disease cycles represent pathogen biology as a series of interconnected stages of development including dormancy, reproduction, dispersal, and pathogenesis. The progression through these stages is determined by a continuous sequence of interactions among host, pathogen, and environment. The stages of the disease cycle form the basis of many plant disease prediction models. The relationship of temperature and moisture to disease development and pathogen reproduction serve as the basis for most contemporary plant disease prediction systems. Pathogen dormancy and inoculum dispersal are considered less frequently. We found extensive research efforts evaluating the performance of prediction models as part of operation disease management systems. These efforts appear to be greater than just a few decades ago, and include novel applications of Bayesian decision theory. Advances in information technology have stimulated innovations in model application. This trend must accelerate to provide the disease management strategies needed to maintain global food supplies.

Description: Genetic studies of the flax-flax rust interaction led to the formulation of the gene-for-gene hypothesis and identified resistance genes (R) in the host plant and pathogenicity genes, including avirulence (Avr) and inhibitor of avirulence genes (I), in the rust pathogen. R genes have now been cloned from four of the five loci in flax and all encode proteins of the Toll, Interleukin-1 receptor, R gene-nucleotide binding site-leucine-rich repeat (TIR-NBS-LRR) class. Avr genes have been cloned from four loci in flax rust and encode small secreted proteins with no between locus similarity and no close homologs in current data bases. It is postulated that Avr proteins enter the host cell, have virulence effector functions, and in resistant host genotypes, are recognized by direct and specific interaction with host R proteins, leading to activation of rust resistance defense responses. Direct interaction between R and Avr proteins is the basis of gene-for-gene specificity in the flax-flax rust system and both R and Avr genes have the signatures of diversifying selection, suggesting the existence of a coevolutionary arms race between the host plant and its obligate rust pathogen.

Description: Potential safety issues have been raised with the development and release of virus-resistant transgenic plants. This review focuses on safety assessment with a special emphasis on crops that have been commercialized or extensively tested in the field such as squash, papaya, plum, grape, and sugar beet. We discuss topics commonly perceived to be of concern to the environment and to human health—heteroencapsidation, recombination, synergism, gene flow, impact on nontarget organisms, and food safety in terms of allergenicity. The wealth of field observations and experimental data is critically evaluated to draw inferences on the most relevant issues. We also express inside views on the safety and benefits of virus-resistant transgenic plants, and recommend realistic risk assessment approaches to assist their timely deregulation and release.

Description: Abstract  Pathogens are powerful evolutionary forces shaping the structure and dynamics of both individual species and of the communities of which they are part, at a broad range of genetic, ecological, spatial, and temporal scales. At all these levels their impact varies from the subtle and little recognized through to the most obvious destruction. Today the direct role of pathogens in natural plant communities is better recognized than at previous times, although the nuances of their interactions and the cascade of ramifications that can flow through changing biotic and abiotic effects are only now gaining recognition. However, as human influence on pathogens increases—either directly through enhanced if accidental dispersal, or through anthropogenic impacts on climate—we may expect to see increasing evidence of pathogens affecting plant species, community structure, and ecosystem function.

Description: Noel T. Keen (1940–2002) made pioneering contributions to molecular plant pathology during a period when the study of disease mechanisms was transformed by the new tools of molecular genetics. His primary contributions involved race-specific elicitors of plant defenses and bacterial pectic enzymes. In collaboration with Brian J. Staskawicz and Frances Jurnak, respectively, Noel cloned the first avirulence gene and determined that pectate lyase C possessed a novel structural motif, known as the parallel β-helix. Noel received his B.S. and M.S. from Iowa State University in Ames and his Ph.D. from the Department of Plant Pathology at the University of Wisconsin in Madison in 1968. He joined the faculty of the Department of Plant Pathology at the University of California at Riverside the same year and remained there his entire career. He served as Chair of the department from 1983 to 1989 and in 1997 assumed the William and Sue Johnson Endowed Chair in Molecular Plant Pathology. He became a Fellow of the American Phytopathological Society in 1991, a Fellow of the American Association for the Advancement of Science in 1996, a Fellow of the American Academy of Microbiology in 1997, and a member of the National Academy of Sciences in 1997. He was serving as President of the American Phytopathological Society (2001–2002) at the time of his death.

Description: Suppressive soils hold considerable potential for managing soilborne pathogens. When the suppressiveness has a biological origin, identifying the causal organisms is the crucial step in realizing this potential. Armed with such knowledge, it may be possible to develop effective and sustainable pest management strategies through application of these organisms or agronomic practices that influence their population densities. This chapter focuses on the development and utilization of a population-based approach for identifying microorganisms involved in specific pathogen suppression. Key experimental design principles of the approach are explored by examining experiments characterizing the biological nature of take-all decline. We also describe how this approach was used to identify microorganisms that suppress the sugarbeet cyst nematode. Additional experimental design considerations and future directions for such investigations are also discussed.

