Harnessing Nanochaperone-Mediated Autophagy for Selective Clearance of Pathogenic Tau Protein in Alzheimer's Disease.

Accumulation of pathological tau is a hallmark of Alzheimer's disease (AD), which correlates more closely with cognitive impairment than does the amyloid-ß (Aß) burden. Autophagy is a powerful process for the clearance of toxic proteins including aberrant tau. However, compromised autophagy is demonstrated in neurodegeneration including AD, and current autophagy inducers remain enormously challenging due to inability of restoring autophagy pathway and lack of targeting specificity. Here, pathogenic tau-specific autophagy based on customized nanochaperone is developed for AD treatment. In this strategy, the nanochaperone can selectively bind to pathogenic tau and maintain tau homeostasis, thereby ensuring microtubule stability which is important for autophagy pathway. Meanwhile, the bound pathogenic tau can be sequestered in autophagosomes by in situ autophagy activation of nanochaperone. Consequently, autophagosomes wrapping with pathogenic tau are able to be trafficked along the stabilized microtubule to achieve successful fusion with lysosomes, resulting in the enhancement of autophagic flux and pathologic tau clearance. After treatment with this nanochaperone-mediated autophagy strategy, the tau burden, neuron damages, and cognitive deficits of AD mice are significantly alleviated in the brain. Therefore, this work represents a promising candidate for AD-targeted therapy and provides new insights into future design of anti-neurodegeneration drugs.

Characteristics and mechanisms of phosphine production in sulfur-based constructed wetlands.

Phosphine (PH3) is an important contributor to the phosphorus cycle and is widespread in various environments. However, there are few studies on PH3 in constructed wetlands (CWs). In this study, lab-scale CWs and batch experiments were conducted to explore the characteristics and mechanisms of PH3 production in sulfur-based CWs. The results showed that the PH3 release flux of sulfur-based CWs varied from 0.86±0.04 ng·m-2·h-1 to 1.88±0.09 ng·m-2·h-1. The dissolved PH3 was the main PH3 form in CWs and varied from 2.73 µg·L-1 to 4.08 µg·L-1. The matrix-bound PH3 was a staging reservoir for PH3 and increased with substrate depth. In addition, the sulfur-based substrates had a significant improvement on PH3 production. Elemental sulfur is more conducive to PH3 production than pyrite. Moreover, there was a significant positive correlation between PH3 production, the dsrB gene, and nicotinamide adenine dinucleotide (NADH). NADH might catalyze the phosphate reduction process. And the final stage of the dissimilatory sulfate reduction pathway driven by the dsrB gene might also provide energy for phosphate reduction. The migration and transformation of PH3 increased the available P (Resin-P and NaHCO3-P) from 35 % to 56 % in sulfur-based CW, and the P adsorption capacity was improved by 12 %. The higher proportion of available P increased the plant uptake rate of P by 17 %. This study improves the understanding of the phosphorus cycle in sulfur-based CW and provides new insight into the long-term stable operation of CWs.

Biodegradation of chloroxylenol by an aerobic enrichment consortium and a newly identified Rhodococcus strain.

Chloroxylenol is a commonly used antimicrobial agent in antibacterial and disinfection products, which has been detected in various environments, such as wastewater treatment plants, rivers, seawater, and even drinking water, with concentrations ranging from ng/L to mg/L. However, the biodegradation of chloroxylenol received limited attention with only sporadic reports available so far. In this study, an efficient chloroxylenol-degrading consortium, which could degrade 20 mg/L chloroxylenol within two days, was obtained after five months of enrichment. Amplicon sequencing analysis revealed a decrease in the α-diversity (e.g., Shannon index and Inv_Simpson index) of the community during the domestication process. Microbial community dynamics were uncovered, with sequences affiliated to Achromobacter, Pseudomonas, and Rhodococcus identified as the most abundant taxonomic groups. From the consortium, five pure isolates were obtained; however, it was found that only one strain of Rhodococcus could degrade chloroxylenol. Strain Rhodococcus sp. DMU2021 could degrade chloroxylenol efficiently under the conditions of temperature 30-40 °C, and neutral/alkaline conditions. Chloroxylenol was toxic to strain DMU2021 and triggered both enzymatic and non-enzymatic antioxidant systems in response. This study provides novel insights into the biodegradation process of chloroxylenol, as well as valuable bioresources for bioremediation.

