Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis

Apolipoprotein E ε4 (APOE ε4) is the strongest genetic risk factor for Alzheimer’s disease (AD). Evidence suggests that the effect of apoE isoforms on amyloid-β (Aβ) accumulation in the brain plays a critical role in AD pathogenesis. Like in humans, apoE4 expression in animal models that develop Aβ-amyloidosis results in greater Aβ and amyloid deposition than with apoE3 expression. However, whether decreasing levels of apoE3 or apoE4 would promote or attenuate Aβ-related pathology has not been directly addressed. To determine the effect of decreasing human apoE levels on Aβ accumulation in vivo, we generated human APOE isoform haploinsufficient mouse models by crossing APPPS1-21 mice with APOE isoform knock-in mice. By genetically manipulating APOE gene dosage, we demonstrate that decreasing human apoE levels, regardless of isoform status, results in significantly decreased amyloid plaque deposition and microglial activation. This differences in amyloid load between apoE3 and apoE4 expressing mice were not due to apoE4 protein being present at lower levels than apoE3. These data suggest that current therapeutic strategies to increase apoE levels without altering its lipidation state may actually worsen Aβ amyloidosis, while increasing apoE degradation or inhibiting its synthesis may be a more effective treatment approach

CFD analysis of fluid flow through reconstructed metal foams

The global energy demand signifies the importance of developing cutting-edge and state of the art heat exchanger technologies. The deployment of porous metal foams in various heat exchangers is one such material that is rapidly gaining attention in the research field. However, an in-depth comparative analysis of fluid flow through metal foams is relatively scarce in the existing literature. This study aims to use computational fluid dynamics (CFD) to examine forced convection of various fluids through digitized samples of porous metal foams. Results have shown that an increase in fluid velocity results in a decline in average fluid temperature. Moreover, the type of fluid has a direct effect on the temperature distribution and spread of the fluid temperature around the foam ligaments. This study aims to address critical queries in the literature namely unravelling forced convection of fluids through metal foams for compact and lightweight heat exchangers. This could potentially serve as a steppingstone to devise ways of mitigating fouling and maximizing heat exchanger performance

Implication of various membranes to remove NOM typically occurring in Korea with respect to DBP, AOC and transport parameters

Bench- and pilot-scale membrane tests were performed to remove natural organic matter (NOM) originating from Paldang Lake in Korea. Membrane performance was demonstrated in terms of DOC, biodegradable organic carbon (BDOC), assimilable organic carbon (AOC), and transport parameters. Various membranes such as reverse osmosis (RO), nanofiltration (NF) and ultrafiltration (UF) were investigated for this study. Four different NF membranes were selected for pilot-scale filtration testing and investigated in terms of both flux decline and DOC removal. To demonstrate the effect of temperature on the source water seasonally, the flux of membranes was measured with pure water at different temperatures ranging from 25 to 7 degrees C. Coagulation/sedimentation treated water was used as feed water without removing residual chlorine; related plants were located at the Suji water treatment plant of Yongin City. To investigate more rigorously the organic fouling for various NF membranes, mass transport behaviors of organic matter solutes were evaluated by an irreversible thermodynamic model. The pore sizes of the NF membranes tested in the pilot slightly increased due to the oxidation of the polymer structure of the membranes from residual chlorine during the 4-month tests. Periodic chemical cleaning with a caustic solution was made to prevent accumulation of foulants on the membrane surface. The NF membranes exhibited stable efficiencies in terms of DOC and AOC removal during the test for 4 monthsclose142

Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl‐tRNA synthetase 1

Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety