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Beyond traditional approaches to understanding the functional role of neuromodulators in sensory cortices  [PDF]
Jean-Marc Edeline
Frontiers in Behavioral Neuroscience , 2012, DOI: 10.3389/fnbeh.2012.00045
Abstract: Over the last two decades, a vast literature has described the influence of neuromodulatory systems on the responses of sensory cortex neurons (review in Gu, 2002; Edeline, 2003; Weinberger, 2003; Metherate, 2004, 2011). At the single cell level, facilitation of evoked responses, increases in signal-to-noise ratio, and improved functional properties of sensory cortex neurons have been reported in the visual, auditory, and somatosensory modality. At the map level, massive cortical reorganizations have been described when repeated activation of a neuromodulatory system are associated with a particular sensory stimulus. In reviewing our knowledge concerning the way the noradrenergic and cholinergic system control sensory cortices, I will point out that the differences between the protocols used to reveal these effects most likely reflect different assumptions concerning the role of the neuromodulators. More importantly, a gap still exists between the descriptions of neuromodulatory effects and the concepts that are currently applied to decipher the neural code operating in sensory cortices. Key examples that bring this gap into focus are the concept of cell assemblies and the role played by the spike timing precision (i.e., by the temporal organization of spike trains at the millisecond time-scale) which are now recognized as essential in sensory physiology but are rarely considered in experiments describing the role of neuromodulators in sensory cortices. Thus, I will suggest that several lines of research, particularly in the field of computational neurosciences, should help us to go beyond traditional approaches and, ultimately, to understand how neuromodulators impact on the cortical mechanisms underlying our perceptual abilities.
Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants  [PDF]
Mira Polajnar,Slavko ?eru,Nata?a Kopitar-Jerala,Eva ?erovnik
Frontiers in Molecular Neuroscience , 2012, DOI: 10.3389/fnmol.2012.00088
Abstract: Epilepsies are characterized by abnormal electrophysiological activity of the brain. Among various types of inherited epilepsies different epilepsy syndromes, among them progressive myoclonus epilepsies with features of ataxia and neurodegeneration, are counted. The progressive myoclonus epilepsy of type 1 (EPM1), also known as Unverricht-Lundborg disease presents with features of cerebellar atrophy and increased oxidative stress. It has been found that EPM1 is caused by mutations in human cystatin B gene (human stefin B). We first describe the role of protein aggregation in other neurodegenerative conditions. Protein aggregates appear intraneurally but are also excreted, such as is the case with senile plaques of amyloid-β (Aβ) that accumulate in the brain parenchyma and vessel walls. A common characteristic of such diseases is the change of the protein conformation toward β secondary structure that accounts for the strong tendency of such proteins to aggregate and form amyloid fibrils. Second, we describe the patho-physiology of EPM1 and the normal and aberrant roles of stefin B in a mouse model of the disease. Furthermore, we discuss how the increased protein aggregation observed with some of the mutants of human stefin B may relate to the neurodegeneration that occurs in rare EPM1 patients. Our hypothesis (Ceru et al., 2005) states that some of the EPM1 mutants of human stefin B may undergo aggregation in neural cells, thus gaining additional toxic function (apart from loss of normal function). Our in vitro experiments thus far have confirmed that four mutants undergo increased aggregation relative to the wild-type protein. It has been shown that the R68X mutant forms amyloid-fibrils very rapidly, even at neutral pH and forms perinuclear inclusions, whereas the G4R mutant exhibits a prolonged lag phase, during which the toxic prefibrillar aggregates accumulate and are scattered more diffusely over the cytoplasm. Initial experiments on the G50E and Q71P missense EPM1 mutants are described.