Description: Abstract  The genus Tilletia is a group of smut fungi that infects grasses either systemically or locally. Basic differences exist between the systemically infecting species, such as the common and dwarf bunt fungi, and locally infecting species. Tilletia indica, which causes Karnal bunt of wheat, and Tilletia horrida, which causes rice kernel smut, are two examples of locally infecting species on economically important crops. However, even species on noncultivated hosts can become important when occurring as contaminants in export grain and seed shipments. In this review, we focus on T. indica and the morphologically similar but distantly related T. horrida, considering history, systematics, and biology. In addition, the controversial generic placement and evolutionary relationships of these two species are discussed in light of recent molecular studies.

Description: The plant cuticle and cell wall separate microbial pathogens from the products of plant metabolism. While microbial pathogens try to breach these barriers for colonization, plants respond to attempted penetration by a battery of wall-associated defense reactions. Successful pathogens circumvent or suppress plant nonself recognition and basal defense during penetration and during microbial reproduction. Additionally, accommodation of fungal infection structures within intact cells requires host reprogramming. Recent data highlight that both early plant defense to fungal penetration and host reprogramming for susceptibility can function at the host cell periphery. Genetic evidence has also widened our understanding of how fungal pathogens are restricted during penetration at the plant cell wall. This review summarizes the current view of how plants monitor and model their cell periphery during interaction with microbial invaders.

Description: Abstract  This review considers the cascade of events that link injuries caused by plant pathogens on crop stands to possible (quantitative and qualitative) crop losses (damage), and to the resulting economic losses. To date, much research has focused on injury control to prevent this cascade of events from occurring. However, this cascade involves a complex succession of components and processes whereby knowledge on crop loss generates entry points for management. Proposed here is a framework linking different types of knowledge on crop loss to a range of decision categories, from tactical to strategic short- or long-term. Important advances in this field are now under way, including a probabilistic treatment of the injury-damage relationship, or analyses of the sources of uncertainty attached to some components of the decision process. Management of injury profiles, rather than individual injuries, and shifts in dimensionality of crop losses are anticipated to contribute to the design of sustainable agricultural systems, and address global issues concerning food security and food safety.

Description: Abstract  The vast majority of plant and animal viruses have RNA genomes. Viral gene expression and replication are controlled by cis-acting elements in the viral genome, which have been viewed conventionally as localized structures. However, recent research has altered this perception and provided compelling evidence for cooperative activity involving distantly positioned RNA elements. This chapter focuses on viral RNA elements that interact across hundreds or thousands of intervening nucleotides to control translation, genomic RNA synthesis, and subgenomic mRNA transcription. We discuss evidence supporting the existence and function of the interactions, and speculate on the regulatory roles that such long-distance interactions play in the virus life cycle. We emphasize viruses in the Tombusviridae and Luteoviridae families in which long-distance interactions are best characterized, but similar phenomena in other viruses are also discussed. Many more examples likely remain undiscovered.

Description: The rice blast pathosystem has been the subject of intense interest in part because of the importance of the disease to world agriculture, but also because both Magnaporthe oryzae and its host are amenable to advanced experimental approaches. The goal of this review is to provide an overview of the system and to point out recent significant studies that update our understanding of the biology of M. orzyae. The genome sequence of M. oryzae has provided insight into how genome structure and pathogen population genetic variability has been shaped by transposable elements. The sequence allows systematic approaches to long-standing areas of investigation, including pathogen development and the molecular basis of compatible and incompatible interactions with its host. Rice blast provides an integrated system to illustrate most of the important concepts governing fungal/plant interactions and serves as an excellent starting point for gaining a broad perspective of issues in plant pathology.

Description: Abstract  Over the past several decades, breeding cool-season turfgrasses for improved disease resistance has been the focus of many turfgrass breeding programs. This review article discusses the dramatic improvements made in breeding Kentucky bluegrass (Poa pratensis) for resistance to leaf spot (caused by Drechslera poae), stem rust (caused by Puccinia graminis), and stripe smut (caused by Ustilago striiformis); perennial ryegrass (Lolium perenne) for resistance to gray leaf spot (caused by Pyricularia grisea), stem rust and crown rust (caused by Puccinia coronata); tall fescue (Festuca arundinacea) for resistance to brown patch (Rhizoctonia solani) and stem rust; creeping bentgrass (Agrostis stolonifera) for resistance to dollar spot (caused by Sclerotinia homoeocarpa); and fine fescues (Festuca spp.) for improved disease resistance. Historically, the dramatic improvements in disease resistance of the cool-season grasses have been attributed to traditional/conventional breeding techniques; however, it is likely that functional genomics and molecular techniques will play a more significant role in the development of cultivated turfgrasses as the specific genes and mechanisms for disease resistance are identified in the future.

Description: Abstract  Plant pathology evolved from its mycology-oriented origins into a science dealing with biochemical mechanisms of diseases, along with enhanced crop production through disease control. This retrospective describes first my personal experience from my introduction to plant pathology, to the establishment of the concept of accessibility as a model pertaining to genetically defined basic compatibility induced by pathogens. I then refer to the development of molecular plant pathology from physiological and biochemical plant pathology fostered by the growth in recombinant technology in the second half of the past century. This progress was best reflected by the U.S.-Japan Seminar Series held at 4–5-year intervals from 1966 to 2003 and documented by publications in major journals of our discipline. These seminars emphasized that progress in science has always been supported by the invention of novel techniques and that knowledge integrated from modern genomics and subsequent proteomics should contribute to the progress of basic life sciences and, more importantly, to the elaboration of rational measures for disease control.