Self-Assembly Nanochaperone with Tunable Hydrophilic-Hydrophobic Surface for Controlled Protein Refolding.

Nanochaperones (nChaps) have significant potential to inhibit protein aggregation and assist in protein refolding. The interaction between nChaps and proteins plays an important role in nChaps performing chaperone-like functions, but the interaction mechanism remains elusive. In this work, a series of nChaps with tunable hydrophilic-hydrophobic surfaces are prepared, and the process of nChaps-assisted denatured protein refolding is systematically explored. It is found that an appropriate hydrophilic-hydrophobic balance on the nChap surface is critical for enhancing protein renaturation. This is because only the optimal interaction between nChap and protein can simultaneously guarantee the suitable capture and sufficient release of client proteins. The findings in this work will provide an effective reference for the design of nChaps and contribute to the development of the potential of nChaps in the future.

Advances in Self-Assembled Peptides as Drug Carriers.

In recent years, self-assembled peptide nanotechnology has attracted a great deal of attention for its ability to form various regular and ordered structures with diverse and practical functions. Self-assembled peptides can exist in different environments and are a kind of medical bio-regenerative material with unique structures. These materials have good biocompatibility and controllability and can form nanoparticles, nanofibers and hydrogels to perform specific morphological functions, which are widely used in biomedical and material science fields. In this paper, the properties of self-assembled peptides, their influencing factors and the nanostructures that they form are reviewed, and the applications of self-assembled peptides as drug carriers are highlighted. Finally, the prospects and challenges for developing self-assembled peptide nanomaterials are briefly discussed.

How yielding cameras affect consecutive pedestrian-vehicle conflicts at non-signalized crosswalks? A mixed bivariate generalized ordered approach.

Yielding cameras are considered to be an effective means of preventing drivers' non-yielding behavior. Notably, as pedestrians' perceived risk and behavior change dynamically during the crossing, the safety effectiveness of such facility could also vary across the consecutive conflicts. This study contributes to the literature by assessing the safety effectiveness of yielding camera from a novel perspective, focusing on the consecutive pedestrian-vehicle conflicts (primary conflict and secondary conflict), using Unmanned Aerial Vehicle (UAV) and roadside camera data. Another key contribution lies in the consideration of primary conflict related factors in the secondary conflict analysis, providing new insights into conflict analysis. The mixed bivariate generalized ordered probit model is proposed to analyze the consecutive conflicts simultaneously. The model results indicate that the yielding camera could decrease both slight and severe conflict probability in primary conflict. However, in secondary conflict, the yielding camera would lower severe conflict probability but increase slight conflict probability. Moreover, several primary conflict related factors reveal significant effects on the secondary conflict severity. Specifically, higher pedestrian speed and driver's yielding behavior in primary conflict could lead to higher crossing risks in the secondary conflict. Conversely, more unsuccessful attempts before primary conflict could decrease the severity level of secondary conflict. Based on the results, several practical implications are provided to improve the effectiveness of yielding camera and enhance pedestrian safety.

Prevent Drug Leakage via the Boronic Acid Glucose-Insensitive Micelle for Alzheimer's Disease Combination Treatment.

Boronic acid (BA) materials have been widely applied to glucose and oxidative stress-sensitive drug delivery for the treatment of cancer, diabetes, and Alzheimer's disease (AD). There are completely various BA-sensitive delivery conditions in different diseases. BA materials in the treatment of diabetes show better performance at a high-glucose environment than normal. In contrast, the concentration of glucose in the brain is much lower than that in the blood of AD patients. Hence, the typical glucose and oxidative stress dual-sensitive BA materials inevitably encounter drug leakage in circulation in AD. Attempts to decrease the glucose-sensitive capacity of BA materials are extremely essential for AD drug delivery. In this study, the epoxy group (electron-donating group) was introduced to increase the pKa values of BA materials by increasing the electron cloud density, and thus, the glucose-insensitive micelle (GIM) was obtained. The treatment effect and the synergism mechanism of the drug-loaded GIM micelle were studied on senescence-accelerated mouse prone 8 mice. This work provided excellent antioxidant drugs (vitamin E succinate, melatonin, and quercetin) and a glucose metabolism drug (insulin) loaded in GIM micelle for AD treatment. The discovery of the combination mechanism is enormously valuable for AD clinical research.

