Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein E allele ε4 (apoE4) is a strong risk factor for developing Alzheimer's disease (AD). Secreted apoE has a critical function in redistributing lipids among central nervous system cells to maintain normal lipid homeostasis. In addition, previous reports have shown that apoE4 is cleaved by a protease in neurons to generate apoE4(1–272) fragment, which is associated with neurofibrillary tanglelike structures and mitochondria, causing mitochondrial dysfunction. However, it still remains unclear how the apoE fragment associates with mitochondria and induces mitochondrial dysfunction.</p> <p>Results</p> <p>To clarify the molecular mechanism, we carried out experiments to identify intracellular apoE-binding molecules and their functions in modulating mitochondria function. Here, we found that apoE4 binds to ubiquinol cytochrome <it>c </it>reductase core protein 2 (UQCRC2) and cytochrome C1, both of which are components of mitochondrial respiratory complex III, and cytochrome <it>c </it>oxidase subunit 4 isoform 1 (COX IV 1), which is a component of complex IV, in Neuro-2a cells. Interestingly, these proteins associated with apoE4(1–272) more strongly than intact apoE4(1–299). Further analysis showed that in Neuro-2a cells expressing apoE4(1–272), the enzymatic activities of mitochondrial respiratory complexes III and IV were significantly lower than those in Neuro-2a cells expressing apoE4(1–299).</p> <p>Conclusion</p> <p>ApoE4(1–272) fragment expressed in Neuro2a cells is associated with mitochondrial proteins, UQCRC2 and cytochrome C1, which are component of respiratory complex III, and with COX IV 1, which is a member of complex IV. Overexpression of apoE4(1–272) fragment impairs activities of complex III and IV. These results suggest that the C-terminal-truncated fragment of apoE4 binds to mitochondrial complexes and affects their activities, and thereby leading to neurodegeneration.</p

Describing coseismic groundwater level rise using tank model in volcanic aquifers, Kumamoto, southern Japan

The change of groundwater levels after the 2016 Mw 7.0 Kumamoto crustal earthquake was evaluated using a simple conceptual hydrological model in an attempt to show the presence, intensity, and probable mechanism of water level rise observed in Kumamoto where a comprehensive observation-well network exists. A tank model was applied to verify 16 wells in the study field. In the model groundwater levels were first calibrated for the periods in ca. 2 years before the main shock using several hydrological parameters including precipitation, evapotranspiration, water recharge and discharge, and artificial recharge by irrigation. Water levels were then simulated by extrapolating this law of water fluctuating patterns for ca. 2.5 years after the main shock of the earthquake, without considering hydrogeological changes due to the earthquake. A difference in groundwater levels between observation and simulation results yields a degree of coseismic water level rises for each well. The coseismic abnormal water level increase was calculated to be ~11 m in 4?5 month after the main shock and was most significantly on the western slope of the Aso caldera rim mountains. The spatial distribution of the coseismic water increases clarified that the most dominate increasing anomalies prevail at mountain feet surrounding the plains, suggesting the occurrence of coseismic mountain water release resulting in the rise of water levels in downslope aquifers. Identified coseismic water level increases still continue up to 2.5 years after the earthquake, probably because changes in hydrogeological properties in mountain aquifers, i.e., permeability, are still sustained. Our forecasting water recovering trends require ca. 3.5?5 year after the earthquake for complete recovery to the original conditions. We demonstrated that our approaches are capable of describing coseismic water level changes and could potentially be applied to other fields

Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons

Background: Recently, several lines of evidence have shown the aberrant expression of cell-cycle-related proteins and tumor suppressor proteins in vulnerable neurons of the Alzheimer's disease (AD) brain and transgenic mouse models of AD; these proteins are associated with various paradigms of neuronal death. It has been reported that ATBF1 induces cell cycle arrest associated with neuronal differentiation in the developing rat brain, and that gene is one of the candidate tumor suppressor genes for prostate and breast cancers in whose cells overexpressed ATBF1 induces cell cycle arrest. However, the involvement of ATBF1 in AD pathogenesis is as yet unknown. Results: We found that ATBF1 was up-regulated in the brains of 17-month-old Tg2576 mice compared with those of age-matched wild-type mice. Moreover, our in vitro studies showed that Aβ1-42 and DNA-damaging drugs, namely, etoposide and homocysteine, increased the expression ATBF1 level in primary rat cortical neurons, whereas the knockdown of ATBF1 in these neurons protected against neuronal death induced by Aβ1-42, etoposide, and homocysteine, indicating that ATBF1 mediates neuronal death in response to these substances. In addition, we found that ATBF1-mediated neuronal death is dependent on ataxia-telangiectasia mutated (ATM) because the blockage of ATM activity by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 function in neuronal death. Furthermore, Aβ1-42 phosphorylates ATM, and ATBF1 interacts with phosphorylated ATM. Conclusions: To the best of our knowledge, this is the first report that Aβ1-42 and DNA-damaging drugs increased the ATBF1 expression level in primary rat cortical neurons; this increase, in turn, may activate ATM signaling responsible for neuronal death through the binding of ATBF1 to phosphorylated ATM. ATBF1 may therefore be a suitable target for therapeutic intervention of AD