Description: Abstract  Research in the effects of climate change on plant disease continues to be limited, but some striking progress has been made. At the genomic level, advances in technologies for the high-throughput analysis of gene expression have made it possible to begin discriminating responses to different biotic and abiotic stressors and potential trade-offs in responses. At the scale of the individual plant, enough experiments have been performed to begin synthesizing the effects of climate variables on infection rates, though pathosystem-specific characteristics make synthesis challenging. Models of plant disease have now been developed to incorporate more sophisticated climate predictions. At the population level, the adaptive potential of plant and pathogen populations may prove to be one of the most important predictors of the magnitude of climate change effects. Ecosystem ecologists are now addressing the role of plant disease in ecosystem processes and the challenge of scaling up from individual infection probabilities to epidemics and broader impacts.

Description: Plasmids are common residents of phytopathogenic bacteria and contribute significantly to host evolution in a multi-faceted manner. Plasmids tend to encode determinants of virulence and ecological fitness that can enhance adaptation to a specific niche or can influence niche expansion. Many of these determinants appear to have been acquired from other bacteria via horizontal transfer, illustrating an important function of plasmids in the acquisition of sequences that enable rapid evolution. These genes can ultimately be delivered to the host chromosome through plasmid integration events, thus stabilizing important acquired determinants within the genome. Most plasmids characterized in phytopathogenic bacteria are self-transmissible and possess suites of genes encoding type IV secretion systems. In addition, the phytopathogenic bacterial plasmid “mobilome” includes insertion sequence and other transposable elements that contribute to the movement of sequences within and between genomes. Possession of mosaic and ever-changing plasmids allows phytopathogenic bacteria to maintain a dynamic, flexible genome and possible advantage in host-pathogen and other environmental interactions that belies the concept of plasmids as apparently selfish genetic elements.

Description: The use of phages for disease control is a fast expanding area of plant protection with great potential to replace the chemical control measures now prevalent. Phages can be used effectively as part of integrated disease management strategies. The relative ease of preparing phage treatments and low cost of production of these agents make them good candidates for widespread use in developing countries as well. However, the efficacy of phages, as is true of many biological control agents, depends greatly on prevailing environmental factors as well as on susceptibility of the target organism. Great care is necessary during development, production and application of phage treatments. In addition, constant monitoring for the emergence of resistant bacterial strains is essential. Phage-based disease control management is a dynamic process with a need for continuous adjustment of the phage preparation in order to effectively fight potentially adapting pathogenic bacteria.

Description: The reniform nematode, Rotylenchulus reniformis, is an emerging problem in U.S. cotton. The impact of this nematode and the extent to which it has and will continue to spread across the U.S. cotton belt are controversial. Long-term changes in cotton production and unique biological attributes of R. reniformis are key factors. Expert opinion surveys indicate that R. reniformis has replaced the root-knot nematode (Meloidogyne incognita) as the major nematode of cotton in Mississippi, Louisiana, and Alabama. In neighboring states the incidence of heavily infested fields has increased during the past 10 years. Estimated annual loss to the U.S. cotton crop is $130M. Crop rotation and nematicides can reduce losses. Introgression of genetic resistance from primitive accessions of other cotton species offers the most promising opportunity to effectively control this pathogen in the long term. Laboratories in several institutions are currently pursuing this goal, with the promise of resistant cultivars adapted to U.S. cotton production regions within three years.

Description: Abstract  Recent advances in sequencing technologies have led to a remarkable increase in the number of sequenced fungal genomes. Several important plant pathogenic fungi are among those that have been sequenced or are being sequenced. Additional fungal pathogens are likely to be sequenced in the near future. Analysis of the available genomes has provided useful information about genes that may be important for plant infection and colonization. Genome features, such as repetitive sequences, telomeres, conserved syntenic blocks, and expansion of pathogenicity-related genes, are discussed in detail with Magnaporthe oryzae (M. grisea) and Fusarium graminearum as examples. Functional and comparative genomic studies in plant pathogenic fungi, although still in the early stages and limited to a few pathogens, have enormous potential to improve our understanding of the molecular mechanisms involved in host-pathogen interactions. Development of advanced genomics tools and infrastructure is critical for efficient utilization of the vast wealth of available genome sequence information and will form a solid foundation for systems biology studies of plant pathogenic fungi.

Description: Animals reject diets that lead to indispensable amino acid (IAA) depletion or deficiency. This behavior is adaptive, as continued IAA depletion is incompatible with maintenance of protein synthesis and survival. Following rejection of the diet, animals begin foraging for a better IAA source and develop conditioned aversions to cues associated with the deficient diet. These responses require a sensory system to detect the IAA depletion and alert the appropriate neural circuitry for the behavior. The chemosensor for IAA deprivation is in the highly excitable anterior piriform cortex (APC) of the brain. Recently, the well-conserved general AA control non-derepressing system of yeast was discovered to be activated by IAA deprivation via uncharged tRNA in mammalian APC. This system provides the sensory limb of the mechanism for recognition of IAA depletion that leads to activation of the APC, diet rejection, and subsequent adaptive strategies.

