Inhibition of CXXC5 function rescues Alzheimer's disease phenotypes by restoring Wnt/ß-catenin signaling pathway.

Alzheimer's disease (AD) is the most prevalent type of dementia and is characterized by cognitive deficits and accumulation of pathological plaques. Owing to the complexity of AD development, paradigms for AD research and drug discovery have shifted to target factors that mediate multiple pathogenesis in AD. Increasing evidence suggests that the suppression of the Wnt/ß-catenin signaling pathway plays substantial roles in AD progression. However, the underlying mechanism for the suppression of Wnt/ß-catenin pathway associated with AD pathogenesis remains unexplored. In this study, we identified that CXXC5, a negative feedback regulator of the Wnt/ß-catenin pathway, was overexpressed in the tissues of AD patients and 5xFAD transgenic mice paired with the suppression of Wnt/ß-catenin pathway and its target genes related to AD. The level of CXXC5 was upregulated, upon aging of 5xFAD mice. AD characteristics including cognitive deficits, amyloid-ß (Aß) plaques, neuronal inflammation, and age-dependent increment of AD-related markers were rescued in Cxxc5-/-/5xFAD mice. 5-methoxyindirubin-3'-oxime (KY19334), a small molecule that restores the suppressed Wnt/ß-catenin pathway via interference of the CXXC5-Dvl interaction, significantly improved the overall pathogenic phenotypes of 5xFAD mice. Collectively, our findings revealed that CXXC5 plays a key role in AD pathogenesis and suggest inhibition of CXXC5-Dvl interaction as a new therapeutic approach for AD.

Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques.

Amyloid-ß (Aß) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer's disease. However, anti-Aß drug development has been impeded by the lack of a target needed for structure-based drug design and low permeability of the blood-brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid-based anti-Aß peptidomimetics that exploit the self-assembling nature of Aß and penetrate the BBB. Herein, we designed a dimeric peptide drug candidate based on the N-terminal fragment of Aß, DAB, found to cross the BBB and solubilize Aß oligomers and fibrils. Administration of DAB reduced amyloid burden in 5XFAD mice, and downregulated neuroinflammation and prevented memory impairment in the Y-maze test. Peptide mapping assays and molecular docking studies were utilized to elucidate DAB-Aß interaction. To further understand the active regions of DAB, we assessed the dissociative activity of DAB with sequence modifications.

Physiological Roles of Monomeric Amyloid-ß and Implications for Alzheimer's Disease Therapeutics.

Alzheimer's disease (AD) progressively inflicts impairment of synaptic functions with notable deposition of amyloid-ß (Aß) as senile plaques within the extracellular space of the brain. Accordingly, therapeutic directions for AD have focused on clearing Aß plaques or preventing amyloidogenesis based on the amyloid cascade hypothesis. However, the emerging evidence suggests that Aß serves biological roles, which include suppressing microbial infections, regulating synaptic plasticity, promoting recovery after brain injury, sealing leaks in the blood-brain barrier, and possibly inhibiting the proliferation of cancer cells. More importantly, these functions were found in in vitro and in vivo investigations in a hormetic manner, that is to be neuroprotective at low concentrations and pathological at high concentrations. We herein summarize the physiological roles of monomeric Aß and current Aß-directed therapies in clinical trials. Based on the evidence, we propose that novel therapeutics targeting Aß should selectively target Aß in neurotoxic forms such as oligomers while retaining monomeric Aß in order to preserve the physiological functions of Aß monomers.

An efficient NIR-to-NIR signal-based LRET system for homogeneous competitive immunoassay.

Upconversion nanoparticles (UCNPs) are promising materials for biological applications based on luminescence resonance energy transfer (LRET). In contrast to classical RET donors such as quantum dots, gold nanoparticles, UCNPs can emit near-infrared (NIR) upon the NIR irradiation, which provides enhanced signal-to-noise due to strong penetration and low autofluorescence in the NIR region known as the diagnostic window. Here we report the first efficient NIR-to-NIR signal-based LRET system for the detection of progesterone, chosen as a proof-of-concept target, via homogeneous competitive immunoassay. To enhance the efficiency of LRET, we constructed inert-core/active-shell/inert-ultrathin shell UCNPs (NaYF4@NaYF4:Yb,Tm@NaYF4) as an LRET donor and a compact progesterone/horseradish peroxidase/IRdyeQC-1 (P-HRP-dyes) complex as an LRET acceptor. The designed donor and acceptor showed significantly improved LRET efficiencies (95% and 85% for donor and acceptor, respectively) compared with conventional donor and acceptor (70% and 50%, respectively). Using the developed NIR-to-NIR LRET system, progesterone was successfully detected with a background-free signal and low limit of detection (1.36 pg/ml in ten-fold diluted human serum). We believe that the efficient NIR-to-NIR signal-based LRET system developed here has potential as a simple probe for homogeneous competitive immunoassay, with the ability to rapidly detect biomarkers.

