Associations between the Genetic Heritability of Dyslipidemia and Dietary Patterns in Korean Adults Based on Sex Differences.

Dyslipidemia can be defined as an abnormality in serum lipid levels that is substantially linked to genetic variations and lifestyle factors, such as diet patterns, and has distinct sex-specific characteristics. We aimed to elucidate the genetic impact of dyslipidemia according to sex and explore the associations between genetic variants and dietary patterns in large-scale population-based cohorts. After performing genome-wide association studies (GWASs) in male, female, and entire cohorts, significant single nucleotide polymorphisms (SNPs) were identified in the three groups, and genetic risk scores (GRSs) were calculated by summing the risk alleles from the selected SNPs. After adjusting for confounding variables, the risk of dyslipidemia was 2.013-fold and 2.535-fold higher in the 3rd quartile GRS group in the male and female cohorts, respectively, than in the 1st quartile GRS group. While instant noodle and soft drink intake were significantly associated with GRS related to hyperlipidemia in male cohorts, coffee consumption was substantially related to GRS related to hyperlipidemia in female cohorts. Considering the influence of genetic factors and dietary patterns, the findings of this study suggest the potential for implementing sex-specific strategic interventions to avoid dyslipidemia.

Endolysosomal impairment by binding of amyloid beta or MAPT/Tau to V-ATPase and rescue via the HYAL-CD44 axis in Alzheimer disease.

Impaired activities and abnormally enlarged structures of endolysosomes are frequently observed in Alzheimer disease (AD) brains. However, little is known about whether and how endolysosomal dysregulation is triggered and associated with AD. Here, we show that vacuolar ATPase (V-ATPase) is a hub that mediates proteopathy of oligomeric amyloid beta (Aß) and hyperphosphorylated MAPT/Tau (p-MAPT/Tau). Endolysosomal integrity was largely destroyed in Aß-overloaded or p-MAPT/Tau-positive neurons in culture and AD brains, which was a necessary step for triggering neurotoxicity, and treatments with acidic nanoparticles or endocytosis inhibitors rescued the endolysosomal impairment and neurotoxicity. Interestingly, we found that the lumenal ATP6V0C and cytosolic ATP6V1B2 subunits of the V-ATPase complex bound to the internalized Aß and cytosolic PHF-1-reactive MAPT/Tau, respectively. Their interactions disrupted V-ATPase activity and accompanying endolysosomal activity in vitro and induced neurodegeneration. Using a genome-wide functional screen, we isolated a suppressor, HYAL (hyaluronidase), which reversed the endolysosomal dysfunction and proteopathy and alleviated the memory impairment in 3xTg-AD mice. Further, we found that its metabolite hyaluronic acid (HA) and HA receptor CD44 attenuated neurotoxicity in affected neurons via V-ATPase. We propose that endolysosomal V-ATPase is a bona fide proteotoxic receptor that binds to pathogenic proteins and deteriorates endolysosomal function in AD, leading to neurodegeneration in proteopathy.Abbreviations: AAV, adeno-associated virus; Aß, amyloid beta; AD, Alzheimer disease; APP, amyloid beta precursor protein; ATP6V0C, ATPase H+ transporting V0 subunit c; ATP6V1A, ATPase H+ transporting V1 subunit A; ATP6V1B2, ATPase H+ transporting V1 subunit B2; CD44.Fc, CD44-mouse immunoglobulin Fc fusion construct; Co-IP, co-immunoprecipitation; CTSD, cathepsin D; HA, hyaluronic acid; HMWHA, high-molecular-weight hyaluronic acid; HYAL, hyaluronidase; i.c.v, intracerebroventricular; LMWHA, low-molecular-weight hyaluronic acid; NPs, nanoparticles; p-MAPT/Tau, hyperphosphorylated microtubule associated protein tau; PI3K, phosphoinositide 3-kinase; V-ATPase, vacuolar-type H+-translocating ATPase; WT, wild-type.

Pathogenic Role of RAGE in Tau Transmission and Memory Deficits.

BACKGROUND: In tauopathies, brain regions with tau accumulation strongly correlate with clinical symptoms, and spreading of misfolded tau along neural network leads to disease progression. However, the underlying mechanisms by which tau proteins enter neurons during pathological propagation remain unclear. METHODS: To identify membrane receptors responsible for neuronal propagation of tau oligomers, we established a cell-based tau uptake assay and screened complementary DNA expression library. Tau uptake and propagation were analyzed in vitro and in vivo using a microfluidic device and stereotactic injection. The cognitive function of mice was assessed using behavioral tests. RESULTS: From a genome-wide cell-based functional screening, RAGE (receptor for advanced glycation end products) was isolated to stimulate the cellular uptake of tau oligomers. Rage deficiency reduced neuronal uptake of pathological tau prepared from rTg4510 mouse brains or cerebrospinal fluid from patients with Alzheimer's disease and slowed tau propagation between neurons cultured in a 3-chamber microfluidic device. RAGE levels were increased in the brains of rTg4510 mice and tau oligomer-treated neurons. Rage knockout decreased tau transmission in the brains of nontransgenic mice after injection with Alzheimer's disease patient-derived tau and ameliorated memory loss after injection with GFP-P301L-tau-AAV. Treatment of RAGE antagonist FPS-ZM1 blocked transsynaptic tau propagation and inflammatory responses and alleviated cognitive impairment in rTg4510 mice. CONCLUSIONS: These results suggest that in neurons and microglia, RAGE binds to pathological tau and facilitates neuronal tau pathology progression and behavioral deficits in tauopathies.

