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Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Chung, Won-Suk,Verghese, Philip B.,Chakraborty, Chandrani,Joung, Julia,Hyman, Bradley T.,Ulrich, Jason D.,Holtzman, David M.,Barres, Ben A. National Academy of Sciences 2016 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.113 No.36
<P>The strongest genetic risk factor influencing susceptibility to lateonset Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by similar to 12-fold whereas E2 allele is associated with an similar to twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.</P>
Brosius Lutz, Amanda,Chung, Won-Suk,Sloan, Steven A.,Carson, Glenn A.,Zhou, Lu,Lovelett, Emilie,Posada, Sean,Zuchero, J. Bradley,Barres, Ben A. National Academy of Sciences 2017 Proceedings of the National Academy of Sciences Vol.114 No.38
<P>Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system's remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury.</P>
Selective Migration and Economic Growth in México
Jaime Lara Lara,Bernardo Garza Gómez,Dania Monárrez Barrón,Emilio Mátar Zambrano,Gustavo Vázquez García 중앙대학교 경제연구소 2023 Journal of Economic Development Vol.48 No.1
The objective of this study is to determine the impact of selective internal migration on regional economic growth in Mexico. The net skilled migration rate has no significant impact on growth. The net migration rate is positively correlated with economic growth, but has no effect when endogeneity is solved. Together, the results indicate that there is no significant and robust causal impact of migration on growth. These results sustain even when we consider the negative effect that population growth rate have on regional economies.
Blood-brain Barrier Damage is Pivotal for SARS-CoV-2 Infection to the Central Nervous System
Rodríguez-Morales Jahir,Guartazaca-Guerrero Sebastián,Rizo-Téllez Salma A.,Viurcos-Sanabria Rebeca,Barrón Eira Valeria,Hernández-Valencia Aldo F.,Nava Porfirio,Escobedo Galileo,Carrillo-Ruiz José Dami 한국뇌신경과학회 2022 Experimental Neurobiology Vol.31 No.4
Transsynaptic transport is the most accepted proposal to explain the SARS-CoV-2 infection of the CNS. Nevertheless, emerging evidence shows that neurons do not express the SARS-CoV-2 receptor ACE2, which highlights the importance of the blood-brain barrier (BBB) in preventing virus entry to the brain. In this study, we examine the presence of SARS-CoV-2 messenger ribonucleic acid (mRNA) and the cytokine profile in cerebrospinal fluids (CSF) from two patients with a brain tumor and COVID-19. To determine the BBB damage, we evaluate the Q- albumin index, which is an indirect parameter to assess the permeability of this structure. The Q-albumin index of the patient with an intraventricular brain tumor suggests that the BBB is undamaged, preventing the passage of SARS-CoV-2 and pro-inflammatory molecules. The development of brain tumors that disrupt the BBB (measured by the Q-albumin index), in this case, a petroclival meningioma (Case 1), allows the free passage of the SARS-CoV-2 virus and probably lets the free transit of pro-inflammatory molecules to the CNS, which leads to a possible activation of the microglia (astrogliosis) and an exacerbated immune response represented by IL-13, IFN-γ, and IL-2 trying to inhibit both the infection and the carcinogenic process.
Shaft resistance of bored cast-in-place concrete piles in oil sand - Case study
Barr, L.,Wong, R.C.K. Techno-Press 2013 Geomechanics & engineering Vol.5 No.2
Pile load tests using Osterberg cells (O-cell) were conducted on cast-in-place concrete piles founded in oil sand fill and in situ oil sand at an industrial plant site in Fort McMurray, Alberta, Canada. Interpreted pile test results show that very high pile shaft resistance (with the Bjerrum-Burland or Beta coefficient of 2.5-4.5) against oil sand could be mobilized at small relative displacements of 2-3% of shaft diameter. Finite element simulations based on linear elastic and elasto-plastic models for oil sand materials were used to analyze the pile load test measurements. Two constitutive models yield comparable top-down load versus pile head displacement curves, but very different behaviour in mobilization of pile shaft and end bearing resistances. The elasto-plastic model produces more consistent matching in both pile shaft and end bearing resistances whereas the linear elastic under- and over-predicts the shaft and end bearing resistances, respectively. The mobilization of high shaft resistance in oil sand under pile load is attributed to the very dense and interlocked structure of oil sand which results in high matrix stiffness, high friction angle, and high shear dilation.
The Economics of Skyscraper Construction in Manhattan: Past, Present, and Future
Barr, Jason Council on Tall Building and Urban Habitat Korea 2016 International journal of high-rise buildings Vol.5 No.2
This paper discusses the economics of skyscraper construction in Manhattan since 1990. First the paper reviews the economic theory of skyscraper height. Next it documents the frequency and heights of skyscraper construction in the last 25 years. Then the paper reviews the relative movements of office rents, condominium prices, and construction costs. Statistical results suggest that the resurgence of Manhattan's skyscraper construction is being driving by the rise in the average price of apartments, and is not being driven by rising office rents or falling construction costs. Statistical evidence shows that the height premium has not been rising over the last decade. Developers have been purchasing air rights (and bidding up the prices) in order to satisfy the demand for supertall buildings. In the next five to ten years, Manhattan is likely to see over thirty 200-meter or taller buildings, as compared to only four since 2010.