The use of Translocator Protein 18 kDa (TSPO) as a clinical neuroimaging biomarker of brain injury and neuroinflammation has increased exponentially in the last decade. There has been a furious pace ...in the development of new radiotracers for TSPO positron emission tomography (PET) imaging and its use has now been extensively described in many neurological and mental disorders. This fast pace of research and the ever-increasing number of new laboratories entering the field often times lack an appreciation of the historical perspective of the field and introduce dogmatic, but unproven facts, related to the underlying neurobiology of the TSPO response to brain injury and neuroinflammation. Paradoxically, while in neurodegenerative disorders and in all types of CNS pathologies brain TSPO levels increase, a new observation in psychiatric disorders such as schizophrenia is decreased brain levels of TSPO measured by PET. The neurobiological bases for this new finding is currently not known, but rigorous experimental design using multiple experimental approaches and careful interpretation of results is critically important to provide the methodological and/or biological underpinnings to this new observation. This review provides a perspective of the early history of validating TSPO as a biomarker of brain injury and neuroinflammation and a critical analysis of controversial topics in the literature related to the cellular sources of the TSPO response. The latter is important in order to provide the correct interpretation of PET studies in neurodegenerative and psychiatric disorders. Furthermore, this review proposes some yet to be explored explanations to new findings in psychiatric disorders and new approaches to quantitatively assess the glial sources of the TSPO response in order to move the field forward.
Manganese (Mn) is an essential metal and has important physiological functions for human health. However, exposure to excess levels of Mn in occupational settings or from environmental sources has ...been associated with a neurological syndrome comprising cognitive deficits, neuropsychological abnormalities and parkinsonism. Historically, studies on the effects of Mn in humans and experimental animals have been concerned with effects on the basal ganglia and the dopaminergic system as it relates to movement abnormalities. However, emerging studies are beginning to provide significant evidence of Mn effects on cortical structures and cognitive function at lower levels than previously recognized. This review advances new knowledge of putative mechanisms by which exposure to excess levels of Mn alters neurobiological systems and produces neurological deficits not only in the basal ganglia but also in the cerebral cortex. The emerging evidence suggests that working memory is significantly affected by chronic Mn exposure and this may be mediated by alterations in brain structures associated with the working memory network including the caudate nucleus in the striatum, frontal cortex and parietal cortex. Dysregulation of the dopaminergic system may play an important role in both the movement abnormalities as well as the neuropsychiatric and cognitive function deficits that have been described in humans and non-human primates exposed to Mn.
Research on immigration, educational achievement, and ethnoraciality has followed the lead of racialization and assimilation theories by focusing empirical attention on the immigrantorigin population ...(immigrants and their children), while overlooking the effect of an immigrant presence on the third-plus generation (U.S.-born individuals of U.S.-born parents), especially its white members. We depart from this approach by placing third-plus-generation individuals at center stage to examine how they adjust to norms defined by the immigrantorigin population. We draw on fieldwork in Cupertino, California, a high-skilled immigrant gateway, where an Asian immigrant-origin population has established and enforces an amplified version of high-achievement norms. The resulting ethnoracial encoding of academic achievement constructs whiteness as having lesser-than status. Asianness stands for highachievement, hard work, and success; whiteness, in contrast, represents low-achievement, laziness, and academic mediocrity. We argue that immigrants can serve as a foil against which the meaning and status of an ethnoracial category is recast, upending how the category is deployed in daily life. Our findings call into question the position that treats the third-plus generation, especially whites, as the benchmark population that sets achievement norms and to which all other populations adjust.