Achieving Long-Term Operational Stability of Perovskite Solar Cells with a Stabilized Efficiency Exceeding 20% after 1000 h.

Perovskite solar cells (PSCs) with mesoporous TiO2 (mp-TiO2) as the electron transport material attain power conversion efficiencies (PCEs) above 22%; however, their poor long-term stability is a critical issue that must be resolved for commercialization. Herein, it is demonstrated that the long-term operational stability of mp-TiO2 based PSCs with PCE over 20% is achieved by isolating devices from oxygen and humidity. This achievement attributes to systematic understanding of the critical role of oxygen in the degradation of PSCs. PSCs exhibit fast degradation under controlled oxygen atmosphere and illumination, which is accompanied by iodine migration into the hole transport material (HTM). A diffusion barrier at the HTM/perovskite interface or encapsulation on top of the devices improves the stability against oxygen under light soaking. Notably, a mp-TiO2 based PSC with a solid encapsulation retains 20% efficiency after 1000 h of 1 sun (AM1.5G including UV) illumination in ambient air.

Dynamic filtration with a perforated disk for dewatering of Tetraselmis suecica.

Dynamic filtration equipped with a perforated disk was adopted for the first time to dewater and concentrate Tetraselmis suecica, from a typical solution of 2-100 g/L of dense biomass suited for the downstream process. An ultrafiltration membrane, polyethersulfone 150 kDa, was found to best perform in terms of high biomass retention and filtration rate. At 1600 rpm, the highest rotation speed of the disk we tested, plateau permeate flux increased up to 20.2 times higher than those with no rotation; this improvement was attributed to fouling reduction (up to 98%) via distinctively high-shear stress on the membrane surface. Even at a high biomass concentration (100 g/L) where fouling formation was very serious, the heightened shear stress caused high flux to be maintained and fouling resistance to be reduced in an effective way. When trans-membrane pressure was increased in a stepwise manner, flux continuously rose at high rotation speed; at low speed, on the other hand, the limiting flux was observed. The dynamic filtration with the perforated disk, which was an effective high-shear stress generator, was proven to be a promising dewatering means of T. suecica, and especially so for the production of highly concentrated biomass.

Evaluation of various harvesting methods for high-density microalgae, Aurantiochytrium sp. KRS101.

Five technologies, coagulation, electro-flotation (EF), electro-coagulation-flotation (ECF), centrifugation, and membrane filtration, were systematically assessed for their adequacy of harvesting Aurantiochytrium sp. KRS101, a heterotrophic microalgal species that has much higher biomass concentration than photoautotrophic species. Coagulation, EF, and ECF were found to have limited efficiency. Centrifugation was overly powerful to susceptible cells like Aurantiochytrium sp. KRS101, inducing cell rupture and consequently biomass loss of over 13%. Membrane filtration, in particular equipped with an anti-fouling turbulence generator, turned out to be best suited: nearly 100% of harvesting efficiency and low water content in harvested biomass were achieved. With rotation rate increased, high permeate fluxes could be attained even with extremely concentrated biomass: e.g., 219.0 and 135.0 L/m(2)/h at 150.0 and 203.0 g/L, respectively. Dynamic filtration appears to be indeed a suitable means especially to obtain highly concentrated biomass that have no need of dewatering and can be directly processed.

Efficient CH3 NH3 PbI3 Perovskite Solar Cells Employing Nanostructured p-Type NiO Electrode Formed by a Pulsed Laser Deposition.

Highly transparent and nanostructured nickel oxide (NiO) films through pulsed laser deposition are introduced for efficient CH3 NH3 PbI3 perovskite solar cells. The (111)-oriented nanostructured NiO film plays a key role in extracting holes and preventing electron leakage as hole transporting material. The champion device exhibits a power conversion efficiency of 17.3% with a very high fill factor of 0.813.