Description: ▪ Abstract  This article, which is partly biographical and partly scientific, summarizes a life in academic medicine. It relates my progress from benchside to bedside and then to academic and research administration, and concludes with the teaching of human biology to college undergraduates. My experience as an intern (anno 1953) treating a youngster in diabetic ketoacidosis underscored our ignorance of the controls in human fuel metabolism. Circulating free fatty acids were then unknown, insulin could not be measured in biologic fluids, and β-hydroxybutyric acid, which was difficult to measure, was considered by many a metabolic poison. The central role of insulin and the metabolism of free fatty acids, glycerol, glucose, lactate, and pyruvate, combined with indirect calorimetry, needed characterization in a near-steady state, namely prolonged starvation. This is the main topic of this chapter. Due to its use by brain, D-β-hydroxybutyric acid not only has permitted man to survive prolonged starvation, but also may have therapeutic potential owing to its greater efficiency in providing cellular energy in ischemic states such as stroke, myocardial insufficiency, neonatal stress, genetic mitochondrial problems, and physical fatigue.

Description: The observation that cycles of sleep and wakefulness occur with a periodicity fixed in time to match the rotation of the Earth on its axis provided a key to unlock the first genetic code for a neurobehavioral pathway in flies and ultimately in mice. As a remarkable outcome of this discovery, we have gained an unprecedented view of the conserved genetic program that encodes a sense of time across all kingdoms of life. The tools are now in hand to begin to understand how important processes such as energy homeostasis and fuel utilization are coordinated to anticipate daily changes in environment caused by the rising and setting of the sun. A better understanding of the impact of circadian gene networks on nutrient balance at the molecular, cellular, and system levels promises to shed light on the emerging association between disorders of diabetes, obesity, sleep, and circadian timing.

Description: ▪ Abstract  Despite significant progress, deficiencies of iron and iodine remain major public health problems affecting ≥30% of the global population. These deficiencies often coexist in children. Recent studies have demonstrated that a high prevalence of iron deficiency among children in areas of endemic goiter may reduce the effectiveness of iodized salt programs. These findings argue strongly for improving iron status in areas of overlapping deficiency, not only to combat anemia but also to increase the efficacy of iodine prophylaxis. The dual fortification of salt with iodine and iron may prove to be an effective and sustainable method to accomplish these important goals.

Description: ▪ Abstract  Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.

Description: By 1950 the vitamins had been identified, but little was known of their functions. Beriberi, pellagra, and ariboflavinosis were disappearing, but kwashiorkor and/or marasmus were common in most developing countries. Requirements for protein were still uncertain, and those for essential amino acids or essential fatty acids were unknown. The author's contributions in the field of vitamins began in the 1950s and have been reported in more than 650 publications and in 20 books or monographs. These contributions include establishing the Institute of Nutrition of Central America and Panama, the Department of Nutrition and Food Science at the Massachusetts Institute of Technology, the World Hunger Program of the United Nations University, and the International Nutrition Foundation. His scientific contributions include identification of synergistic interactions of nutrition and infection, use of potassium iodate for fortifying crude moist salt, research in the epidemiology of kwashiorkor and marasmus, development of a successful low-cost protein-rich food for infants and young children, establishment of human protein requirements, and investigation of single-cell protein for food use.

Description: ▪ Abstract  In recent years, the number of proteins implicated in iron homeostasis has increased dramatically, and genetic causes have apparently been identified for the major disorders associated with tissue iron overload. These dramatic steps forward have transformed the way we look at iron-related disorders, particularly hemochromatosis. This review presents a concept of this disease that is based on this new knowledge and stems from the idea that, beyond their genetic diversities, all known hemochromatoses originate from the same metabolic error, the genetic disruption of human tendency for circulatory iron constancy. Hepcidin, the iron hormone, seems to hold a central pathogenic place in hemochromatosis, similar to insulin in diabetes: Genetically determined lack of hepcidin synthesis or activity may cause the disease.

Description: ▪ Abstract  Overweight and obesity are rapidly growing to epidemic proportions in the United States and globally. Since sustainable weight loss is only achieved by bariatric surgery, medicine has seen an explosion in the diversity and number of bariatric procedures performed over the past few years. Systematic studies of postoperative outcomes and investigations into the physiology and biology of weight loss provide a more comprehensive understanding of the sequelae of bariatric surgery. Adipose tissue is the predominant site of fat stores. Increasing obesity results in an overload of lipids within the body's natural storage sink (i.e., the adipocyte) followed by the necessary deposition of fat within ectopic sites such as muscle, liver, and pancreas. The resulting metabolic derangements are associated with insulin resistance, central obesity, and chronic inflammation as adipose tissue acts as an endocrine organ, producing and secreting a host of biologic mediators. Whereas there are conflicting data on the cardiovascular effects of peripheral, subcutaneous liposuction, malabsorptive bariatric procedures result almost universally in significant amelioration of insulin resistance, hypertension, dyslipidemia, and hepatic steatosis. Concomitant changes in adipocyte-derived hormones may provide mechanistic explanations to the observed improvements.

