Scientific interest in the relationship between cognition and action has increased markedly in the past several years, fueled by the discovery of mirror neurons in monkey prefrontal and parietal cortex and by the emergence of a movement in cognitive psychology, termed the embodied cognition framework, which emphasizes the role of simulation in cognitive representations. Guided by a functional neuroanatomic model called the Two Action Systems account, which posits numerous points of differentiation between structure- and function-based actions, we focus on two of the major issues under recent scrutiny: the relationship between representations for action production and recognition, and the role of action in object representations. We suggest that mirror neurons in humans are not critical for full action understanding, and that only function-based (and not structure-based) action is a component of embodied object concepts.
apraxia; praxis; objects; attention; dorso-dorsal; dorso-ventral
The immune toxicity of the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to as dioxin, has been studied for over 35 years but only recently has the profound immune suppression induced by TCDD exposure been linked to induction of regulatory T cells (Tregs). The effects of TCDD are mediated through its binding to the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. The subsequent AHR-dependent effects on immune responses are determined by the cell types involved, their activation status, and the type of antigenic stimulus. Collectively, studies indicate that TCDD inhibits CD4+ T cell differentiation into T helper (Th)1, Th2, and Th17 effector cells, while inducing Foxp3-negative and/or preserving Foxp3+ Tregs. Although it is not yet clear how activation of AHR by TCDD induces Tregs, there is a potential therapeutic role for alternative AHR ligands in the treatment of immune-mediated disorders.
2,3,7,8 tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; regulatory T cells; dendritic cells; indoleamine 2,3-dioxygenase; Foxp3; NF-κB
Signaling by H2O2, α,β-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (HNE) and related chemical species, is thought to differ from signaling by other second messengers because the oxidants and other electrophiles can readily undergo nonenzymatic reactions and are therefore classified as “reactive.” This brief review will describe how and when the chemistry of signaling is similar or differs from classic second messengers, such as cyclic AMP, or posttranslational signaling, such as farnesylation or ubiquitination. The chemistry of cysteine provides a common factor that underlies signaling by H2O2 and HNE. Nonetheless, as H2O2 and HNE are rapidly metabolized in vivo, spatial considerations are extremely important in their actions. Therefore, the locations of sources of H2O2 and α,β-unsaturated aldehydes, the NADPH oxidases, mitochondria, membrane lipids, and redox cycling toxicants, as well as their targets, are key factors. The activation of the JNK pathway by HNE and endogenously generated H2O2 illustrates these principles.
hydrogen peroxide; superoxide; 4-hydroxynonenal; thiol; thiolate; protein tyrosine phosphatase; glutathionylation; thioredoxin
Epigenetics holds promise to explain some puzzles concerning the risk and course of psychiatric disorders. Epigenetic information is essential as a set of operating instructions for the genome, which is heritable with DNA. The epigenetic regulation of gene expression can plausibly be influenced by the environment of one’s ancestors, prenatal exposures, and by early life events. Some epigenetic mechanisms may alter neurophysiology throughout life by programming gene expression, perhaps in anticipation of certain life experiences. These epigenetic signals are only meta-stable and may be perturbed by stochastic events, errors, or by environmental toxins. This introduction considers the possibility that epigenetic change that may occur as paternal age advances or during fetal adversity may be causally related to the susceptibility for schizophrenia.
epigenetics; reproduction; genetics; paternal age; schizophrenia
A wide range of parameters influence allosteric communications between the α- and β-subunits of the Trp synthase α2β2 multienzyme complex with L-Ser, including monovalent cations, pH, temperature, ligands, organic solvents, and hydrostatic pressure. The conformational change from closed to open can be monitored either by absorbance at 423 nm or fluorescence at 495 nm from the pyridoxal-5′-phosphate-L-Ser complex. Pressure perturbation was used to quantify the effects of monovalent cations, ligands, and mutations on the conformational equilibrium of Trp synthase. P-jump kinetics in the presence of Na+, NH4+, and Na+ together with benzimidazole were also examined. The plots of lnk versus P are nonlinear and require a compressibility (β‡o) term to obtain a good fit. β‡o is positive for the Na+ enzyme but negative for NH4+ and Na+ with benzimidazole. These results suggest that there is a large contribution of solvation to the kinetics of the conformational change of Trp synthase. The relaxation kinetics are also different if the P-jumps are made by increasing or decreasing pressure, suggesting that the enzyme conformations are ensembles of microstates.