Impacts of enforcement cameras on pedestrians' risk perception and drivers' behaviors at non-signalized crosswalks.

INTRODUCTION: Pedestrians are more vulnerable to traffic crashes than other road users, particularly at non-signalized crosswalks. Safety measures (such as law enforcement cameras) can be implemented to regulate road users' behavior and traffic safety. This study evaluates the effects of such cameras on pedestrian-vehicle conflicts by investigating different interaction patterns of pedestrian risk perception and driving style. DATA: Field investigations were conducted at four non-signalized crosswalks. Video data were collected using unmanned aerial vehicles and roadside cameras. METHOD: Two-step cluster analysis and k-means cluster analysis were employed to classify the pedestrian's behavior and driving style, respectively. Surrogate safety measures were adopted to measure the pedestrian-vehicle conflicts. RESULTS AND CONCLUSIONS: The results suggest that the implementation of cameras would decrease both the actual and perceived risks of pedestrians, while the heterogeneity between the actual and perceived risk is more obvious at camera sites. They also indicate that the cameras have a positive influence on reducing drivers' aggressiveness and conflict severity. In terms of pedestrian-vehicle interaction patterns, the most severe conflicts occur when the pedestrian perceived risk level is low and the driving style is aggressive. Such dangerous interactions are observed more frequently at camera sites. In contrast, a safer interaction pattern is associated with a moderate driving style and cautious crossing behavior, which is more frequently observed at comparison sites. However, regardless of which interaction pattern is observed, the conflict severity is found to be lower at camera sites, indicating the effectiveness of the cameras. PRACTICAL APPLICATIONS: Supplementary facilities, such as warning signs, flash lights, and speed control measures, should be implemented to maintain the effectiveness of the law enforcement cameras.

Ultra-stable dextran conjugated prodrug micelles for oxidative stress and glycometabolic abnormality combination treatment of Alzheimer's disease.

Sophisticated nanomedicines are continually being developed, but big obstacles remain before they finish the drug release mission. The first challenge is rupture possibility of structure when infinite dilution, competitive reaction of electrolytes and protein in blood circulation. In addition, low responsive drug release efficiency in the lesion site remains the major challenge for clinical application of nanomedicine combination treatment. In this study, we discussed the opportunities for Alzheimer's disease (AD) combination therapy based on the thermodynamically ultra-stable dextran conjugated prodrug micelles. Dextran-nateglinide conjugated prodrug micelles (NA) and dextran-vitamin E succinate conjugated prodrug micelles (VES) presented ultra-low critical micelle concentration of ~10-5 mM and high physiological stability when challenged by NaCl, sodium dodecyl sulphate (SDS), dodecyl dimethyl benzyl ammonium chloride (DDBAC) and no rupture of structure happened. The NA/insulin polymer-drug conjugate micelles (NA/INS PDC) and VES/insulin polymer-drug conjugate micelles (VES/INS PDC) efficiently cleaved by reactive oxygen species (ROS), leading to over 80% release of the encapsulated and conjugated drugs. The combination of nateglinide and insulin, vitamin E succinate and insulin improved the glucose metabolism, reduced oxidative stress, improved the mitochondrial function and recovered the cognitive capacity of mice. This work demonstrated a paradigm for specific and high efficacy AD combination therapy.

Hydrophilic hindering and hydrophobic growing: a vesicle glycometabolism multi-drug combination therapeutic against Alzheimer's disease.

Advanced drug vehicle exploitation and the sophisticated synergy mechanism revelation are two great difficulties in combination therapy. Compared with most readily available polymer micelles, some undiscovered complex chemical design principles limit the expanding research of polymer vesicles. Here, polycaprolactone (PCL)-g-Dextran vesicle that dextran brush steric hindrance guide PCL lamellae-aligned growth was synthesized. The effect of the glycometabolism multi-drug vesicle combination treatment and synergism mechanism were investigated on senescence-accelerated mouse prone 8 (SAMP8) mice. The main insulin sensitizer drug could improve the memory ability of mice to a small extent, and the main insulin secretion promoter drug had little beneficial effect. Moreover, the triple anti-insulin resistant drugs of insulin (INS), repaglinide (REP) and metformin hydrochloride (MET) activated the glycometabolism-related bio-signals, and the energy cycle was normalized successfully. The insulin intracellular uptake and utilization efficiency could be the reason for the gap. The upregulation of the brain-derived neurotrophic factor (BDNF) protein confirmed that the crosstalk between the mitochondria and synapse contributes to the nerve repair. This study provided an excellent drug combination vesicle to treat Alzheimer's disease (AD). The discovery of the combination mechanism leads to an improvement in the AD clinical treatment.

