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Mostrando las entradas de 2018

#brain: The mysterious origins of microglia

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The origin of microglia, the resident macrophage population of the CNS, has been a long-standing matter of debate. Here we discuss two seminal studies published in 2007 in Nature Neuroscience that significantly contributed to a better understanding of microglia ontogeny and homeostasis in the adult brain.
REFERENCE:
Ginhoux F, Garel S. The mysterious origins of microglia. Nat. Neurosci. 2018 Jul;21(7):897-899. doi: 10.1038/s41593-018-0176-3.

Viral Triggers and Inflammatory Mechanisms in Pediatric Epilepsy. Review

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Experimental and clinical findings suggest a crucial role for inflammation in the onset of pediatric seizures; this mechanism is not targeted by conventional antiepileptic drugs and may contribute to refractory epilepsy. Several triggers, including infection with neurotropic viruses such as human herpesvirus 6 (HHV-6), other herpesviruses, and picornaviruses, appear to induce activation of the innate and adaptive immune systems, which results in several neuroinflammatory responses, leading to enhanced neuronal excitability, and ultimately contributing to epileptogenesis. This review discusses the proposed mechanisms by which infection with herpesviruses, and particularly with HHV-6, and ensuing inflammation may lead to seizure generation, and later development of epilepsy. We also examine the evidence that links herpesvirus and picornavirus infections with acute seizures and chronic forms of epilepsy. Understanding the mechanisms by which specific viruses may trigger a cascade of alt…

Differential antiviral immunity to Japanese encephalitis virus in developing cortical organoids

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Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) poses a serious threat to the world's public health yet without a cure. Certain JEV-infected neural cells express a subset of previously identified intrinsic antiviral interferon stimulated genes (ISGs), indicating brain cells retain autonomous antiviral immunity. However, whether this happens in composited brain remains unclear. Human pluripotent stem cell (hPSC)-derived organoids can model disorders caused by human endemic pathogens such as Zika virus, which may potentially address this question and facilitate the discovery of a cure for JE. We thus generated telencephalon organoid and infected them with JEV. We found JEV infection caused significant decline of cell proliferation and increase of cell death in brain organoid, resulting in smaller organoid spheres. JEV tended to infect astrocytes and neural progenitors, especially the population representing outer radial glial cells (oRGCs) of dev…

Virus-like particles and enterovirus antigen found in the brainstem neurons of #Parkinson's disease

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Background: In a previous study on encephalitis lethargica, we identified a virus related to enterovirus in autopsy brain material. Transmission electron microscopy (TEM), immunohistochemistry (IHC) and molecular analysis were employed.  Our present objective was to investigate, using a similar approach, as to whether virus-like particles (VLP) and enterovirus antigen are present in Parkinson's disease (PD) brainstem neurons. Methods: Fixed tissue from autopsy specimens of late onset PD and control brainstem tissue were received for study. The brain tissue was processed for TEM and IHC according to previous published methods. Results:  We observed VLP in the brainstem neurons of all the cases of PD that were examined.  In the neurons' cytoplasm there were many virus factories consisting of VLP and endoplasmic reticulum membranes. In some neurons, the virus factories contained incomplete VLP. Complete VLP in some neurons' virus factories had an average diameter of 31 n…

Herpes Virus Encephalitis in Adults: Current Knowledge and Old Myths

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Herpes simplex virus (HSV) encephalitis is uncommon in clinical practice, but is frequently suspected in patients with acute alterations of consciousness. Symptoms and physical signs are nonspecific, and diagnostic confirmation typically hinges on demonstration of viral DNA in cerebrospinal fluid.BrainMRI is helpful in diagnosis and provides prognostic information. Early initiation of intravenous acyclovir is essential to optimize the patient's chances of favorable recovery. HSV encephalitis can trigger an autoimmune reaction with the possible appearance of antibodies to neuronal surface antigens. Thus, recrudescence of neurologic impairment after a treated episode of HSV encephalitis warrants consideration of secondary autoimmune encephalitis. REFERENCE: Rabinstein AA. Herpes Virus Encephalitis in Adults: Current Knowledge and Old Myths. Neurol Clin. 2017 Nov;35(4):695-705. doi: 10.1016/j.ncl.2017.06.006. Epub 2017 Aug 10. Review. PubMed PMID: 28962808.

