This paper reviews age differences in emotion processing and how they may relate to age-related changes in the brain. Compared with younger adults, older adults react less to negative situations, ignore irrelevant negative stimuli better, and remember relatively more positive than negative information. Older adults’ ability to insulate their thoughts and emotional reactions from negative situations is likely due to a number of factors, such as being less influenced by interoceptive cues, selecting different emotion regulation strategies, having less age-related decline in prefrontal regions associated with emotional control than in other prefrontal regions, and engaging in emotion regulation strategies as a default mode in their everyday lives. Healthy older adults’ avoidance of processing negative stimuli may contribute to their well-maintained emotional well-being. However, when cardiovascular disease leads to additional prefrontal white matter damage, older adults have fewer cognitive control mechanisms available to regulate their emotions, making them more vulnerable to depression. In general, while age-related changes in the brain help shape emotional experience, shifts in preferred strategies and goal priorities are also important influences.
emotion regulation; aging; fMRI; ventromedial prefrontal cortex; amygdala
The caudal gene family (in mice and humans Cdx1, Cdx2, and Cdx4) has been studied extensively during early development as regulators of axial elongation and antero-posterior patterning. In the adult, Cdx1 and Cdx2, but not Cdx4, have been intensively studied for their function in intestinal tissue homeostasis and the pathogenesis of gastrointestinal cancers. Involvement in embryonic hematopoiesis was first demonstrated in zebrafish, where cdx genes render posterior lateral plate mesoderm competent to respond to genes specifying hematopoietic fate, and compound mutations in cdx genes thus result in a bloodless phenotype. Parallel studies performed in zebrafish embryos and murine embryonic stem cells (ESC) delineate conserved pathways between fish and mammals, corroborating a BMP/Wnt-Cdx-Hox axis during blood development that can be employed to augment derivation of blood progenitors from pluripotent stem cells in vitro. The molecular regulation of Cdx genes appears complex, as more recent data suggest involvement of non-Hox–related mechanisms and the existence of auto- and cross-regulatory loops governed by morphogens. Here we will review the role of Cdx genes during hematopoietic development by comparing effects in zebrafish and mice and discuss their participation in malignant blood diseases.
Cdx; hematopoiesis; leukemia; Hox; blood development
The engineering of insulin analogs represents a triumph of structure-based protein design. A framework has been provided by structures of insulin hexamers. Containing a zinc-coordinated trimer of dimers, such structures represent a storage form of the active insulin monomer. Initial studies focused on destabilization of subunit interfaces. Because disassembly facilitates capillary absorption, such targeted destabilization enabled development of rapid-acting insulin analogs. Converse efforts were undertaken to stabilize the insulin hexamer and promote higher-order self-assembly within the subcutaneous depot toward the goal of enhanced basal glycemic control with reduced risk of hypoglycemia. Current products either operate through isoelectric precipitation (insulin glargine, the active component of Lantus®; Sanofi-Aventis) or employ an albumin-binding acyl tether (insulin detemir, the active component of Levemir®; Novo-Nordisk). To further improve pharmacokinetic properties, modified approaches are presently under investigation. Novel strategies have recently been proposed based on subcutaneous supramolecular assembly coupled to (a) large-scale allosteric reorganization of the insulin hexamer (the TR transition), (b) pH-dependent binding of zinc ions to engineered His-X3-His sites at hexamer surfaces, or (c) the long-range vision of glucose-responsive polymers for regulated hormone release. Such designs share with wild-type insulin and current insulin products a susceptibility to degradation above room temperature, and so their delivery, storage, and use require the infrastructure of an affluent society. Given the global dimensions of the therapeutic supply chain, we envisage that concurrent engineering of ultra-stable protein analog formulations would benefit underprivileged patients in the developing world.
protein design; bottom-up; nanotechnology; zinc finger; hormone
Heteromorphic sex chromosomes, where one sex has two different types of sex chromosomes, face very different evolutionary consequences than do the autosomes. Two important features of sex chromosomes arise from being present in only copy in one of the sexes: dosage compensation and the meiotic silencing of sex chromosomes. Other differences arise because sex chromosomes spend unequal amounts of time in each sex. Thus, the impact of evolutionary processes (mutation, selection, genetic drift, and meiotic drive) differs substantially between each sex chromosome, and between the sex chromosomes and the autosomes. Sex chromosomes also play a disproportionate role in Haldane’s rule and other important patterns related to hybrid incompatibility, and thus speciation. We review the consequences of sex chromosomes on hybrid incompatibility. A theme running through this review is that epigenetic processes, notably those related to chromatin, may be more important to the evolution of sex chromosomes and the evolution of hybrid incompatibility than previously recognized.
sex chromosomes; hybrid incompatibility; speciation; evolution
Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA–associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA–associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA–associated HT in stroke.
rt-PA; Sur1; glyburide; MMP-9; cerebral ischemia; stroke
The analysis of complex genetic traits, including mapping and identification of causative genes, has long been an enigma of genetic biology, whether in the animal sciences or in medical sciences. Traits of agricultural interest and traits of medical interest are often under the influence of both environmental factors and multiple genes, each with modest contributions to the total variance in the trait. Although the number of known mutations underlying complex traits is still relatively small, advances in genomics have greatly enhanced traditional pathways to their analysis and gene mining. The candidate gene approach, linkage analysis, and association studies are all significantly more powerful with recent advances in genome mapping, sequencing, and analysis of individual variation. Avenues to gene discovery are discussed with emphasis on genome wide association studies (GWAS) and the use of single nucleotide polymorphisms (SNPs) as revealed by increasingly powerful commercially available microarrays.
genomics; complex traits; animals, disease resistance; GWAS
“Diabetes and Oral Disease: Implications for Health Professionals” was a one-day conference convened by the Columbia University College of Dental Medicine, the Columbia University College of Physicians and Surgeons, and the New York Academy of Sciences on May 4, 2011in New York City. The program included an examination of the bidirectional relationship between oral disease and diabetes and the inter-professional working relationships for the care of people who have diabetes. The overall goal of the conference was to promote discussion among the healthcare professions who treat people with diabetes, encourage improved communication and collaboration among them and ultimately, improve patient management of the oral and overall effects of diabetes. Attracting over 150 members of the medical and dental professions from eight different countries, the conference included speakers from academia and government and was divided into four sessions. This report summarizes the scientific presentations of the event.
diabetes; oral disease; meeting report
Leptin, an adipocyte-derived cytokine, crosses the blood–brain barrier to act on many regions of the central nervous system (CNS). It participates in the regulation of energy balance, inflammatory processes, immune regulation, synaptic formation, memory condensation, and neurotrophic activities. This review focuses on the newly identified actions of leptin on astrocytes. We first summarize the distribution of leptin receptors in the brain, with a focus on the hypothalamus, where the leptin receptor is known to mediate essential feeding suppression activities, and on the hippocampus, where leptin facilitates memory, reduces neurodegeneration, and plays a dual role in seizures. We will then discuss regulation of the nonneuronal leptin system in obesity. Its relationship with neuronal leptin signaling is illustrated by in vitro assays in primary astrocyte culture and by in vivo studies on mice after pretreatment with a glial metabolic inhibitor or after cell-specific deletion of intracellular signaling leptin receptors. Overall, the glial leptin system shows robust regulation and plays an essential role in obesity. Strategies to manipulate this nonneuronal leptin signaling may have major clinical impact.
leptin; CNS; obesity; astrocytes; blood–brain barrier
Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders.
autonomic nervous system; brain-derived neurotrophic factor; cognition; diabetes; exercise; neurogenesis; synaptic plasticity
In the last 50 years, the average self-reported sleep duration in the United States has decreased by 1.5–2 hours in parallel with an increasing prevalence of obesity and diabetes. Epidemiological studies and meta-analyses report a strong relationship between short or disturbed sleep, obesity, and abnormalities in glucose metabolism. This relationship is likely to be bidirectional and causal in nature, but many aspects remain to be elucidated. Sleep and the internal circadian clock influence a host of endocrine parameters. Sleep curtailment in humans alters multiple metabolic pathways, leading to more insulin resistance, possibly decreased energy expenditure, increased appetite, and immunological changes. On the other hand, psychological, endocrine, and anatomical abnormalities in individuals with obesity and/or diabetes can interfere with sleep duration and quality, thus creating a vicious cycle. In this review, we address mechanisms linking sleep with metabolism, highlight the need for studies conducted in real-life settings, and explore therapeutic interventions to improve sleep, with a potential beneficial effect on obesity and its comorbidities.
