Early social isolation results in adult behavioral and cognitive dysfunction that correlates with white matter alterations. However, how social deprivation influences myelination and the significance ...of these myelin defects in the adult remained undefined. We show that mice isolated for 2 weeks immediately after weaning have alterations in prefrontal cortex function and myelination that do not recover with reintroduction into a social environment. These alterations, which occur only during this critical period, are phenocopied by loss of oligodendrocyte ErbB3 receptors, and social isolation leads to reduced expression of the ErbB3 ligand neuregulin-1. These findings indicate that social experience regulates prefrontal cortex myelination through neuregulin-1/ErbB3 signaling and that this is essential for normal cognitive function, thus providing a cellular and molecular context to understand the consequences of social isolation.
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While neurons in the central nervous system (CNS) have the capacity to regenerate their axons after injury, they fail to do so, in part because regeneration is limited by growth inhibitory proteins ...present in CNS myelin. Myelin-associated glycoprotein (MAG) was the first myelin-derived growth inhibitory protein identified, and its inhibitory activity was initially elucidated in 1994 independently by the Filbin lab and the McKerracher lab using cell-based and biochemical techniques, respectively. Since that time we have gained a wealth of knowledge concerning the numerous growth inhibitory proteins that are present in myelin, and we also have dissected many of the neuronal signaling pathways that act as stop signs for axon regeneration. Here we give an overview of the early research efforts that led to the identification of myelin-derived growth inhibitory proteins, and the importance of this family of proteins for understanding neurotrauma and CNS diseases. We further provide an update on how this knowledge has been translated towards current clinical studies in regenerative medicine.
Object Lessons is a series of short, beautifully designed books about the hidden lives of ordinary things. "Nothing's bulletproof," the salesman said. "The thing's only bullet resistant." The New ...York Times reporter Kenneth R. Rosen had just purchased his first Kevlar vest and was headed off on assignment in Iraq. He was travelling into Mosul when he came to realize that the idea of a bulletproof vest is more effective than the vest itself. From its very inception, poly-paraphenylene terephthalamide, as it is known, was meant for tires. The strong yet lightweight fiber was the creation of Stephanie Kwolek who, anticipating a gas shortage, focused her attention on producing a tire that could save on gas mileage. Soon it would surpass nylon. Its humble roots and applications are often lost to the colloquialism of the word "Kevlar," now synonymous with weapons shielding and tank armor. But in fact, Kevlar is used as a material in more than 200 applications, including tennis rackets, skis, and parachute lines. What Rosen learned through an intimate use of his bulletproof vest was that it acts as a metaphor for all the precautions we take toward digital, physical, and social security; at their most extreme, bulletproof vests represent a human desire to forge ahead. Bulletproof Vest is at once an introspective journey into the properties and precisions of Kevlar on a molecular level and on the world stage. It is also an ode to living precariously, an open letter that defends the notion that life is worth the risk. Object Lessons is published in partnership with an essay series in the The Atlantic.
Intraneuronal beta-amyloid (Abeta(i)) accumulates early in Alzheimer's disease (AD) and inclusion body myositis. Several organelles, receptor molecules, homeostatic processes, and signal transduction ...components have been identified as sensitive to Abeta. Although prior studies implicate the insulin-PI3K-Akt signaling cascade, a specific step within this or any essential metabolic or survival pathway has not emerged as a molecular target. We tested the effect of Abeta42 on each component of this cascade. In AD brain, the association between PDK and Akt, phospho-Akt levels and its activity were all decreased relative to control. In cell culture, Abeta(i) expression inhibited both insulin-induced Akt phosphorylation and activity. In vitro experiments identified that beta-amyloid (Abeta), especially oligomer preparations, specifically interrupted the PDK-dependent activation of Akt. Abeta(i) also blocked the association between PDK and Akt in cell-based and in vitro experiments. Importantly, Abeta did not interrupt Akt or PI3K activities (once stimulated) nor did it affect more proximal signal events. These results offer a novel therapeutic strategy to neutralize Abeta-induced energy failure and neuronal death.