Hydrophilic polymer driven crystallization self-assembly: an inflammatory multi-drug combination nanosystem against Alzheimer's disease.

The hydrophobic polymer driven crystallization of self-assembled micelles is usually sufficient for their purposes in materials chemistry studies. However, with the state of smart drug delivery research, micelles alone are not enough. The principles of the self assembly driven by hydrophilic dextran brushes together with charged poly(3-acrylamidophenyl boronic acid) (PPBA) are uncovered in this study. A series of poly(ε-caprolactone)-block-poly(3-acrylamidophenyl boronic acid)-dextran (PCL-b-PPBA-Dex) micelles and vesicles are investigated as potential Alzheimer's disease (AD) treatments. Three inflammatory microenvironment responsive micelles, including celecoxib drug-loaded micelles (CEL), ibuprofen drug-loaded micelles (IBU) and telmisartan drug-loaded micelles (TEL), are developed. In vivo, CEL/IBU (mixture of CEL and IBU) and CEL/TEL (mixture of CEL and TEL) suppress the activation of glia and reduce the levels of inflammatory mediators through eliminating cyclooxygenase 2 (COX-2) signals. The CEL/TEL combination nanosystem is better at correcting neuroinflammation and improving the spatial memory ability of a senescence-accelerated mouse prone 8 model (SAMP8). We consider that the inflammation responsive combination nanosystem provides a new potential treatment for AD clinical patients.

Safety effects of law enforcement cameras at non-signalized crosswalks: A case study in China.

Pedestrians are vulnerable when crossing the street, especially at non-signalized crosswalks. In China, in spite of the priority that laws entitle the pedestrians, the yielding rates at non-signalized crosswalks are relatively low. In light of this situation, law enforcement cameras have been used to increase the percentage of drivers yielding to pedestrians. This study investigates the effectiveness of law enforcement cameras on drivers yielding behavior and vehicle-pedestrian conflicts at non-signalized crosswalks. Using Unmanned Aerial Vehicle (UAV) and roadside video recording, information including pedestrian characteristics, vehicular characteristics and environmental factors are collected. The conflict indicators used include Post-Encroachment Time (PET), Time to Collision (TTC), and Deceleration to Safety Time (DST). In this study, a conflict classification framework based on PET, TTC and DST using Support Vector Machine algorithm is employed. A multinomial logit regression model is used to identify the factors contributing to the conflicts. Then, binary logit regression models are constructed to analyze the effects of law enforcement cameras on drivers yielding behavior. Conflict study reveals that the implementation of law enforcement cameras would increase the probability of slight conflict but decrease the probability of serious conflict. Yielding behavior analysis shows that the illegitimate yielding behavior percentages are over 10 %, indicating the necessity of improving the awareness of yielding rules, and the implementation of law enforcement cameras would increase the yielding and legitimate yielding probability. Moreover, factors including the adjacent vehicle yielding behavior, number of lanes between pedestrian and vehicle, pedestrian speed change, pedestrian waiting time, pedestrian accepted gap time, vehicle upstream speed and vehicle speed change are significantly associated with conflict severity and drivers yielding behavior. We recommend that supplementary facilities and measures should be used to improve the safety performance of law enforcement cameras.

Analytical Model for the Channel Maximum Temperature in Ga2O3 MOSFETs.

In this work, we proposed an accurate analytical model for the estimation of the channel maximum temperature of Ga2O3 MOSFETs with native or high-thermal-conductivity substrates. The thermal conductivity of Ga2O3 is anisotropic and decreases significantly with increasing temperature, which both are important for the thermal behavior of Ga2O3 MOSFETs and thus considered in the model. Numerical simulations are performed via COMSOL Multiphysics to investigate the dependence of channel maximum temperature on power density by varying device geometric parameters and ambient temperature, which shows good agreements with analytical model, providing the validity of this model. The new model is instructive in effective thermal management of Ga2O3 MOSFETs.