sleep; obesity; insulin resistance; diabetes; appetite
The blood–brain barrier (BBB) regulates the blood-to-brain passage of gastrointestinal hormones, thus informing the brain about feeding and nutritional status. Disruption of this communication results in dysregulation of feeding and body weight control. Leptin, which crosses the BBB to inform the CNS about adiposity, provides an example. Impaired leptin transport, especially coupled with central resistance, results in obesity. Various substances/conditions regulate leptin BBB transport. For example, triglycerides inhibit leptin transport. This may represent an evolutionary adaptation in that hypertriglyceridemia occurs during starvation. Inhibition of leptin, an anorectic, during starvation could have survival advantages. The large number of other substances that influence feeding is explained by the complexity of feeding. This complexity includes cognitive aspects; animals in the wild are faced with cost/benefit analyses to feed in the safest, most economical way. This cognitive aspect partially explains why so many feeding substances affect neurogenesis, neuroprotection, and cognition. The relation between triglycerides and cognition may be partially mediated through triglyceride's ability to regulate the BBB transport of cognitively active gastrointestinal hormones such as leptin, insulin, and ghrelin.
Blood–brain barrier; leptin; feeding; cognition, obesity; central nervous system; evolution
Several clinical and experimental lines of evidence have highlighted the detrimental effects of visceral adipose tissue excess on cardiometabolic parameters. Besides, recent findings have shown the effects of gluco-and mineralocorticoid hormones on adipose tissue and have also underscored the interplay existing between such adrenal steroids and their respective receptors in the modulation of adipose tissue biology. While the fundamental role played by glucocorticoids on adipocyte differentiation and storage was already well known, the relevance of the mineralocorticoids in the physiology of the adipose organ is of recent acquisition. The local and systemic renin–angiotensin–aldosterone system (RAAS) acting on adipose tissue seems to contribute to the development of the cardiometabolic phenotype so that its modulation can have deep impact on human health. A better understanding of the pathophysiology of the adipose organ is of crucial importance in order to identify possible therapeutic approaches that can avoid the development of such cardiovascular and metabolic sequelae.
adipose tissue; glucocorticoids; mineralocorticoids
Resistance to obesity is becoming an exception rather than the norm, and understanding mechanisms that lead some to remain lean in spite of an obesigenic environment is critical if we are to find new ways to reverse this trend. Levels of energy intake and physical activity both contribute to body weight management, but it is challenging for most to adopt major long-term changes in either factor. Physical activity outside of formal exercise, also referred to as activity of daily living, and in stricter form, spontaneous physical activity (SPA), may be an attractive modifiable variable for obesity prevention. In this review, we discuss individual variability in SPA and NEAT (nonexercise thermogenesis, or the energy expended by SPA) and its relationship to obesity resistance. The hypothalamic neuropeptide orexin (hypocretin) may play a key role in regulating SPA and NEAT. We discuss how elevated orexin signaling capacity, in the context of a brain network modulating SPA, may play a major role in defining individual variability in SPA and NEAT. Greater activation of this SPA network leads to a lower propensity for fat mass gain and therefore may be an attractive target for obesity prevention and therapy.
orexin; obesity; spontaneous physical activity; nonexercise activity thermogenesis; energy expenditure
Obesity, particularly the abdominal phenotype, has been ascribed to an individual maladaptation to chronic environmental stress exposure mediated by a dysregulation of related neuroendocrine axes. Alterations in the control and action of the hypothalamic–pituitary–adrenal axis play a major role in this context, with the participation of the sympathetic nervous system. The ability to adapt to chronic stress may differ according to sex, with specific pathophysiological events leading to the development of stress-related chronic diseases. This seems to be influenced by the regulatory effects of sex hormones, particularly androgens. Stress may also disrupt the control of feeding, with some differences according to sex. Finally, the amount of experimental data in both animals and humans may help to shed more light on specific phenotypes of obesity, strictly related to the chronic exposure to stress. This challenge may potentially imply a different pathophysiological perspective and, possibly, a specific treatment.
cortisol; androgens; stress; obesity
Increased availability of tasty, energy-dense foods has been blamed as a major factor in the alarmingly high prevalence of obesity, diabetes, and metabolic disease, even in young age. A heated debate has started as to whether some of these foods should be considered addictive, similar to drugs and alcohol. One of the main arguments for food addiction is the similarity of the neural mechanisms underlying reward generation by foods and drugs. Here, we will discuss how food intake can generate reward and how behavioral and neural reward functions are different in obese subjects. Because most studies simply compare lean and obese subjects, it is not clear whether predisposing differences in reward functions cause overeating and weight gain, or whether repeated exposure or secondary effects of the obese state alter reward functions. While studies in both rodents and humans demonstrate preexisting differences in reward functions in the obese, studies in rodent models using calorie restriction and gastric bypass surgery show that some differences are reversible by weight loss and are therefore secondary to the obese state.