Description: ▪ Abstract  The benefits of specialty supplemented enteral diets administered to critically ill and critically injured patients and those undergoing major surgical procedures have been documented in a number of randomized prospective studies. It is unclear which nutrient or combination of nutrients causes the beneficial effects, but there are significant reductions in infectious complications depending upon the patient populations studied. It is imperative that the data be interpreted in the context of individual patient risk since specialty formulas appear most beneficial in patients at risk of subsequent complications or in those with significant pre-existing malnutrition. Although controversy exists regarding the use of specialty supplemented enteral diets in critically ill patients, they have been administered safely with minimal risk of adverse outcome in malnourished patients and in the critically ill and critically injured.

Description: Glutathione peroxidase-1 (GPX1) represents the first identified mammalian selenoprotein, and our understanding in the metabolic regulation and function of this abundant selenoenzyme has greatly advanced during the past decade. Selenocysteine insertion sequence–associating factors, adenosine, and Abl and Arg tyrosine kinases are potent, Se-independent regulators of GPX1 gene, protein, and activity. Overwhelming evidences have been generated using the GPX1 knockout and transgenic mice for the in vivo protective role of GPX1 in coping with oxidative injury and death mediated by reactive oxygen species. However, GPX1 exerts an intriguing dual role in reactive nitrogen species (RNS)-related oxidative stress. Strikingly, knockout of GPX1 rendered mice resistant to toxicities of drugs including acetaminophen and kainic acid, known as RNS inducers. Intracellular and tissue levels of GPX1 activity affect apoptotic signaling pathway, protein kinase phosphorylation, and oxidant-mediated activation of NFκB. Data are accumulating to link alteration or abnormality of GPX1 expression to etiology of cancer, cardiovascular disease, neurodegeneration, autoimmune disease, and diabetes. Future research should focus on the mechanism of GPX1 in the pathogeneses and potential applications of GPX1 manipulation in the treatment of these disorders.

Description: Creatine and phosphocreatine serve not only as an intracellular buffer for adenosine triphosphate, but also as an energy shuttle for the movement of high-energy phosphates from mitochondrial sites of production to cytoplasmic sites of utilization. The spontaneous loss of creatine and of phosphocreatine to creatinine requires that creatine be continuously replaced; this occurs by a combination of diet and endogenous synthesis. Vegetarians obtain almost no dietary creatine. Creatine synthesis makes major demands on the metabolism of glycine, arginine, and methionine. Large doses of creatine monohydrate are widely taken, particularly by athletes, as an ergogenic supplement; creatine supplements are also taken by patients suffering from gyrate atrophy, muscular dystrophy, and neurodegenerative diseases. Children with inborn errors of creatine synthesis or transport present with severe neurological symptoms and a profound depletion of brain creatine. It is evident that creatine plays a critical, though underappreciated, role in brain function.

Description: Autophagy is a process of cellular “self-eating” in which portions of cytoplasm are sequestered within double-membrane cytosolic vesicles termed autophagosomes. The autophagosome cargo is delivered to the lysosome, broken down, and the resulting amino acids recycled after release back into the cytosol. Autophagy occurs in all eukaryotes and can be up-regulated in response to various nutrient limitations. Under these conditions, autophagy may become essential for viability. In addition, autophagy plays a role in certain diseases, acting to prevent some types of neurodegeneration and cancer, and in the elimination of invading pathogens. We review the current information on the mechanism of autophagy, with a focus on its role in protein metabolism and intracellular homeostasis.

Description: ▪ Abstract  Choline is an essential nutrient needed for the structural integrity and signaling functions of cell membranes; for normal cholinergic neurotransmission; for normal muscle function; for lipid transport from liver; and it is the major source of methyl groups in the diet. Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain and spinal cord structure and function and influencing risk for neural tube defects and lifelong memory function. Choline is derived not only from the diet, but from de novo synthesis as well. Though many foods contain choline, there is at least a twofold variation in dietary intake in humans. When deprived of dietary choline, most men and postmenopausal women developed signs of organ dysfunction (fatty liver or muscle damage), while less than half of premenopausal women developed such signs. Aside from gender differences, there is significant variation in the dietary requirement for choline that can be explained by very common genetic polymorphisms.

Description: Caloric restriction (CR), the consumption of fewer calories without malnutrition, and reduced insulin and/or IGFI receptor signaling delay many age-related physiological changes and extend the lifespan of many model organisms. Here, we present and review microarray and biochemical studies indicating that the potent anticancer effects of CR and disrupted insulin/IGFI receptor signaling evolved as a byproduct of the role of many mitotic tissues as reservoirs of metabolic energy. We argue that the longevity effects of CR are derived from repeated cycles of apoptosis and autophagic cell death in mitotically competent tissues and protein turnover and cellular repair in postmitotic tissues. We review studies showing that CR initiated late in life can rapidly induce many of the benefits of lifelong CR, including its anticancer effects. We also discuss evidence from liver and heart indicating that many benefits of lifelong CR are recapitulated in mitotic and postmitotic tissues when CR is initiated late in life.