Dysfunction of Immune Systems and Host Genetic Factors in Hepatitis C Virus Infection with Persistent Normal ALT  [PDF]
Yasuteru Kondo,Yoshiyuki Ueno,Tooru Shimosegawa
Hepatitis Research and Treatment , 2011, DOI: 10.1155/2011/713216
Abstract: Patients with chronic hepatitis C (CHC) virus infection who have persistently normal alanine aminotransferase levels (PNALT) have mild inflammation and fibrosis in comparison to those with elevated ALT levels. The cellular immune responses to HCV are mainly responsible for viral clearance and the disease pathogenesis during infection. However, since the innate and adaptive immune systems are suppressed by various kinds of mechanisms in CHC patients, the immunopathogenesis of CHC patients with PNALT is still unclear. In this review, we summarize the representative reports about the immune suppression in CHC to better understand the immunopathogenesis of PNALT. Then, we summarize and speculate on the immunological aspects of PNALT including innate and adaptive immune systems and genetic polymorphisms of HLA and cytokines. 1. Introduction Hepatitis C virus (HCV) is noncytopathic virus that causes chronic hepatitis and hepatocellular carcinoma (HCC) [1]. Approximately 70–80% of those acutely infected will become persistently infected with HCV [1]. Around 30% of CHC patients exhibit PNALT and show milder disease activity and slower progression to hepatic cirrhosis [2–6]. However, it is reported that about 40% of these progress to the active stage of inflammation, but the incidence of HCC in the PNALT was lower than that in those with elevated ALT levels [7]. Cellular and humoral immune responses to HCV play an important role in the pathogenesis of active and nonactive chronic hepatitis [8]. Numerous studies have indicated that failure of the cellular immune response, including type 1 helper T cells (Th1) hypo-responsiveness, cytotoxic T lymphocyte (CTL) exhaustion, excessive function of CD4+??CD25+??FOXP3+ regulatory T cells, and failure of lymphoid cells via direct binding and/or infection in B cells, T cells, NK cells, and DCs occurs in CHC patients [9–21]. Since the liver damage in CHC is mainly induced by Th1 and/or CTL related responses [22–24], these responses might be strongly suppressed in PNALT. Given the involvement of immune responses, genetic factors including polymorphism of HLA and cyotokine-related genes could also contribute to the activity of inflammation in CHC patients [25–37]. Many groups, including us, have reported on the relationship between certain HLA and ALT levels in CHC patients [25, 27–29]. Moreover, some groups indicated the polymorphism of certain cytokines-related genes contributed to the level of inflammation [30–37]. In a genomewide association study (GWAS), IL28B polymorphism was shown to influence the outcome of Peg-IFN
Role of Leptin in the Activation of Immune Cells
Patricia Fernández-Riejos,Souad Najib,Jose Santos-Alvarez,Consuelo Martín-Romero,Antonio Pérez-Pérez,Carmen González-Yanes,Víctor Sánchez-Margalet
Mediators of Inflammation , 2010, DOI: 10.1155/2010/568343
Abstract: Adipose tissue is an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that may be present in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. One of these functions is the connection between nutritional status and immune competence. The adipocyte-derived hormone leptin has been shown to regulate the immune response, innate and adaptive response, both in normal and pathological conditions. The role of leptin in regulating immune response has been assessed in vitro as well as in clinical studies. It has been shown that conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders such as autoimmune diseases are associated with increased secretion of leptin and production of proinflammatory pathogenic cytokines. Thus, leptin is a mediator of the inflammatory response.
Trauma: the role of the innate immune system
F Hietbrink, L Koenderman, GT Rijkers, LPH Leenen
World Journal of Emergency Surgery , 2006, DOI: 10.1186/1749-7922-1-15
Abstract: Trauma is one of the major causes of mortality in people under the age of 50 in the Western world. Patients die as a direct consequence of their sustained injuries, or by the additional damage caused by subsequent immune reactions [1]. About 5% of the patients admitted after severe trauma develops (multiple) organ failure (MOF). Multiple organ failure is a clinical syndrome in which the functionality of several organs fail subsequently or simultaneously (i.e. liver, lungs, kidneys, heart). This review outlines the initiating factors and underlying mechanisms for the development of post-traumatic organ failure. It provides a pathophysiological basis for the so-called damage control concept. This concept involves a treatment strategy in which a staged approach of surgery in severely injured patients and post-traumatic immunomonitoring have become important aspects, to minimize the negative effects of a dysfunctional innate immune system.Multiple organ failure after trauma has a multifactorial etiology, which can be divided in endogenous and exogenous factors. Endogenous factors, such as genetic predisposition and physical condition form the basis of the patient s susceptibility for the development of organ failure. Recent studies have shown that genetic variations (e.g. TNF-α polymorphisms) are strongly associated with the development of organ failure [2]. Exogenous factors, like the injury itself (the "first hit" or "trauma-load") and the resuscitation or surgical intervention (the "second hit" or "intervention load") play a key role in the development and clinical presentation of organ failure. Organ damage and subsequent organ failure is the result of a dysfunctional immune system. A localized inflammatory reaction after injury is physiological, which can be explained by the "danger model", an immunological theory coined by Matzinger. The "danger model" explains that alarm signals can provoke an inflammatory reaction [3]. These alarm signals can be secreted by heal
Neurosteroids as Neuromodulators in the Treatment of Anxiety Disorders  [PDF]
Patrizia Longone,Rainer Rupprecht
Frontiers in Endocrinology , 2011, DOI: 10.3389/fendo.2011.00055
Abstract: Anxiety disorders are the most common psychiatric disorders. They are frequently treated with benzodiazepines, which are fast acting highly effective anxiolytic agents. However, their long-term use is impaired by tolerance development and abuse liability. In contrast, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment but have a slow onset of action. Neurosteroids are powerful allosteric modulators of GABAA and glutamate receptors. However, they also modulate sigma receptors and they are modulated themselves by SSRIs. Both pre-clinical and clinical studies have shown that neurosteroid homeostasis is altered in depression and anxiety disorders and antidepressants may act in part through restoring neurosteroid disbalance. Moreover, novel drugs interfering with neurosteroidogenesis such as ligands of the translocator protein (18 kDa) may represent an attractive pharmacological option for novel anxiolytics which lack the unwarranted side effects of benzodiazepines. Thus, neurosteroids are important endogenous neuromodulators for the physiology and pathophysiology of anxiety and they may constitute a novel therapeutic approach in the treatment of these disorders.