Direct Low-Temperature Growth of Single-Crystalline Anatase TiO2 Nanorod Arrays on Transparent Conducting Oxide Substrates for Use in PbS Quantum-Dot Solar Cells.

We report on the direct growth of anatase TiO2 nanorod arrays (A-NRs) on transparent conducting oxide (TCO) substrates that can be directly applied to various photovoltaic devices via a seed layer mediated epitaxial growth using a facile low-temperature hydrothermal method. We found that the crystallinity of the seed layer and the addition of an amine functional group play crucial roles in the A-NR growth process. The A-NRs exhibit a pure anatase phase with a high crystallinity and preferred growth orientation in the [001] direction. Importantly, for depleted heterojunction solar cells (TiO2/PbS), the A-NRs improve both electron transport and injection properties, thereby largely increasing the short-circuit current density and doubling their efficiency compared to TiO2 nanoparticle-based solar cells.

Understanding the role of the dye/oxide interface via SnO2-based MK-2 dye-sensitized solar cells.

To understand the role of the dye/oxide interface, a model system using a nanocrystalline SnO2 and 3-hexyl thiophene based MK-2 dye is proposed. A thin interfacial TiO2 blocking layer (IBL) is introduced in between SnO2 and MK-2 and its effects on photocurrent-voltage, electron transport-recombination, and density of states (DOS) are systematically investigated. Compared to the bare SnO2 film, the insertion of IBL leads to a 14-fold improvement in the power conversion efficiency (PCE) despite little change in the dye adsorption amount, which is due to the 7-fold and 2-fold increase in the photocurrent density and voltage, respectively. The charge collection efficiency is substantially improved from 38% to 96% mainly due to the increase in the electron lifetime. The IBL is also found to enhance the dye regeneration efficiency as confirmed by the 15-fold faster dye bleaching recovery dynamics. The recombination resistance increases and the DOS decreases after surface modification of SnO2, which is responsible for the doubly increased voltage. This study suggests that the interfacial layer between the oxide and the dye plays a crucial role in retarding recombination, improving charge collection efficiency, increasing diffusion length, accelerating dye regeneration and narrowing the density of states.

Engineering of Sn-porphyrin networks on the silica surface: sensing of nitrophenols in water.

Sn-porphyrin networks were engineered on the surface of a thin layer chromatography (TLC) plate via Sonogashira coupling of the Sn-porphyrin building block and 1,4-diiodobenzene. The Sn-porphyrin film showed a strong Soret band absorption at 422 nm, emission at 600-630 nm, and excellent sensing performance toward nitrophenols in water.

Hollow Microporous Organic Networks Bearing Triphenylamines and Anthraquinones: Diffusion Pathway Effect in Visible Light-Driven Oxidative Coupling of Benzylamines.

Hollow microporous organic networks were prepared by using silica spheres as the template and tris(4-ethynylphenyl)amine and 2,6-diiodo-9,10-anthraquinone as the building blocks for the Sonogashira coupling. The resultant materials bearing triphenylamine and anthraquinone moieties showed efficient visible light absorption and catalytic activities in the photochemical oxidative coupling of benzylamines. Through the comparison studies of hollow and nonhollow catalytic materials, the diffusion pathway effect of the substrates was clearly observed in the photochemical conversion of benzylamines.

Systemic blockage of nitric oxide synthase by L-NAME increases left ventricular systolic pressure, which is not augmented further by Intralipid®.