Aberrant role of pyruvate kinase M2 in the regulation of gamma-secretase and memory deficits in Alzheimer's disease.

Toxic amyloid beta (Aß) species cause synaptic dysfunction and neurotoxicity in Alzheimer's disease (AD). As of yet, however, there are no reported regulators for gamma-secretase, which links a risky environment to amyloid accumulation in AD. Here, we report that pyruvate kinase M2 (PKM2) is a positive regulator of gamma-secretase under hypoxia. From a genome-wide functional screen, we identify PKM2 as a gamma-secretase activator that is highly expressed in the brains of both patients and murine models with AD. PKM2 regulates Aß production and the amount of active gamma-secretase complex by changing the gene expression of aph-1 homolog. Hypoxia induces PKM2 expression, thereby promoting gamma-secretase activity. Moreover, transgenic expression of PKM2 in 3xTg AD model mice enhances hippocampal production of Aß and exacerbates the impairment of spatial and recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aß production and memory impairment under hypoxia.

Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation.

Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer's disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.

Self-Aggregation-Controlled Rapid Chemical Bath Deposition of SnO2 Layers and Stable Dark Depolarization Process for Highly Efficient Planar Perovskite Solar Cells.

Planar perovskite solar cells (PSCs) incorporating n-type SnO2 have attracted significant interest because of their excellent photovoltaic performance. However, the film fabrication of SnO2 is limited by self-aggregation and inhomogeneous growth of the intermediate phase, which produces poor morphology and properties. In this study, a self-controlled SnO2 layer is fabricated directly on a fluorine-doped tin oxide (FTO) surface through simple and rapid chemical bath deposition. The PSCs based on this hydrolyzed SnO2 layer exhibit an excellent power conversion efficiency of 20.21 % with negligible hysteresis. Analysis of the electrochemical impedance spectroscopy on the charge transport dynamics indicates that the bias voltage influences both interfacial charge transportation and the ionic double layer under illumination. The hydrolyzed SnO2 -based PSCs demonstrate a faster ionic charge response time of 2.5 ms in comparison with 100.5 ms for the hydrolyzed TiO2 -based hysteretic PSCs. The results of quasi-steady-state carrier transportation indicate that a dynamic hysteresis in the J-V curves can be explained by complex ionic-electronic kinetics owing to the slow ionic charge redistribution and hole accumulation caused by electrode polarization, which causes an increase in charge recombination. This study reveals that SnO2 -based PSCs lead to a stabilized dark depolarization process compared with TiO2 -based PSCs, which is relevant to the charge transport dynamics in the high-performing planar SnO2 -based PSCs.

The Design of a CMOS Nanoelectrode Array with 4096 Current-Clamp/Voltage-Clamp Amplifiers for Intracellular Recording/Stimulation of Mammalian Neurons.

CMOS microelectrode arrays (MEAs) can record electrophysiological activities of a large number of neurons in parallel but only extracellularly with low signal-to-noise ratio. Patch clamp electrodes can perform intracellular recording with high signal-to-noise ratio but only from a few neurons in parallel. Recently we have developed and reported a neuroelectronic interface that combines the parallelism of the CMOS MEA and the intracellular sensitivity of the patch clamp. Here, we report the design and characterization of the CMOS integrated circuit (IC), a critical component of the neuroelectronic interface. Fabricated in 0.18-µm technology, the IC features an array of 4,096 platinum black (PtB) nanoelectrodes spaced at a 20 µm pitch on its surface and contains 4,096 active pixel circuits. Each active pixel circuit, consisting of a new switched-capacitor current injector--capable of injecting from ±15 pA to ±0.7 µA with a 5 pA resolution--and an operational amplifier, is highly configurable. When configured into current-clamp mode, the pixel intracellularly records membrane potentials including subthreshold activities with ∼23 µVrms input referred noise while injecting a current for simultaneous stimulation. When configured into voltage-clamp mode, the pixel becomes a switched-capacitor transimpedance amplifier with ∼1 pArms input referred noise, and intracellularly records ion channel currents while applying a voltage for simultaneous stimulation. Such voltage/current-clamp intracellular recording/stimulation is a feat only previously possible with the patch clamp method. At the same time, as an array, the IC overcomes the lack of parallelism of the patch clamp method, measuring thousands of mammalian neurons in parallel, with full-frame intracellular recording/stimulation at 9.4 kHz.