The role of interferon-gamma on immune and allergic responses
Teixeira, Leonardo K;Fonseca, Bruna PF;Barboza, Bianca A;Viola, Jo?o PB;
Memórias do Instituto Oswaldo Cruz , 2005, DOI: 10.1590/S0074-02762005000900024
Abstract: allergic diseases have been closely related to th2 immune responses, which are characterized by high levels of interleukin (il) il-4, il-5, il-9 and il-13. these cytokines orchestrate the recruitment and activation of different effector cells, such as eosinophils and mast cells. these cells along with th2 cytokines are key players on the development of chronic allergic inflammatory disorders, usually characterized by airway hyperresponsiveness, reversible airway obstruction, and airway inflammation. accumulating evidences have shown that altering cytokine-producing profile of th2 cells by inducing th1 responses may be protective against th2-related diseases such as asthma and allergy. interferon-g (ifn-g), the principal th1 effector cytokine, has shown to be crucial for the resolution of allergic-related immunopathologies. in fact, reduced production of this cytokine has been correlated with severe asthma. in this review, we will discuss the role of ifn-g during the generation of immune responses and its influence on allergic inflammation models, emphasizing its biologic properties during the different aspects of allergic responses.
Chemical modulators of the innate immune response alter gypsy moth larval susceptibility to Bacillus thuringiensis
Nichole A Broderick, Kenneth F Raffa, Jo Handelsman
BMC Microbiology , 2010, DOI: 10.1186/1471-2180-10-129
Abstract: We explored the potential role of the insect immune response in mortality caused by B. thuringiensis in conjunction with gut bacteria. Two lines of evidence support such a role. First, ingestion of B. thuringiensis by gypsy moth larvae led to the depletion of their hemocytes. Second, pharmacological agents that are known to modulate innate immune responses of invertebrates and vertebrates altered larval mortality induced by B. thuringiensis. Specifically, Gram-negative peptidoglycan pre-treated with lysozyme accelerated B. thuringiensis-induced killing of larvae previously made less susceptible due to treatment with antibiotics. Conversely, several inhibitors of the innate immune response (eicosanoid inhibitors and antioxidants) increased the host's survival time following ingestion of B. thuringiensis.This study demonstrates that B. thuringiensis infection provokes changes in the cellular immune response of gypsy moth larvae. The effects of chemicals known to modulate the innate immune response of many invertebrates and vertebrates, including Lepidoptera, also indicate a role of this response in B. thuringiensis killing. Interactions among B. thuringiensis toxin, enteric bacteria, and aspects of the gypsy moth immune response may provide a novel model to decipher mechanisms of sepsis associated with bacteria of gut origin.The gut epithelium and its associated microorganisms provide an important barrier that protects animals from the external environment. This barrier serves both to prevent invasion by potential pathogens and limit the elicitation of host responses to the resident microbiota [1,2]. Dysfunction of this barrier, which can occur as a result of alterations of the normal gut ecology, impairment of host immune defenses, or physical disruption of intestinal epithelia, may lead to pathological states [3-6].To breach the gut barrier, many enteric pathogens have evolved specific strategies such as production of toxins that physically disrupt cells of the gut
The immune role of the arthropod exoskeleton  [PDF]
Y Moret,J Moreau
Invertebrate Survival Journal , 2012,
Abstract: The exoskeleton or cuticle of arthropods is an important feature that contributes to their great success in colonising numerous habitats on earth. It has numerous functions among which to provide protection against parasites. Whereas often regarded as a simple physical barrier to the outside world, the immune protection of the cuticle is slightly more complex than that. Here, we provide an overview of the cuticle defensive traits against parasites and examine their variation as a response to parasitism. It appears that the cuticle is an efficient line of defense, which includes physical, biochemical and physiological defensive components that are potentially subject to genetic and plastic variation in response to parasitism. It also appears that the cuticle defense systems are relatively understudied despite it may determine for large part the success of parasitic attacks.
Immune Aspects and Myometrial Actions of Progesterone and CRH in Labor
Nikolaos Vrachnis,Fotodotis M. Malamas,Stavros Sifakis,Panayiotis Tsikouras,Zoe Iliodromiti
Clinical and Developmental Immunology , 2012, DOI: 10.1155/2012/937618
Abstract: Progesterone and corticotropin-releasing hormone (CRH) have a critical role in pregnancy and labor, as changes related to these hormones are crucial for the transition from myometrial quiescence to contractility. The mechanisms related to their effect differ between humans and other species, thus, despite extensive research, many questions remain to be answered regarding their mediation in human labor. Immune responses to progesterone and CRH are important for labor. Progesterone acts as an immunomodulator which controls many immune actions during pregnancy, and its withdrawal releases the inhibitory action on inflammatory pathways. In humans, a “functional” progesterone withdrawal occurs with onset of labor through changes in progesterone metabolism, progesterone receptors, and other molecules that either facilitate or antagonize progesterone function. Placental CRH acts on the fetal pituitary-adrenal axis to stimulate adrenal production of androgens and cortisol and also acts directly on myometrial cells via its receptors. CRH also affects inflammatory signals and vice versa. Interactions between progesterone and CRH additionally occur during labor. We describe the role of these two hormones in human myometrium and their interactions with the immune system during labor.
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