Description: The objective of this review is to evaluate the evidence for a link between maternal obesity and poor lactation performance. In nonhuman species, excess maternal fatness is deleterious for lactation and also for maternal health and survival. These effects occur during pregnancy and as milk production is beginning. They may result in poor growth and survival of the young. In women, there is a negative association between maternal obesity and the initiation as well as the continuation of breastfeeding. This appears to be derived from biological as well as sociocultural factors that are still poorly understood. Excessive gestational weight gain, complications of pregnancy and delivery, and the condition of the infant at birth may also contribute to this association. Given the increasingly high rates of obesity among women of reproductive age worldwide and the importance of breastfeeding for infant health, further study of this association is essential.

Description: ▪ Abstract  Research describing fatty acids as modulators of inflammation and immune responses abounds. Many of these studies have focused on one particular group of fatty acids, omega-3. The data from animal studies have shown that these fatty acids can have powerful anti-inflammatory and immunomodulatory activities in a wide array of diseases (e.g., autoimmunity, arthritis, and infection). However, the evidence from human trials is more equivocal. In this review, a historical framework for understanding how and why fatty acids may affect the immune system is provided. Second, highlights of two recent landmark reports from the Agency for Healthcare Research and Quality are presented. These reports critically evaluate the evidence from human clinical trials of omega-3 fatty acids and rheumatoid arthritis, asthma, and a few other immune-mediated diseases. Third, the data from human clinical trials investigating the impact of various bioactive fatty acids on ex vivo and in vivo immune response are reviewed. Limitations in experimental design and immune assays commonly used are discussed. The discordance between expectation and evidence in this field has been a disappointment. Recommendations for improving both animal-based and human studies are provided.

Description: ▪ Abstract  About one third of all pregnant women in the United States are obese. Maternal obesity at conception alters gestational metabolic adjustments and affects placental, embryonic, and fetal growth and development. Neural tube defects and other developmental anomalies are more common in infants born to obese women; these defects have been linked to poor glycemic control. Preeclampsia, a gestational disorder occurring more frequently in obese women, appears to be due to a subclinical inflammatory state that impairs early placentation and development of its blood supply. Fetal growth and development during the last half of pregnancy depends on maternal metabolic adjustments dictated by placental hormones and the subsequent oxygen and nutrient supply. Maternal obesity affects these metabolic adjustments as well. Basal metabolic rates are significantly higher in obese women, and maternal fat gain is lower, possibly in response to altered leptin function. The usual increase in insulin resistance seen in late pregnancy is enhanced in obese mothers, causing marked postprandial increases in glucose, lipids, and amino acids and excessive fetal exposure to fuel sources, which in turn increases fetal size, fat stores, and risk for disease postnatally. Impaired glucose tolerance, gestational diabetes, and hyperlipidemia are more common among obese mothers. To date, little attention has been given to the role of diet among obese women in preventing these problems. However, studies of women with impaired glucose tolerance show that replacing refined carbohydrates and saturated fat with complex, low-glycemic carbohydrates and polyunsaturated fatty acids improves metabolic homeostasis and pregnancy outcomes. Thus, current dietary guidelines regarding the amount and type of carbohydrates and fat for nonpregnant women seem appropriate for pregnant women as well.

Description: The liver plays a key role for the maintenance of blood glucose homeostasis under widely changing physiological conditions. In the overnight fasted state, breakdown of hepatic glycogen and synthesis of glucose from lactate, amino acids, glycerol, and pyruvate contribute about equally to hepatic glucose production. Postprandial glucose uptake by the liver is determined by the size of the glucose load reaching the liver, the rise in insulin concentration, and the route of glucose delivery. Hepatic glycogen stores are depleted within 36 to 48 hours of fasting, but gluconeogenesis continues to provide glucose for tissues with an obligatory glucose requirement. Glucose output from the liver increases during exercise; during short-term intensive exertion, hepatic glycogenolysis is the primary source of extra glucose for skeletal muscle, and during prolonged exercise, hepatic gluconeogenesis becomes gradually more important in keeping with falling insulin and rising glucagon levels. Type 1 diabetes is accompanied by diminished hepatic glycogen stores, augmented gluconeogenesis, and increased basal hepatic glucose production in proportion to the severity of the diabetic state. The hyperglycemia of type 2 diabetes is in part caused by an overproduction of glucose from the liver that is secondary to accelerated gluconeogenesis.

Description: This review summarizes information regarding how human energy metabolism is affected by pregnancy, and current estimates of energy requirements during pregnancy are presented. Such estimates can be calculated using either increases in basal metabolic rate (BMR) or increases in total energy expenditure (TEE). The two modes of calculation give similar results for a complete pregnancy but different distributions of energy requirements in the three trimesters. Recent information is presented regarding the effect of pregnancy on BMR, TEE, diet-induced thermogenesis, and physical activity. The validity of energy intake (EI) data recently assessed in well-nourished pregnant women was evaluated using information regarding energy metabolism during pregnancy. The results show that underreporting of EI is common during pregnancy and indicate that additional longitudinal studies, taking the total energy budget during pregnancy into account, are needed to satisfactorily define energy requirements during the three trimesters of gestation.