Background: Excess accumulation of manganese (Mn) in the brain results in a neurological syndrome with cognitive, psychiatric, and movement abnormalities. The highest concentrations of Mn in the ...brain are achieved in the basal ganglia, which may precipitate a form of parkinsonism with some clinical features that are similar and some that are different to those in Parkinson's disease (PD). Recently, scientists have debated the possibility that Mn may have an etiological role in PD or that it may accelerate the expression of PD. Objective: The goal of this review was to examine whether chronic Mn exposure produces dopamine neuron degeneration and PD or whether it has a distinct neuropathology and clinical presentation. Data source: I reviewed available clinical, neuroimaging, and neuropathological studies in humans and nonhuman primates exposed to Mn or other human conditions that result in elevated brain Mn concentrations. Data extraction: Human and nonhuman primate literature was examined to compare clinical, neuroimaging, and neuropathological changes associated with Mn-induced parkinsonism. Data synthesis: Clinical, neuroimaging, and neuropathological evidence was used to examine whether Mn-induced parkinsonism involves degeneration of the nigrostriatal dopaminergic system as is the case in PD. Conclusions: The overwhelming evidence shows that Mn-induced parkinsonism does not involve degeneration of midbrain dopamine neurons and that L-dopa is not an effective therapy. New evidence is presented on a putative mechanism by which Mn may produce movement abnormalities. Confirmation of this hypothesis in humans is essential to make rational decisions about treatment, devise effective therapeutic strategies, and set regulatory guidelines.
Lead (Pb²⁺) is a ubiquitous environmental neurotoxicant that continues to threaten public health on a global scale. Epidemiological studies have demonstrated detrimental effects of Pb²⁺ on childhood ...IQ at very low levels of exposure. Recently, a mechanistic understanding of how Pb²⁺ affects brain development has begun to emerge. The cognitive effects of Pb²⁺ exposure are believed to be mediated through its selective inhibition of the N-methyl-d -aspartate receptor (NMDAR). Studies in animal models of developmental Pb²⁺ exposure exhibit altered NMDAR subunit ontogeny and disruption of NMDAR-dependent intracellular signaling. Additional studies have reported that Pb²⁺ exposure inhibits presynaptic calcium (Ca²⁺) channels and affects presynaptic neurotransmission, but a mechanistic link between presynaptic and postsynaptic effects has been missing. Recent work has suggested that the presynaptic and postsynaptic effects of Pb²⁺ exposure are both due to inhibition of the NMDAR by Pb²⁺, and that the presynaptic effects of Pb²⁺ may be mediated by disruption of NMDAR activity-dependent signaling of brain-derived neurotrophic factor (BDNF). These findings provide the basis for the first working model to describe the effects of Pb²⁺ exposure on synaptic function. Here, we review the neurotoxic effects of Pb²⁺ exposure and discuss the known effects of Pb²⁺ exposure in light of these recent findings.
Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson's disease. In fact, the most successful parkinsonian ...drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal "direct pathway" (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder.
TSPO Finds NOX2 in Microglia for Redox Homeostasis Guilarte, Tomás R; Loth, Meredith K; Guariglia, Sara R
Trends in pharmacological sciences (Regular ed.),
05/2016, Letnik:
37, Številka:
5
Journal Article
Recenzirano
Odprti dostop
During the past decade, translocator protein 18 kDa (TSPO), previously named peripheral benzodiazepine receptor, has gained a great deal of attention based on its use as a clinical biomarker of ...neuroinflammation with therapeutic potential. However, there is a paucity of knowledge on the function(s) of TSPO in glial cells. Here, we identify a novel function of TSPO in microglia that is not associated with steroidogenesis. We propose that a TSPO interaction with NADPH oxidase (NOX2) links the generation of reactive oxygen species (ROS) to the induction of an antioxidant response to maintain redox homeostasis. This line of investigation may provide a greater understanding of TSPO glial cell biology, and the knowledge gained may prove beneficial in devising therapeutic strategies.
•We study informality and financial frictions using an entrepreneurship model.•The model accounts for informal firms and workers hired off the books by formal firms.•The hiring of informal workers by ...formal businesses alleviates financial constraints.•Reducing firm informality improves macro outcomes while worker informality does not.•The output cost of public financing with labor taxes rises with financial frictions.
What are the aggregate effects of informality in a financially constrained economy? We develop and calibrate an entrepreneurship model to data on matched employer-employee from both formal and informal sectors in Brazil. The model distinguishes between informality on the business side and the hiring of informal workers by formal businesses. Policies that reduce business informality increase aggregate output by 10.8%, TFP by 6.6%, and tax revenue by 33.2%. On the contrary, output and TFP decrease when policies reduce the intensive margin of informality, underscoring that the informal economy can play a positive role in an economy with financial frictions.
PDF