Recovery of Lost Nexus Synergy via Payment for Environmental Services in Kumamoto, Japan

The objective of this study is to characterize and quantify the “trans-spatial nexus synergy” benefit of subsidized water ponding in the water-energy-food nexus in Kumamoto, Japan. After years of decreased rice production in upstream areas and associated declines in groundwater levels, the Kumamoto city government implemented a subsidy program whereby farmers in the Shira River basin receive payments to water their fields, which provides valuable groundwater recharge to downstream Kumamoto city. We quantify the economic benefits of this subsidy program, which include avoided additional energy costs to obtain scarcer levels of groundwater, as well as net revenue from the crops in the Shira River basin that would otherwise not be grown in the absence of the subsidy. These annual benefits can be combined and compared to the annual cost of the government subsidy. We also calculate potential historical losses that may have occurred in the region as a result of land use transitions from rice farming to urban use, which disrupted the nexus synergy between the watered fields and the groundwater table

Electronic and Magnetic Phase Diagram of a Superconductor, SmFeAsO1-xFx

A crystallographic and magnetic phase diagram of SmFeAsO1-xFx is determined as a function of x in terms of temperature based on electrical transport and magnetization, synchrotron powder x-ray diffraction, 57Fe Mossbauer spectra (MS), and 149Sm nuclear resonant forward scattering (NRFS) measurements. MS revealed that the magnetic moments of Fe were aligned antiferromagnetically at ~144 K (TN(Fe)). The magnetic moment of Fe (MFe) is estimated to be 0.34 myuB/Fe at 4.2 K for undoped SmFeAsO; MFe is quenched in superconducting F-doped SmFeAsO. 149Sm NRFS spectra revealed that the magnetic moments of Sm start to order antiferromagnetically at 5.6 K (undoped) and 4.4 K (TN(Sm)) (x = 0.069). Results clearly indicate that the antiferromagnetic Sm sublattice coexists with the superconducting phase in SmFeAsO1-xFx below TN(Sm), while antiferromagnetic Fe sublattice does not coexist with the superconducting phase.Comment: Accepted in New Journal of Physic

Manual on the proper use of the 211At-labeled PSMA ligand ([211At]PSMA-5) for clinical trials of targeted alpha therapy (1st edition)

The version of record of this article, first published in Annals of Nuclear Medicine, is available online at Publisher’s website: https://doi.org/10.1007/s12149-024-01916-6.Recently, an astatine-labeled prostate-specific membrane antigen (PSMA) ligand ([211At]PSMA-5) has been developed for the targeted alpha therapy of patients with prostate cancer. This manual delineates its physicochemical characteristics to assist healthcare professionals in understanding the α-ray-emitting drug of [211At]PSMA-5 when administered to patients. The safety considerations regarding the handling and use of this drug in clinical trials are outlined, based on the proper usage manual of previous studies. The dose limits, as defined by the guidelines of the International Commission on Radiological Protection (ICRP) and the International Atomic Energy Agency (IAEA), are assessed for patients’ caregivers and the general public. According to the calculations provided in this manual, clinical trials involving [211At]PSMA-5 can be safely conducted for these populations even if patients are released after its administration. Moreover, this manual provides comprehensive guidance on the handling of [211At]PSMA-5 for healthcare facilities, and compiles a list of precautionary measures to be distributed among patients and their caregivers. While this manual was created by a research team supported by Ministry of Health, Labour, and Welfare in Japan and approved by Japanese Society of Nuclear Medicine, its applicability extends to healthcare providers in other countries. This manual aims to facilitate conducting clinical trials using [211At]PSMA-5 in patients with prostate cancer

TRANSPORT AND TRANSFORMATION OF CHEMICAL COMPONENTS IN THE GROUNDWATER FLOW SYSTEM OF JAKARTA METROPOLITAN AREA

ABSTRACT The aim of this study is to examine the transport and transformation of chemical components within the groundwater flow in Jakarta area, and to evaluate the effects of accelerated urbanization on it. The collected data showed that the current hydraulic potential in the Jakarta metropolitan area is below sea level because of prior excess abstraction of groundwater. The distribution of Cl- and Mn2- concentration in groundwater suggests that the decline in hydraulic potential has caused the intrusion of seawater to shallow groundwater and the movement of shallow groundwater into deep groundwater. It implies an accumulation of contaminants in deep aquifers. On the other hands, the presentation of NO3--N in groundwater is suggested to be attenuated by the processes of denitrification and dilution in the coastal area