tryptophan synthase; allostery; pyridoxal-5′-phosphate; compressibility; solvation
CXCL12/SDF-1 dynamically regulates hematopoietic stem cell (HSC) attraction in the bone marrow (BM). Circadian regulation of bone formation and HSC traffic is relayed in bone and BM by β-adrenergic receptors (β-AR) expressed on HSCs, osteoblasts and mesenchymal stem / progenitor cells. Circadian HSC release from the BM follows rhythmic secretion of norepinephrine (NE) from nerve terminals, β3-AR activation and Cxcl12 downregulation, possibly due to reduced Sp1 nuclear content. Here, we show that β-AR stimulation in stromal cells causes Sp1 degradation, partially mediated by 26S proteasome. Inverted trends of circulating hematopoietic progenitors and BM Cxcl12 mRNA levels change acutely after light onset, shown to induce sympathetic efferent activity. In BM stromal cells, activation of β3-AR downregulates Cxcl12, whereas β2-AR stimulation induces clock gene expression. Double-deficiency in β2- and β3-ARs compromises enforced mobilization. Therefore, β2- and β3-ARs have specific roles in stromal cells and cooperate during progenitor mobilization.
β-adrenergic receptors; bone marrow stromal cells; circadian; clock; CXCL12/SDF-1; hematopoietic progenitor mobilization
Reactive species derived from oxygen and nitric oxide are produced during inflammation and promote oxidation and nitration of biomolecules, including unsaturated fatty acids. Among the products of these reactions are α,β-unsaturated carbonyl and nitro derivatives of fatty acids, electrophilic species whose reactivity with nucleophilic amino acids provides a means of posttranslational protein modification and signaling. These electrophilic fatty acids activate cytosolic and nuclear stress–response pathways (through Nrf2/Keap1 and PPARγ, for example). There is also growing evidence that mitochondria generate electrophilic species. This appreciation, when combined with the role of mitochondrial dysfunction in conditions where exogenously delivered electrophiles exhibit therapeutic benefit, suggests that mitochondrial electrophile targets are also important in the resolution and prevention of inflammatory injury. Cardioprotective signaling pathways in particular appear to converge on mitochondria, with nitro-fatty acids recently shown to protect against cardiac ischemia/reperfusion injury in a murine model. Although numerous mitochondrial proteins are subject to modification by electrophiles, defining the targets most relevant to cytoprotection during inflammatory stress remains a clinically relevant goal.
electrophiles; mitochondria; redox signaling; ischemia-reperfusion
The hematopoietic stem cell (HSC) niche is currently defined as the specific microenvironment in the bone marrow (BM) which anatomically harbors HSCs and governs their fate. It plays a pivotal role in regulating the survival and self-renewal ability of HSCs, protecting them from exhaustion while preventing their excessive proliferation. Many different stromal cell types have been proposed as putative constituents of the niche, but their integrated function is still unrevealed. Mechanisms by which stem/progenitor cell behavior is regulated in the niche include cell-to-cell interaction and the production of growth factors, cytokines, and extracellular matrix proteins. The HSC niche is a dynamic entity reflecting and responding to the needs of the organism. An understanding of how the niche participates in the maintenance of tissue homeostasis and repair offers new opportunities for the development of novel therapeutic tools.