Increased cross-linking micelle retention in the brain of Alzheimer's disease mice by elevated asparagine endopeptidase protease responsive aggregation.

Current forms of medication for Alzheimer's disease (AD) provide a symptomatic benefit limited to those with early onset, but there is no single drug available for later stage patients. Given the recent failures of AD drugs in clinical trials, an intensive treatment strategy based on drug combination that is approved is attractive. At present, the greatest difficulty lies in the low accumulation of drugs in the brain. All hydrophilic drugs are limited by the physical and biochemical barriers within the blood-brain barrier and lipophilic drugs are often transported back into the blood by efflux pumps located in the blood-brain barrier. Here, we select elevated asparagine endopeptidase (AEP) as a target to trigger in situ cross-linking of small sized particles to form large sized drug clusters to block the efflux of the brain. Subsequently, responsive cross-linking micelles (RCMs) loaded with the acetylcholinesterase inhibitor, donepezil (DON), the microtubule therapeutic agent, Paclitaxel (PTX), and the glucose metabolism disorder regulator, insulin (INS) are investigated, with a focus on high levels of drug accumulation in the brain in AD. These smart multi-drug delivery RCMs provide a powerful system for AD treatment and can be adapted for other central nervous system (CNS) disorders.

Effects of Post Annealing on Electrical Performance of Polycrystalline Ga2O3 Photodetector on Sapphire.

Effects of post annealing on the physical and electrical properties of solar-blind polycrystalline gallium oxide (Ga2O3) ultraviolet photodetectors on the sapphire substrate are investigated. The grain size of poly-Ga2O3 becomes larger with the post annealing temperature (PAT) increasing from 800 °C to 1000 °C, but it gets smaller with further raising PAT to 1100 °C. A blue shift is observed at the absorption edge of the transmittance spectra of Ga2O3 on sapphire as increasing PAT, due to the incorporation of Al from the sapphire substrate into Ga2O3 to form (AlxGa1-x)2O3. The high-resolution X-ray diffraction and transmittance spectra measurement indicate that the substitutional Al composition and bandgap of (AlxGa1-x)2O3 annealed at 1100 °C can be above 0.30 and 5.10 eV, respectively. The Rmax of the sample annealed at 1000 °C increases about 500% compared to the as-deposited device, and the sample annealed at 1000 °C has short rise time and decay time of 0.148 s and 0.067 s, respectively. This work may pave a way for the fabrication of poly-Ga2O3 ultraviolet photodetector and find a method to improve responsivity and speed of response.

Spatial analysis of hemorrhagic fever with renal syndrome in Zibo City, China, 2009-2012.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China, where human cases account for 90% of the total global cases. Zibo City is one of the most serious affected areas in Shandong Province China with the HFRS incidence increasing sharply from 2009 to 2012. However, the hotspots of HFRS in Zibo remained unclear. Thus, a spatial analysis was conducted with the aim to explore the spatial, spatial-temporal and seasonal patterns of HFRS in Zibo from 2009 to 2012, and to provide guidance for formulating regional prevention and control strategies. METHODS: The study was based on the reported cases of HFRS from the National Notifiable Disease Surveillance System. Annualized incidence maps and seasonal incidence maps were produced to analyze the spatial and seasonal distribution of HFRS in Zibo City. Then spatial scan statistics and space-time scan statistics were conducted to identify clusters of HFRS. RESULTS: There were 200 cases reported in Zibo City during the 4-year study period. One most likely cluster and one secondary cluster for high incidence of HFRS were identified by the space-time analysis. And the most likely cluster was found to exist at Yiyuan County in October to December 2012. The human infections in the fall and winter reflected a seasonal characteristic pattern of Hantaan virus (HTNV) transmission. The secondary cluster was detected at the center of Zibo in May to June 2009, presenting a seasonal characteristic of Seoul virus (SEOV) transmission. CONCLUSION: To control and prevent HFRS in Zibo city, the comprehensive preventive strategy should be implemented in the southern areas of Zibo in autumn and in the northern areas of Zibo in spring.