Description: Dietary proteins and amino acids are important modulators of glucose metabolism and insulin sensitivity. Although high intake of dietary proteins has positive effects on energy homeostasis by inducing satiety and possibly increasing energy expenditure, it has detrimental effects on glucose homeostasis by promoting insulin resistance and increasing gluconeogenesis. Varying the quality rather than the quantity of proteins has been shown to modulate insulin resistance induced by Western diets and has revealed that proteins derived from fish might have the most desirable effects on insulin sensitivity. In vitro and in vivo data also support an important role of amino acids in glucose homeostasis through modulation of insulin action on muscle glucose transport and hepatic glucose production, secretion of insulin and glucagon, as well as gene and protein expression in various tissues. Moreover, amino acid signaling is integrated by mammalian target of rapamycin, a nutrient sensor that operates a negative feedback loop toward insulin receptor substrate 1 signaling, promoting insulin resistance for glucose metabolism. This integration suggests that modulating dietary proteins and the flux of circulating amino acids generated by their consumption and digestion might underlie powerful new approaches to treat various metabolic diseases such as obesity and diabetes.

Description: ▪ Abstract  Severe iodine deficiency was the main cause of endemic goiter and cretinism. Most of the previously iodine-deficient areas are now supplemented, mainly with iodized salt. The geographical distribution of severe endemic areas has been progressively reduced, and at present, approximately 200 million people living in remote places are still at risk of severe iodine deficiency. International public health programs should be focused first on reaching these populations, and second on auditing and monitoring the operational work of supplementation programs. This second point is essential to prevent iodine-induced hyperthyroidism or interruptions of iodine supplement distribution, which could be catastrophic for the fetus and the young infant. Echography brings a complementary tool to clinical assessment of goiter by palpation. Inductively coupled plasma–mass spectrometry brings at least a definitive gold standard for iodine measurement and thyroid hormone measurement. Thiocyanate overload has been clearly documented as a goitrogen in Central Africa, and when associated with selenium deficiency, it may be included as risk factor for endemic myxedematous cretinism. Variable exposure to different environmental risk factors is likely the explanation of the variable distribution of two types of endemic cretinism (neurological and myxedematous), and the clinical overlap of the pathogeny of both syndromes is more important than previously described. It is possible that Kashin-Beck osteoarthropathy is another evanescent endemic disease that will disappear with the correction of iodine deficiency.

Description: Evolutionary anthropological and ethnographic studies are used to develop a general conceptual framework for understanding prehistoric, historic, and contemporary variation in human lactation and complementary feeding patterns. Comparison of similarities and differences in human and nonhuman primate lactation biology suggests humans have evolved an unusually flexible strategy for feeding young. Several lines of indirect evidence are consistent with a hypothesis that complementary feeding evolved as a facultative strategy that provided a unique adaptation for resolving tradeoffs between maternal costs of lactation and risk of poor infant outcomes. This evolved flexibility may have been adaptive in the environments in which humans evolved, but it creates potential for mismatch between optimal and actual feeding practices in many contemporary populations.

Description: In the past several years, tremendous progress has been achieved with the discovery and characterization of vertebrate taste receptors from the T1R and T2R families, which are involved in recognition of bitter, sweet, and umami taste stimuli. Individual differences in taste, at least in some cases, can be attributed to allelic variants of the T1R and T2R genes. Progress with understanding how T1R and T2R receptors interact with taste stimuli and with identifying their patterns of expression in taste cells sheds light on coding of taste information by the nervous system. Candidate mechanisms for detection of salts, acids, fat, complex carbohydrates, and water have also been proposed, but further studies are needed to prove their identity.

Description: Extensive human epidemiologic and animal model data indicate that during critical periods of prenatal and postnatal mammalian development, nutrition and other environmental stimuli influence developmental pathways and thereby induce permanent changes in metabolism and chronic disease susceptibility. The biologic mechanisms underlying this “developmental origins hypothesis” are poorly understood. This review focuses on the likely involvement of epigenetic mechanisms in the developmental origins of health and disease (DOHaD). We describe permanent effects of transient environmental influences on the developmental establishment of epigenetic gene regulation and evidence linking epigenetic dysregulation with human disease. We propose a definition of “epigenetic epidemiology” and delineate how this emerging field provides a basis from which to explore the role of epigenetic mechanisms in DOHaD. We suggest strategies for future human epidemiologic studies to identify causal associations between early exposures, long-term changes in epigenetic regulation, and disease, which may ultimately enable specific early-life interventions to improve human health.

Description: ▪ Abstract  Hepcidin, a peptide hormone made in the liver, is the principal regulator of systemic iron homeostasis. Hepcidin controls plasma iron concentration and tissue distribution of iron by inhibiting intestinal iron absorption, iron recycling by macrophages, and iron mobilization from hepatic stores. Hepcidin acts by inhibiting cellular iron efflux through binding to and inducing the degradation of ferroportin, the sole known cellular iron exporter. Synthesis of hepcidin is homeostatically increased by iron loading and decreased by anemia and hypoxia. Hepcidin is also elevated during infections and inflammation, causing a decrease in serum iron levels and contributing to the development of anemia of inflammation, probably as a host defense mechanism to limit the availability of iron to invading microorganisms. At the opposite side of the spectrum, hepcidin deficiency appears to be the ultimate cause of most forms of hemochromatosis, either due to mutations in the hepcidin gene itself or due to mutations in the regulators of hepcidin synthesis. The emergence of hepcidin as the pathogenic factor in most systemic iron disorders should provide important opportunities for improving their diagnosis and treatment.