obesity; diabetes; palatable food; hedonic eating; food addiction; liking; wanting; motivation; mesolimbic dopamine system
Chromatin remodeling is a prerequisite for most nuclear functions, including transcription, silencing, and DNA replication. Accumulating evidence shows that many physiological processes require highly sophisticated events of chromatin remodeling. Recent findings have linked cellular metabolism, epigenetic state, and the circadian clock. The control of a large variety of neuronal, behavioral, and physiological responses follows diurnal rhythms. This is possible through a transcriptional regulatory network that governs a significant portion of the genome. The harmonic oscillation of gene expression is paralleled by critical events of chromatin remodeling that appear to provide specificity and plasticity in circadian regulation. Accumulating evidence shows that the circadian epigenome appears to share intimate links with cellular metabolic processes. These notions indicate that the circadian epigenome might integrate tissue specificity within biological pacemakers, bridging systems physiology to metabolic control. This review highlights several advances related to the circadian epigenome, the contribution of NAD+ as a critical signaling metabolite, and its effects on epigenetic state, followed by more recent reports on circadian metabolomics analyses.
circadian clock; epigenetics; metabolism
In modern life, children are unlikely to obtain sufficient or regular sleep and waking schedules. Inadequate sleep affects the regulation of homeostatic and hormonal systems underlying somatic growth, maturation, and bioenergetics. Therefore, assessments of the obesogenic lifestyle, including as dietary and physical activity, need to be coupled with accurate evaluation of sleep quality and quantity, and coexistence of sleep apnea. Inclusion of sleep as an integral component of research studies on childhood obesity should be done as part of the study planning process. Although parents and health professionals have quantified normal patterns of activities in children, sleep has been almost completely overlooked. As sleep duration in children appears to have declined, reciprocal obesity rates have increased. Also, increases in pediatric obesity rates have markedly increased the risk of obstructive sleep apnea syndrome (OSAS) in children. Obesity and OSAS share common pathways underlying end-organ morbidity, potentially leading to reciprocal amplificatory effects. The relative paucity of data on the topics covered in the perspective below should serve as a major incentive toward future research on these critically important concepts.
sleep; obesity; children; sleep apnea
Many animal and human studies show counterintuitive effects of environmental influences on energy balance and life span. Relatively low social and/or economic status seems to be associated with and produce greater adiposity, and reduced provision (e.g., caloric restriction) of food produces greater longevity. We suggest that a unifying factor may be perceptions of the environment as “energetically insecure” and inhospitable to reproduction, which may in turn provoke adiposity-increasing and longevity-extending mechanisms. We elaborate on two main aspects of resources (or the perceptions thereof) on body weight and longevity. We first discuss the effects of social dominance on body weight regulation in human and animal models. Second, we examine models of the interactions between caloric restriction, body composition, and longevity. Finally, we put forth a relational model of the influences of differing environmental cues on body composition and longevity.
hunger; fatness; caloric restriction; social status; longevity
The strategy of antigenic variation is to present a constantly changing population phenotype that enhances parasite transmission, through evasion of immunity arising within, or existing between, host animals. Trypanosome antigenic variation occurs through spontaneous switching among members of a silent archive of many hundreds of variant surface glycoprotein (VSG) antigen genes. As with such contingency systems in other pathogens, switching appears to be triggered through inherently unstable DNA sequences. The archive occupies subtelomeres, a genome partition that promotes hypermutagenesis and, through telomere position effects, singular expression of VSG. Trypanosome antigenic variation is augmented greatly by the formation of mosaic genes from segments of pseudo-VSG, an example of implicit genetic information. Hypermutation occurs apparently evenly across the whole archive, without direct selection on individual VSG, demonstrating second-order selection of the underlying mechanisms. Coordination of antigenic variation, and thereby transmission, occurs through networking of trypanosome traits expressed at different scales from molecules to host populations.