HSC niche; stem cells; microenvironment; osteoblastic cells; perivascular cells; regeneration
Ambient air pollution has been linked to cardiovascular and respiratory morbidity and mortality in epidemiology studies. Frequently, oxidative and nitrosative stress are hypothesized to mediate these pollution effects, however precise mechanisms remain unclear. This paper describes the methodology for a major panel study to examine air pollution effects on these and other mechanistic pathways. The study took place during the drastic air pollution changes accompanying the 2008 Olympics in Beijing, China. After a general description of air pollution health effects, we provide a discussion of panel studies and describe the unique features of this study that make it likely to provide compelling results. This study should lead to a clearer and more precise definition of the role of oxidative and nitrosative stress, as well as other mechanisms, in determining acute morbidity and mortality from air pollution exposure.
panel study; oxidative stress; exhaled breath condensate; 2008 Olympics
Epidemiological studies have linked exposure to traffic-related air pollutants to increased respiratory and cardiovascular morbidity and mortality. Evidence from human, animal, and in vitro studies supports an important role for oxidative stress in the pathophysiological pathways underlying the adverse health effects of air pollutants. In controlled-exposure studies of animals and humans, emissions from diesel engines, a major source of traffic-related air pollutants, cause pulmonary and systemic inflammation that is mediated by redox-sensitive signaling pathways. Assessment of human responses to traffic-related air pollution under realistic conditions is challenging due to the complex, dynamic nature of near-roadway exposure. Noninvasive measurement of biomarkers in breath and breath condensate may be particularly useful for evaluating the role of oxidative stress in acute responses to exposures that occur in vehicles or during near-roadway activities. Promising biomarkers include nitric oxide in exhaled breath, and nitrite/nitrate, malondialdehyde, and F2-isoprostanes in exhaled breath condensate.
air pollution; traffic; oxidative stress; exhaled breath; airways; biomarkers
Two kinds of evidence suggest that female fertility may end at an earlier age in modern people than in ancestral populations or in our closest living relatives, chimpanzees. We investigate both to see whether fertility schedules or ovarian follicle counts falsify the alternative hypothesis that the age of terminal fertility changed little in the human lineage while greater longevity evolved due to grandmother effects. We use 19th century Utah women to represent non-contracepting humans, and compare their fertility by age with published records for wild chimpanzees. Then we revisit published counts of ovarian follicular stocks in both species. Results show wide individual variation in age at last birth and oocyte stocks in both humans and chimpanzees. This heterogeneity, combined with interspecific differences in adult mortality, has large and opposing effects on fertility schedules. Neither realized fertility nor rates of follicular atresia stand as evidence against the hypothesis that ages at last birth changed little while greater longevity evolved in our lineage.
grandmother hypothesis; fertility decline; menopause; heterogeneity; follicular depletion; chimpanzee comparisons
Sulfur mustard (SM) is a chemical weapon that targets the skin, eyes, and lung. It was first employed during World War I and it remains a significant military and civilian threat. As a bifunctional alkylating agent, SM reacts with a variety of macromolecules in target tissues including nucleic acids, proteins and lipids, as well as small molecular weight metabolites such as glutathione. By alkylating subcellular components, SM disrupts metabolism, a process that can lead to oxidative stress. Evidence for oxidative stress in tissues exposed to SM or its analogs include increased formation of reactive oxygen species, the presence of lipid peroxidation products and oxidized proteins, and increases in antioxidant enzymes such as superoxide dismutase, catalase, and glutathione-S-transferase. Inhibition of antioxidant enzymes including thioredoxin reductase by SM can also disrupt cellular redox homeostasis. Consistent with these findings, SM-induced toxicity has been shown to be reduced by antioxidants in both in vitro and in vivo models. These data indicate that drugs that target oxidative stress pathways may represent important candidates for reducing SM-induced tissue injury.