Intravenous lipid emulsions (LEs) are effective in the treatment of toxicity associated with various drugs such as local anesthetics and other lipid soluble agents. The goals of this study were to examine the effect of LE on left ventricular hemodynamic variables and systemic blood pressure in an in vivo rat model, and to determine the associated cellular mechanism with a particular focus on nitric oxide. Two LEs (Intralipid(®) 20% and Lipofundin(®) MCT/LCT 20%) or normal saline were administered intravenously in an in vivo rat model following induction of anesthesia by intramuscular injection of tiletamine/zolazepam and xylazine. Left ventricular systolic pressure (LVSP), blood pressure, heart rate, maximum rate of intraventricular pressure increase, and maximum rate of intraventricular pressure decrease were measured before and after intravenous administration of various doses of LEs or normal saline to an in vivo rat with or without pretreatment with the non-specific nitric oxide synthase inhibitor N(ω)-nitro-L-arginine-methyl ester (L-NAME). Administration of Intralipid(®) (3 and 10 ml/kg) increased LVSP and decreased heart rate. Pretreatment with L-NAME (10 mg/kg) increased LSVP and decreased heart rate, whereas subsequent treatment with Intralipid(®) did not significantly alter LVSP. Intralipid(®) (10 ml/kg) increased mean blood pressure and decreased heart rate. The increase in LVSP induced by Lipofundin(®) MCT/LCT was greater than that induced by Intralipid(®). Intralipid(®) (1%) did not significantly alter nitric oxide donor sodium nitroprusside-induced relaxation in endothelium-denuded rat aorta. Taken together, systemic blockage of nitric oxide synthase by L-NAME increases LVSP, which is not augmented further by intralipid(®).

Discrepancy of optimum ratio in bulk heterojunction photovoltaic devices: initial cell efficiency vs long-term stability.

Organic photovoltaic devices are difficult to commercialize because of their vulnerability to chemical degradation related with oxygen and water and to physical degradation with aging at high temperatures. We investigated the photophysical degradation behaviors of a series of poly(3-hexylthiophene) (P3HT)/[6,6]-phenyl C61-butyric acid methyl ester (PC60BM) bulk heterojunctions (BHJs) as a model system according to the donor-acceptor ratio. We found that the optimum P3HT:PC60BM ratio in terms of long-term stability differs from that in terms of initial cell efficiency. On the basis of cell performance decays and time-resolved photoluminescence measurements, we investigated the effects of oxygen and material self-aggregation on the stability of an organic photovoltaic device. We also observed the changes in morphological geometry and analyzed the surface elements to verify the mechanisms of degradation.

Quantum-dot-sensitized solar cell with unprecedentedly high photocurrent.

The reported photocurrent density (J(SC)) of PbS quantum dot (QD)-sensitized solar cell was less than 19 mA/cm(2) despite the capability to generate 38 mA/cm(2), which results from inefficient electron injection and fast charge recombination. Here, we report on a PbS:Hg QD-sensitized solar cell with an unprecedentedly high J(SC) of 30 mA/cm(2). By Hg(2+) doping into PbS, J(SC) is almost doubled with improved stability. Femtosecond transient study confirms that the improved J(SC) is due to enhanced electron injection and suppressed charge recombination. EXAFS reveals that Pb-S bond is reinforced and structural disorder is reduced by interstitially incorporated Hg(2+), which is responsible for the enhanced electron injection, suppressed recombination and stability. Thanks to the extremely high J(SC), power conversion efficiency of 5.6% is demonstrated at one sun illumination.

Synthesis of a CdSe-graphene hybrid composed of CdSe quantum dot arrays directly grown on CVD-graphene and its ultrafast carrier dynamics.

We report the original fabrication and performance of a photocurrent device that uses directly grown CdSe quantum dots (QDs) on a graphene basal plane. The direct junction between the QDs and graphene and the high quality of the graphene grown by chemical vapor deposition enables highly efficient electron transfer from the QDs to the graphene. Therefore, the hybrids show large photocurrent effects with a fast response time and shortened photoluminescence (PL) lifetime. The PL lifetime quenching can be explained as being due to the efficient electron transfer as evidenced by femtosecond transient absorption spectroscopy. These hybrids are expected to find applications in flexible electronics and optoelectronic devices.

Excitation dynamics in anisotropic nanostructures of star-shaped CdS.

Unique starlike CdS particles were prepared from the lyotropic triblock copolymer solution system. The starlike CdS consists of a spherical core and dozens of the attached conical nanolobes. From the comparative studies with the spherical and rod-shaped CdS nanoparticles, the unique photophysical property is presented for the starlike CdS particle. The experimental results suggest that the photogenerated charge carriers at the tip-edge region of the conical nanolobe in the starlike CdS system diffuse into the thicker inner part including the core region, which is possibly due to the decreasing excited state potential gradient from the tip edge to the thicker inner part. This type of charge carrier diffusion dynamics from the surrounding to the thicker inner part in this anisotropic morphology of the starlike CdS semiconductor closely resembles the energy transfer dynamics in the organic dendrimers.