A nanoelectrode array for obtaining intracellular recordings from thousands of connected neurons.

Current electrophysiological or optical techniques cannot reliably perform simultaneous intracellular recordings from more than a few tens of neurons. Here we report a nanoelectrode array that can simultaneously obtain intracellular recordings from thousands of connected mammalian neurons in vitro. The array consists of 4,096 platinum-black electrodes with nanoscale roughness fabricated on top of a silicon chip that monolithically integrates 4,096 microscale amplifiers, configurable into pseudocurrent-clamp mode (for concurrent current injection and voltage recording) or into pseudovoltage-clamp mode (for concurrent voltage application and current recording). We used the array in pseudovoltage-clamp mode to measure the effects of drugs on ion-channel currents. In pseudocurrent-clamp mode, the array intracellularly recorded action potentials and postsynaptic potentials from thousands of neurons. In addition, we mapped over 300 excitatory and inhibitory synaptic connections from more than 1,700 neurons that were intracellularly recorded for 19 min. This high-throughput intracellular-recording technology could benefit functional connectome mapping, electrophysiological screening and other functional interrogations of neuronal networks.

Investigation of Hole-Transporting Poly(triarylamine) on Aggregation and Charge Transport for Hysteresisless Scalable Planar Perovskite Solar Cells.

Organometallic halide perovskite solar cells (PSCs) have unique photovoltaic properties for use in next-generation solar energy harvesting systems. The highest efficiency of PSCs reached 22.1% on a laboratory scale of <0.1 cm2 device area. Thus, scaling up is the next step toward commercialization, but the difficulty in controlling the quality of large-area perovskite thin films remains a fundamental challenge. It has also been frequently reported that the J- V hysteresis is intensified in PSCs with areas larger than 1 cm2. In this study, we have fabricated a large-area perovskite layer using PbICl films, providing an intrinsic porous layer and enhancing the uniformity of the perovskite layer at areas larger than 1 cm2. Furthermore, we have investigated the polymeric properties of the prevalent hole-transporting material poly(triarylamine) (PTAA) with its photovoltaic performance. Two types of PTAAs, poly[bis(4-phenyl)(2,4-dimethylphenyl)amine] and poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine], were compared. A series of PTAAs with different molecular weights ( Mw) and polydispersity indices were studied, as the molecular weight of the PTAA is a key factor in determining the electrical properties and photovoltaic performance of the system. The fabricated PSCs with an aperture area of 1 cm2 based on a high-molecular-weight PTAA achieved a power conversion efficiency of 16.47% with negligible hysteresis and excellent reproducibility.

Pimozide reduces toxic forms of tau in TauC3 mice via 5' adenosine monophosphate-activated protein kinase-mediated autophagy.

In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non-mTOR pathways is a new option for autophagy-based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK-Unc-51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase-cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40-insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR-independent AMPK-ULK1 axis.

Radiation Resistant Vanadium-Graphene Nanolayered Composite.

Ultra high strength V-graphene nanolayers were developed for the first time that was demonstrated to have an excellent radiation tolerance as revealed by the He(+) irradiation study. Radiation induced hardening, evaluated via nanopillar compressions before and after He(+) irradiation, is significantly reduced with the inclusion of graphene layers; the flow stresses of V-graphene nanolayers with 110 nm repeat layer spacing showed an increase of 25% while pure V showed an increase of 88% after He(+) dosage of 13.5 dpa. The molecular dynamics simulations confirmed that the graphene interface can spontaneously absorb the nearby crystalline defects that are produced from a collision cascade, thereby enhancing the lifetime of the V-graphene nanolayers via this self-healing effect. In addition, the impermeability of He gas through the graphene resulted in suppression of He bubble agglomerations that in turn reduced embrittlement. In-situ SEM compression also showed the ability of graphene to hinder crack propagation that suppressed the failure.

Strengthening effect of single-atomic-layer graphene in metal-graphene nanolayered composites.

Graphene is a single-atomic-layer material with excellent mechanical properties and has the potential to enhance the strength of composites. Its two-dimensional geometry, high intrinsic strength and modulus can effectively constrain dislocation motion, resulting in the significant strengthening of metals. Here we demonstrate a new material design in the form of a nanolayered composite consisting of alternating layers of metal (copper or nickel) and monolayer graphene that has ultra-high strengths of 1.5 and 4.0 GPa for copper-graphene with 70-nm repeat layer spacing and nickel-graphene with 100-nm repeat layer spacing, respectively. The ultra-high strengths of these metal-graphene nanolayered structures indicate the effectiveness of graphene in blocking dislocation propagation across the metal-graphene interface. Ex situ and in situ transmission electron microscopy compression tests and molecular dynamics simulations confirm a build-up of dislocations at the graphene interface.