oxidative stress; reactive oxygen species; nitric oxide; vesicants; dermatotoxicity
Despite an increasing number of military service members in need of mental health treatment following deployment to Iraq and Afghanistan, numerous psychological and practical barriers limit access to care. Perceived stigma about admitting psychological difficulties as well as frequent long distances to treatment facilities reduce many veterans' willingness and ability to receive care. Telemedicine and virtual human technologies offer a unique potential to expand services to those in greatest need. Telemedicine-based treatment has been used to address multiple psychiatric disorders, including posttraumatic stress disorder, depression, and substance use, as well as to provide suicide risk assessment and intervention. Clinician education and training has also been enhanced and expanded through the use of distance technologies, with trainees practicing clinical skills with virtual patients and supervisors connecting with clinicians via videoconferencing. The use of these innovative and creative vehicles offer a significant and as yet unfulfilled promise to expand delivery of high quality psychological therapies, regardless of clinician and patient location.
telemedicine; virtual reality; videoconferencing; barriers to care; OIF/OEF veterans
Bone is a dynamic tissue that adapts to its local loading environment. Mechanotransduction, the process by which cells convert mechanical forces into biochemical signals, is important for maintaining bone health and homeostasis. It is less clear, however, what the cellular mechanosensor(s) are that sense and initiate these signaling cascades. Primary cilia are solitary, rigid structures that extend from cell body into the extracellular space; as a result, they are prime candidates for mechanosensing in bone. They have been shown to be critical in development, and they have been implicated in mechanosensing in other tissue types including liver and kidney. This review discusses the potential for primary cilia to play an important role in bone mechanotransduction and possible avenues for future study.
bone; osteocyte; primary cilia; mechanosensor; mechanotransduction
The drugs of abuse, methamphetamine and MDMA, produce long-term decreases in markers of biogenic amine neurotransmission. These decreases have been traditionally linked to nerve terminals and are evident in a variety of species, including rodents, nonhuman primates, and humans. Recent studies indicate that the damage produced by these drugs may be more widespread than originally believed. Changes indicative of damage to cell bodies of biogenic and nonbiogenic amine–containing neurons in several brain areas and endothelial cells that make up the blood–brain barrier have been reported. The processes that mediate this damage involve not only oxidative stress but also include excitotoxic mechanisms, neuroinflammation, the ubiquitin proteasome system, as well as mitochondrial and neurotrophic factor dysfunction. These mechanisms also underlie the toxicity associated with chronic stress and human immunodeficiency virus (HIV) infection, both of which have been shown to augment the toxicity to methamphetamine. Overall, multiple mechanisms are involved and interact to promote neurotoxicity to methamphetamine and MDMA. Moreover, the high coincidence of substituted amphetamine abuse by humans with HIV and/or chronic stress exposure suggests a potential enhanced vulnerability of these individuals to the neurotoxic actions of the amphetamines.
amphetamine; methamphetamine; MDMA; neurotoxicity; apoptosis; excitotoxicity; neuroinflammation; proteasome; ubiquitination; neurodegeneration; drug abuse
Inducing expression of endogenous fetal globin (γ-globin) gene expression to 60-70% of alpha globin synthesis produces β-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced γ-globin expression in beta thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as 7 years. However, prior generations were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic sodium 2,2-dimethylbutyrate is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of 3 major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used world-wide.
thalassemia; short chain fatty acids; butyrates; erythropoiesis; fetal globin; quantitative trait loci
Rapid advances in our understanding of the immune network have led to treatment modalities for malignancies and autoimmune diseases based on modulation of the immune response. Yet therapeutic modulation has resulted in immune dysregulation and opportunistic autoimmune sequelae, despite prescreening efforts in clinical trials. This review focuses on recent clinical data on opportunistic autoimmune disorders arising from three immunotherapeutic modalities: (1) systemic immunomodulators, including interferon-α (also used to treat hepatitis C patients) and interferon-β; (2) monoclonal antibodies to CTLA-4 and CD52, and (3) hematopoietic stem cell transplantation. Uncategorized predisposing factors in these patients include major histocompatibility complex and gender genetics, prevalence of different autoimmune diseases, prior chemotherapy, underlying disorder (e.g., hepatitis C), and preconditioning regimens as part of organ and stem cell transplants. Not unexpectedly, the prevalent autoimmune thyroid disease surfaced frequently. Our combination models to study the balance between thyroid autoimmunity and tumor immunity upon regulatory T-cell perturbation are briefly described.