Description: Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for use by other organs as energy substrates. In response to changes in nutritional state, lipolysis rates are precisely regulated through hormonal and biochemical signals. These signals modulate the activity of lipolytic enzymes and accessory proteins, allowing for maximal responsiveness of adipose tissue to changes in energy requirements and availability. Recently, a number of novel adipocyte triacylglyceride lipases have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte lipolysis. We have also begun to better appreciate the role of a number of nonenzymatic proteins that are critical to triacylglyceride breakdown. This review provides an overview of key mediators of lipolysis and the regulation of this process by changes in nutritional status and nutrient intakes.

Description: ▪ Abstract  It is now established that dietary n-3 polyunsaturated fatty acids (PUFAs) are involved in health promotion and disease prevention, particularly those traditionally derived from marine sources (e.g., eicosapentaenoic acid and docosahexaenoic acid). A number of organizations have made specific recommendations for the general population to increase their intakes of these nutrients. In response to and along with these recommendations, n-3 PUFAs are being incorporated into nontraditional food sources because of advances in the technology to safely enrich/fortify our food supply. Fatty acid compositions of traditional oils (e.g., canola and soybean) are being genetically modified to deliver more highly concentrated sources of n-3 PUFA. The advent of algal sources of docosahexaenoic acid provides one of the few terrestrial sources of this fatty acid in a concentrated form. All of this is possible because of newer technologies (microencapsulation) and improved processing techniques that ensure stability and preserve the integrity of these unstable fatty acids.

Description: ▪ Abstract  Cancer metastases (spread to distant organs from the primary tumor site) signify systemic, progressive, and essentially incurable malignant disease. Anorexia and wasting develop continuously throughout the course of incurable cancer. Overall, in Westernized countries nearly exactly half of current cancer diagnoses end in cure and the other half end in death; thus, cancer-associated cachexia has a high prevalence. The pathophysiology of cancer-associated cachexia has two principal components: a failure of food intake and a systemic hypermetabolism/hypercatabolism syndrome. The superimposed metabolic changes result in a rate of depletion of physiological reserves of energy and protein that is greater than would be expected based on the prevailing level of food intake. These features indicate a need for nutritional support, metabolic management, and a clear appreciation of the context of life-limiting illness.

Description: Dietary and supplemental vitamin E is absorbed and delivered to the liver, but of the various antioxidants with vitamin E activity, only α-tocopherol is preferentially recognized by the α-tocopherol transfer protein (α-TTP) and is transferred to plasma, while the other vitamin E forms (e.g., γ-tocopherol or tocotrienols) are removed from the circulation. Hepatic α-TTP is required to maintain plasma and tissue α-tocopherol concentrations. The liver is the master regulator of the body's vitamin E levels in that it not only controls α-tocopherol concentrations, but also appears to be the major site of vitamin E metabolism and excretion. Vitamin Es are metabolized similarly to xenobiotics; they are initially ω-oxidized by cytochrome P450s, undergo several rounds of β-oxidation, and then are conjugated and excreted. As a result of these various mechanisms, liver α-tocopherol and other vitamin E concentrations are closely regulated; thus, any potential adverse vitamin E effects are limited.

Description: Humans have a large variability in body fat distribution, which has tremendous implications for metabolic health. Obese individuals with an upper-body-fat distribution have increased health complications such as dyslipidemia, hypertension, insulin resistance, and type 2 diabetes in comparison with lower-body-obese individuals. Additionally, females have more body fat, a greater proportion of fat in their lower body, and much less visceral fat than do lean males at the same body mass index. The reasons for these differences in body fat distribution have not been clearly identified but could be important. Herein we review what has been learned about regional differences in triglyceride storage capacity and lipolysis as they relate to the causes and consequences of regional fat accumulation. Both sex and site differences in regional fat storage have been described. In contrast, with the exception of variations between men and women in the contribution of visceral adipose tissue to hepatic FFA delivery, most studies have failed to show important sex differences in regional lipolysis in vivo.

Description: ▪ Abstract  The regulation of energy homeostasis is critical for normal physiology and survival. Energy flux must be rigorously monitored and adjusted to ensure that fuel intake and expenditure remain within acceptable limits. The central nervous system (CNS) is, in large part, responsible for conducting this energy-monitoring function and for integrating the numerous inputs. It has become evident that neurons of the CNS monitor and respond to levels of metabolic intermediates that reflect peripheral energy status. Intermediates in the fatty acid biosynthetic pathway have been implicated as hypothalamic signaling mediators that sense and respond to changes in circulating fuels. Genetic and pharmacologic manipulation of the enzymes of fatty acid metabolism have led to the hypothesis that neuronal metabolic intermediates affect neural outputs that modify both feeding behavior and energy expenditure. This review focuses on the regulatory roles of these enzymes and intermediates in the regulation of food intake and energy balance.