genome hyperevolution; antigenic variation; parasite; trypanosome; subtelomere
Obesity is an established risk and progression factor for many cancers. In the United States more than one-third of adults, and nearly one in five children, are currently obese. Thus, a better understanding of the mechanistic links between obesity and cancer is urgently needed to identify intervention targets and strategies to offset the procancer effects of obesity. This review synthesizes the evidence on key biological mechanisms underlying the obesity–cancer association, with particular emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and perturbations in the tumor microenvironment. These interrelated pathways and processes represent mechanistic targets for disrupting the obesity–cancer link.
obesity; cancer; growth factors; inflammation; microenvironment
Macrophage migration inhibitory factor (MIF) is a unique protein that participates in inflammation, immune responses, and cell growth. An array of in vitro and in vivo experiments has demonstrated that MIF is profoundly involved in the pathogenesis of acute and chronic inflammatory disorders, such as inflammatory bowel disease (IBD). Blockade of MIF bioactivities by either neutralizing anti-MIF antibodies or antagonists prevents inflammatory cytokine cascade, which strongly suggests that an anti-MIF therapeutic strategy is feasible for treatment of IBD. Recently, we developed a new therapeutic approach for IBD by administration of antisense MIF oligonucleotides in conjugation with schizophyllan (SPG), a member of the glucan family. SPG specifically binds Dectin-1 expressed in antigen-presenting cells (APCs), and the antisense MIF/SPG complex is incorporated into the cells. In in vivo experiments of colitis models in mice, we found that intraperitoneal administration of the complex ameliorated the clinical signs of colitis and improved the histological scores. This novel therapy designed to knock down the MIF production in APCs is expected to be clinically applicable for the treatment of IBD.
β-(1–3)-glucan; Crohn’s disease; Dectin-1; inflammatory bowel disease; macrophage migration inhibitory factor; ulcerative colitis
Interferon tau (IFNT), a novel multifunctional type I interferon secreted by
trophectoderm, is the pregnancy recognition signal in ruminants that also has
antiviral, antiproliferative, and immunomodulatory bioactivities. IFNT, with
progesterone, affects availability of the metabolic substrate in the uterine
lumen by inducing expression of genes for transport of select nutrients into the
uterine lumen that activate mammalian target of rapamycin (mTOR) cell signaling
responsible for proliferation, migration, and protein synthesis by conceptus
trophectoderm. As an immunomodulatory protein, IFNT induces an anti-inflammatory
state affecting metabolic events that decrease adiposity and
glutamine:fructose-6-phosphate amidotransferase 1 activity, while increasing
insulin sensitivity, nitric oxide production by endothelial cells, and brown
adipose tissue in rats. This short review focuses on effects of IFNT and
progesterone affecting transport of select nutrients into the uterine lumen to
stimulate mTOR cell signaling required for conceptus development, as well as
effects of IFNT on the immune system and adiposity in rats with respect to its
potential therapeutic value in reducing obesity.
amino acids; fat; glucose; interferon tau; pregnancy; uterus
Living organisms are continuously exposed to environmental pollutants. Because of its critical location, the skin is a major interface between the body and the environment and provides a biological barrier against an array of chemical and physical environmental pollutants. The skin can be defined as our first defense against the environment because of its constant exposure to oxidants, including ultraviolet (UV) radiation and other environmental pollutants such as diesel fuel exhaust, cigarette smoke (CS), halogenated hydrocarbons, heavy metals, and ozone (O3). The exposure to environmental pro-oxidant agents leads to the formation of reactive oxygen species (ROS) and the generation of bioactive molecules that can damage skin cells. This short review provides an overview of the effects and mechanisms of action of CS, O3, and UV on cutanous tissues.
ozone; cigarette smoke; skin
Feedback control of deep brain stimulation (DBS) in Parkinson's disease has great potential to improve efficacy, reduce side effects, and decrease the cost of treatment. In this, the timing and intensity of stimulation are titrated according to biomarkers that capture current clinical state. Stimulation may be at standard high frequency or intelligently patterned to directly modify specific pathological rhythms. The search for and validation of appropriate feedback signals are therefore crucial. Signals recorded from the DBS electrode currently appear to be the most promising source of feedback. In particular, beta-frequency band oscillations in the local field potential recorded at the stimulation target may capture variation in bradykinesia and rigidity across patients, but this remains to be confirmed within patients. Biomarkers that reliably reflect other impairments, such as tremor, also need to be established. Finally, whether brain signals are causally important needs to be established before stimulation can be specifically patterned rather than delivered at empirically defined high frequency.
Parkinson's; DBS; feedback control; LFP; beta