opportunistic autoimmunity; immunotherapeutic sequelae; immunotherapy; autoimmunity; immune dysregulation
Acute cerebral ischemia elicits an innate immune response that leads to a cascade of events that culminates in necrotic death of neurons and injury to their supportive structures in the neurovascular unit. Indeed, clinical studies have shown a close relationship between elevated levels of inflammatory markers and the risk for ischemic stroke. However, the signaling pathways that link these events are not well understood. A central regulator of inflammatory response is the transcription factor, nuclear factor-kappa B (NF-κB). The activation of NF-κB is required for the transcriptional induction of many proinflammatory mediators involved in innate immunity, such as cellular adhesion molecules, cytokines, and growth factors. Therefore, factors that modulate the activity of NF-κB could potentially regulate inflammatory processes in ischemic stroke. Here, we review the relationship between NF-κB and ischemic stroke, its role in the neurovascular unit, and discuss some animal models that suggest that this relationship is causal.
NF-kappa B; stroke; innate immunity; inflammation; cerebral ischemia
Evidence has accumulated over the past several years demonstrating that lung injury following inhalation of irritants like ozone is due, not only to direct effects of the chemical, but also indirectly to the actions of inflammatory mediators released by infiltrating macrophages. Among the mediators involved in the cytotoxic process, reactive nitrogen species (RNS) are of particular interest because of their well-documented cytotoxic potential. Findings that macrophage suppression blocks RNS production and ozone-induced toxicity provide strong support for a role of these cells and inflammatory mediators in lung injury. Recent investigations have focused on understanding pathways by which macrophages become activated to release RNS. One protein that has attracted considerable attention is caveolin-1, a membrane scaffolding molecule that functions to negatively regulate cell signaling. The fact that expression of caveolin-1 is down-regulated in macrophages after ozone inhalation suggests a mechanism controlling the release of cytotoxic mediators by these inflammatory cells.
macrophages; ozone; nitric oxide; caveolin; TNFα
Spinal motoneurons (MNs) amplify synaptic inputs by producing strong dendritic persistent inward currents (PICs), which allow the MN to generate the firing rates and forces necessary for normal behaviors. However, PICs prolong MN depolarization after the initial excitation is removed, tend to “wind-up” with repeated activation and are regulated by a diffuse neuromodulatory system that affects all motor pools. We have shown that PICs are very sensitive to reciprocal inhibition from Ia afferents of antagonist muscles and as a result PIC amplification is related to limb configuration. Because reciprocal inhibition is tightly focused, shared only between strict anatomical antagonists, this system opposes the diffuse effects of the descending neuromodulation that facilitates PICs. Because inhibition appears necessary for PIC control, we hypothesize that Ia inhibition interacts with Ia excitation in a “push–pull” fashion, in which a baseline of simultaneous excitation and inhibition allows depolarization to occur via both excitation and disinhibition (and vice versa for hyperpolarization). Push–pull control appears to mitigate the undesirable affects associated with the PIC while still taking full advantage of PIC amplification.
PIC; neuromodulation; push–pull; motoneuron
Mammalian reproduction requires that nursing mothers transfer large amounts of calcium to their offspring through milk. As a result, lactation is associated with dramatic alterations in bone and mineral metabolism, including reversible bone loss. One theme that has emerged from recent studies examining these adaptations is that the lactating breast actively participates in regulating bone and mineral metabolism. This review will detail our current knowledge of interactions between the breast, skeleton and hypothalamus during lactation and will consider implications that this reproductive physiology has for the pathophysiology of osteoporosis and breast cancer.