The dynamic blood–brain barrier

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With the endothelium as its central unit, theblood-brain barrier(BBB) is a complex multicellular structure separating the central nervous system (CNS) from the systemic circulation. Disruption of the BBB has now been implicated in a multitude of acute and chronic CNS disorders indicating the potentially devastating effects of BBB breakdown onbrainfunction. However, the healthy BBB is not an impermeable wall, but rather a communication 'centre', responding to and passing signals between the CNS andblood. New studies are identifying BBB-specific transport pathways that tightly regulate the entry and exit of molecules to and from thebrain. They are revealing a highly plasticbarrierin which dynamic changes in BBB components like paracellular tight junction complexes can contribute to BBB maintenance. Here, we provide a succinct overview of the current state-of-play in BBB research and summarize novel findings into BBB regulation in homeostatic regulation of thebrain. REFERENCE: Ke…

The blood-brain barrier

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Bloodvessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. Thebloodvessels that vascularize the central nervous system (CNS) possess unique properties, termed theblood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between thebloodand thebrain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of thesebarrierproperties are an important component of pathology and progression of different neurological diseases. The physiologicalbarrieris coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of thebloodvessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate thebarrierproper…

Microglia Development and function

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Proper development and function of the mammalian central nervous system (CNS) depend critically on the activity of parenchymal sentinels referred to as microglia. Although microglia were first described as ramified brain-resident phagocytes, research conducted over the past century has expanded considerably upon this narrow view and ascribed many functions to these dynamic CNS inhabitants. Microglia are now considered among the most versatile cells in the body, possessing the capacity to morphologically and functionally adapt to their ever-changing surroundings. Even in a resting state, the processes of microglia are highly dynamic and perpetually scan the CNS. Microglia are in fact vital participants in CNS homeostasis, and dysregulation of these sentinels can give rise to neurological disease. In this review, we discuss the exciting developments in our understanding of microglial biology, from their developmental origin to their participation in CNS homeostasis and pathophysiologic…

Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity

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Although we are beginning to understand the late stage of neurodegenerative diseases, the molecular defects associated with the initiation of impaired cognition are poorly characterized. Here, we demonstrate that in the adult brain, the coxsackievirus and adenovirus receptor (CAR) is located on neuron projections, at the presynapse in mature neurons, and on the soma of immature neurons in the hippocampus. In a proinflammatory or diseased environment, CAR is lost from immature neurons in the hippocampus. Strikingly, in hippocampi of patients at early stages of late-onset Alzheimer’s disease (AD), CAR levels are significantly reduced. Similarly, in triple-transgenic AD mice, CAR levels in hippocampi are low and further reduced after systemic inflammation. Genetic deletion of CAR from the mouse brain triggers deficits in adult neurogenesis and synapse homeostasis that lead to impaired hippocampal plasticity and cognitive deficits. We propose that post-translational CAR loss of function …

Physical biology of human brain development

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Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular …

HIV-associated synaptic degeneration

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Human immunodeficiency virus (HIV) infection induces neuronal injuries, with almost 50% of infected individuals developing HIV-associated neurocognitive disorders (HAND). Although highly activate antiretroviral therapy (HAART) has significantly reduced the incidence of severe dementia, the overall prevalence of HAND remains high. Synaptic degeneration is emerging as one of the most relevant neuropathologies associate with HAND. Previous studies have reported critical roles of viral proteins and inflammatory responses in this pathogenesis. Infected cells, including macrophages, microglia and astrocytes, may release viral proteins and other neurotoxins to stimulate neurons and cause excessive calcium influx, overproduction of free radicals and disruption of neurotransmitter hemostasis. The dysregulation of neural circuits likely leads to synaptic damage and loss. Identification of the specific mechanism of the synaptic degeneration may facilitate the development of effective therapeuti…

Guillain–Barré syndrome, transverse myelitis and infectious diseases

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Guillain–Barré syndrome (GBS) and transverse myelitis (TM) both represent immunologically mediated polyneuropathies of major clinical importance. Both are thought to have a genetic predisposition, but as of yet no specific genetic risk loci have been clearly defined. Both are considered autoimmune, but again the etiologies remain enigmatic. Both may be induced via molecular mimicry, particularly from infectious agents and vaccines, but clearly host factor and co-founding host responses will modulate disease susceptibility and natural history. GBS is an acute inflammatory immune-mediated polyradiculoneuropathy characterized by tingling, progressive weakness, autonomic dysfunction, and pain. Immune injury specifically takes place at the myelin sheath and related Schwann-cell components in acute inflammatory demyelinating polyneuropathy, whereas in acute motor axonal neuropathy membranes on the nerve axon (the axolemma) are the primary target for immune-related injury. Outbreaks of GBS …

Complete genome sequence from Zika Virus, from Oaxaca, México

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Zika virus (ZIKV) is an emerging arthropod-borne flavivirus associated with severe congenital malformations and neurological complications. Although the ZIKV genome is well characterized, there is limited information regarding changes after cell isolation and culture adaptation. We isolated, and passaged in Vero cells, ZIKV from the serum of a symptomatic male patient and compared the viral genomes before and after culture. Single nucleotide polymorphisms were characteristic among serum-circulating genomes, while such diversity decreased after cell culture.

REFERENCE:
Boukadida, Celia et al. “Complete Genome Sequences, before and after Mammalian Cell Culture, of Zika Virus Isolated from the Serum of a Symptomatic Male Patient from Oaxaca, Mexico.” Genome Announcements 5.12 (2017): e00072–17. PMC. Web. 18 Jan. 2018.