Upon peripheral nerve injury, specific molecular events, including increases in the expression of selected neurotrophic factors, are initiated to prepare the tissue for regeneration. However, the ...mechanisms underlying these events and the nature of the cells involved are poorly understood. We used the injury‐induced upregulation of glial cell‐derived neurotrophic factor (GDNF) expression as a tool to gain insights into these processes. We found that both myelinating and nonmyelinating Schwann cells are responsible for the dramatic increase in GDNF expression after injury. We also demonstrate that the GDNF upregulation is mediated by a signaling cascade involving activation of Schwann cell purinergic receptors, followed by protein kinase C signaling which activates protein kinase D (PKD), which leads to increased GDNF transcription. Given the potent effects of GDNF on survival and repair of injured peripheral neurons, we propose that targeting these pathways may yield therapeutic tools to treat peripheral nerve injury and neuropathies.
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While neurons have long been considered the major player in multiple brain functions such as perception, emotion, and memory, glial cells have been relegated to a far lesser position, acting as ...merely a "glue" to support neurons. Multiple lines of recent evidence, however, have revealed that glial cells such as oligodendrocytes, astrocytes, and microglia, substantially impact on neuronal function and activities and are significantly involved in the underlying pathobiology of psychiatric disorders. Indeed, a growing body of evidence indicates that glial cells interact extensively with neurons both chemically (e.g., through neurotransmitters, neurotrophic factors, and cytokines) and physically (e.g., through gap junctions), supporting a role for these cells as likely significant modifiers not only of neural function in brain development but also disease pathobiology. Since questions have lingered as to whether glial dysfunction plays a primary role in the biology of neuropsychiatric disorders or a role related solely to their support of neuronal physiology in these diseases, informative and predictive animal models have been developed over the last decade. In this article, we review recent findings uncovered using glia-specific genetically modified mice with which we can evaluate both the causation of glia dysfunction and its potential role in neuropsychiatric disorders such as autism and schizophrenia.
If you think tycoons are the only ones who can make big money in commercial real estate, think again. Real estate guru Ken Rosen lays out the fundamentals for building real estate wealth. By adhering ...to the Big Six, a step-by-step formula that has enabled the author to buy and sell over $500 million in investment real estate since 1975, you can take advantage of real estate opportunities and ensure your financial future.
Receptor tyrosine kinases (RTKs) were believed until recently to act at the cell membrane in a singular fashion (i.e., binding of ligands on the extracellular domain would activate the intrinsic ...tyrosine kinase activity in the intracellular domain), which would then start a cascade involving other intracellular signaling molecules that would act as effectors. However, new evidence indicates that some RTKs can signal through a different modality; they can move into the nucleus where they directly exert their actions. Although some studies have showed that the proteolytically released intracellular domain of several RTKs can move to the nucleus where they influence gene expression and cell function, others suggest that RTKs can also move to the nucleus as holoproteins. The identification of this novel signaling mechanism calls for a critical reevaluation of the mechanisms of action of RTKs and their biological roles.
Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been reported in Alzheimer disease tissue and in cultured cells that overexpress amyloid ...precursor protein. Mitochondrial dysfunction contributes to neurodegeneration in Alzheimer disease partly through formation of reactive oxygen species and the release of sequestered molecules that initiate programmed cell death pathways. The heat shock proteins (HSP) are cytoprotective against a number of stressors, including accumulations of misfolded proteins and reactive oxygen species. We reported on the property of Hsp70 to protect cultured neurons from cell death caused by intraneuronal β-amyloid. Here we demonstrate that Hsp60, Hsp70, and Hsp90 both alone and in combination provide differential protection against intracellular β-amyloid stress through the maintenance of mitochondrial oxidative phosphorylation and functionality of tricarboxylic acid cycle enzymes. Notably, β-amyloid was found to selectively inhibit complex IV activity, an effect selectively neutralized by Hsp60. The combined effect of HSPs was to reduce the free radical burden, preserve ATP generation, decrease cytochrome c release, and prevent caspase-9 activation, all important mediators of β-amyloid-induced neuronal dysfunction and death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This Report explores the intersection of company law and the law of succession in the United States of America. U.S. company law features a complex variety of business entity forms, available in ...different U.S. states, with their own legal rules related to important issues such as the how much ownership is separated from control. The death of an owner, and the potential distribution of her rights and interests to heirs, can be a significant turning point in a business entity’s life as personal succession and business succession intersect. This paper offers a structure for understanding the complexity of the U.S. system by examining some potential legal effects of the death of an owner and by identifying a set of key factors of the U.S. approach to succession issues. Significant factors include the federalist nature of the U.S. system, the importance of small and family-owned businesses, and an emphasis on freedom of choice in business entity governance. Considering why these factors are critical to understanding the U.S. approach offers general insight into the current state of U.S. law as well as possible directions the law might move in the future.
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