Osteoporosis; Bone Metastases; Lactation; Estrogen Deficiency; Calcium-Sensing Receptor; Parathyroid Hormone-Related Protein
Addiction to opiates and illicit use of psychostimulants is a chronic, relapsing brain disease that, if left untreated, can cause major medical, social and economic problems. This article reviews recent progress in studies of association of gene variants with vulnerability to develop opiate and cocaine addictions, focusing primarily on genes of the opioid and monoaminergic systems. In addition, we provide the first evidence of a cis-acting polymorphism and a functional haplotype in the PDYN gene, of significantly higher DNA methylation rate of the OPRM1 gene in the lymphocytes of heroin addicts, and significant differences in genotype frequencies of three single nucleotide polymorphisms of the P-glycoprotein gene (ABCB1) between “higher” and “lower” methadone doses in methadone-maintained patients. In genome-wide and multi-gene association studies, we have found association of a number of new genes and new variants of known genes with heroin addiction. Finally, we have described the development and application of a novel technique: molecular haplotyping for studies in genetics of drug addiction.
opiate and cocaine addiction; genetics of drug addiction; epigenetics; pharmacogenetics; allele-specific gene expression; molecular haplotyping
Hyperglycemia is a common occurrence in hospitalized patients, and several studies have shown a strong association between hyperglycemia and the risk of complications, prolonged hospitalization, and death for patients with and without diabetes. Past studies have shown that glucose management in the intensive care setting improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality, and that the importance of hyperglycemia also applies to noncritically ill patients. Based on several past observational and interventional studies, aggressive control of blood glucose had been recommended for most adult patients with critical illness. Recent randomized controlled trials, however, have shown that aggressive glycemic control compared to conventional control with higher blood glucose targets is associated with an increased risk of hypoglycemia and may not result in the improvement in clinical outcomes. This review aims to give an overview of the evidence for tight glycemic control (blood glucose targets <140 mg/dL), the evidence against tight glycemic control, and the updated recommendations for the inpatient management of diabetes in the critical care setting and in the general wards.
inpatient hyperglycemia; guidelines; intensive care unit; general wards; hypoglycemia
Stroke induces a complex web of pathophysiology that may evolve over hours to days and weeks after onset. It is now recognized that inflammation is an important phenomenon that can dramatically influence outcomes after stroke. In this minireview, we explore the hypothesis that inflammatory signals after stroke are biphasic in nature. The high-mobility group box 1 (HMGB1) protein is discussed as an example of this idea. HMGB1 is normally present in the nucleus. Under ischemic conditions, it is released extracellularly from many types of cells. During the acute phase poststroke, HMGB1 promotes necrosis and influx of damaging inflammatory cells. However, during the delayed phase poststroke, HMGB1 can mediate beneficial plasticity and recovery in many cells of the neurovascular unit. These emerging findings support the hypothesis that inflammation after stroke can be both detrimental and beneficial, depending on the cellular situations involved.
stroke; inflammation; stroke recovery; HMGB1
Adults with better jobs enjoy better health: job title was, in fact, the social gradient metric first used to study the relationship between social class and chronic disease etiology, a core finding now replicated in most developed countries. What has been less well proved is whether this correlation is causal, and if so, through what mechanisms. During the past decade, much research has been directed at these issues.Best evidence in2009 suggests that occupation does affect health. Most recent research on the relationship has been directed at disentangling the pathways through which lower-status work leads to adverse health outcomes. This review focuses on six areas of recent progress: (1) the role of status in a hierarchical occupational system; (2) the roles of psychosocial job stressors; (3) effects of workplace physical and chemical hazard exposures; (4) evidence that work organization matters as a contextual factor; (5) implications for the gradient of new forms of nonstandard or “precarious” employment such as contract and shift work; and (6) emerging evidence that women may be impacted differently by adverse working conditions, and possibly more strongly, than men.
occupational health; psycho-social stressors; work organization; women in the workplace; nonstandard work