Assessment of an Initial Roadmap for Protein-Protein-Small Molecule Networks in the Brain of Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the fatal and leading causes of death. Amyloid-beta (Abeta) and transition metal ions [which can bind each other and may influence peptide aggregation, producing toxic oligomeric Abeta species, and reactive oxygen species (ROS)] have been suggested to be involved in AD pathogenesis. In addition, there may be interactions of Abeta with other proteins [i.e., human serum albumin (HSA), S100 proteins]. Unfortunately, a clear relationship between Abeta, metal ions, and other proteins in AD etiology has not been identified. In order to understand the role of metal-associated Abeta (metal–Abeta) species in AD, several chemical tools have been studied and presented their abilities toward A-beta. The structural moieties responsible for such reactivities, however, are not completely elucidated. To gain a better understanding of structure-interaction-reactivity relationships between small molecules and metal-free Abeta or metal–Abeta, naturally occurring flavonoids (morin, quercetin, galangin, and luteolin) with structural variations (i.e., the number and position of hydroxyl functionality) and two series of rationally designed chemical reagents were investigated. Four flavonoids in this study could significantly modulate aggregation pathways of metal–Abeta over metal-free Abeta and mediate Abeta-linked cytotoxicity to different extents. The variations of hydroxyl groups within a flavonoid backbone can modify their reactivity toward Abeta species. In addition, the motif of N1,N1-dimethylbenzene-1,4-diamine could be considered to be essential for targeting and modulating Abeta aggregation pathways and scavenging free radicals. Moreover, we have examined the interactions of Abeta with other proteins (i.e., HSA, S100 proteins) with and without metal ions and their influence on the peptide aggregation. HSA and S100 proteins could alter the Abeta aggregation pathways by directly binding to Abeta followed by formation of complexes which possibly are less toxic than protein-free Abeta aggregates. Taken together, the studies described in this thesis demonstrate the pivotal functionalities of chemical tools for their reactivity toward metal-free and metal-bound Abeta, as well as present the initial information on a link of protein–protein–small molecule (metal) networks to AD etiology. Our overall results and observations will be able to provide insight into new discovery of chemical tools and therapeutics toward AD.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/116719/1/hyuckjin_1.pd

A novel ensemble decision tree-based CHi-squared Automatic Interaction Detection (CHAID) and multivariate logistic regression models in landslide susceptibility mapping

An ensemble algorithm of data mining decision tree (DT)-based CHi-squared Automatic Interaction Detection (CHAID) is widely used for prediction analysis in variety of applications. CHAID as a multivariate method has an automatic classification capacity to analyze large numbers of landslide conditioning factors. Moreover, it results two or more nodes for each independent variable, where every node contains numbers of presence or absence of landslides (dependent variable). Other DT methods such as Quick, Unbiased, Efficient Statistic Tree (QUEST) and Classification and Regression Trees (CRT) are not able to produce multi branches based tree. Thus, the main objective of this paper is to use CHAID method to perform the best classification fit for each conditioning factors, then, combined it with logistic regression (LR) to find the corresponding coefficients of best fitting function that assess the optimal terminal nodes. In the first step, a landslide inventory map with 296 landslide locations were extracted from various sources over the Pohang-Kyeong Joo catchment (South Korea). Then, the inventory was randomly split into two datasets, 70 % was used for training the models, and the remaining 30 % was used for validation purpose. Thirteen landslide conditioning factors were used for the susceptibility modeling. Then, CHAID was applied and revealed that some conditioning factors such as altitude, soil drain, soil texture and TWI, as terminal nodes and reflected the best classification fit. Then, a proposed ensemble technique was applied and the interpretations of the coefficients showed that the relationship between the decision tree branch nodes distance from drain, soil drain, and TWI, respectively, leads to better consequences assessment of landslides in the current study area. The validation results showed that both success and prediction rates, 75 and 79 %, respectively. This study proved the efficiency and reliability of ensemble DT and LR model in landslide susceptibility mapping

A novel ensemble bivariate statistical evidential belief function with knowledge-based analytical hierarchy process and multivariate statistical logistic regression for landslide susceptibility mapping

This study compares the landslide susceptibility maps from four application models, namely, (1) the bivariate model of the Dempster–Shafer based evidential belief function (EBF); (2) integration of the EBF in the knowledge-based analytical hierarchy process (AHP) as a pairwise comparison model processed by using all available causative factors; (3) integration of the EBF in the knowledge-based AHP as a pairwise comparison model by using high nominated causative factor weights only; and (4) integrated EBF in the logistic regression (LR) as a multivariate model by using nominated causative factor weights only. These models were tested in Pohang and Gyeongju Cities (South Korea) by using the geographic information system GIS platform. In the first step, a landslide inventory map consisting of 296 landslide locations were prepared from various data sources. Then, a total of 15 landslide causative factors (slope angle, slope aspect, curvature, surface roughness, altitude, distance from drainages, stream power index, topographic wetness index, wood age, wood diameter, wood type, forest density, soil thickness, soil texture, and soil drainage) were extracted from the database and then converted into a raster. Final susceptibility maps exhibit close results from the two models. Models 1 and 3 predicted 82.3% and 80% of testing data during the analysis, respectively. Thus, Models 1 and 3 show better performance than LR. These resultant maps can be used to extend the capability of bivariate statistical based model, by finding the relationship between each single conditioning factor and landslide locations, moreover, the proposed ensemble model can be used to show the inter-relationships importance between each conditioning factors, without the need to refer to the multivariate statistic. The research outcome may provide powerful tools for natural hazard assessment and land use planning

Urinary bladder rupture during voiding cystourethrography

Voiding cystourethrography (VCUG) is a commonly performed diagnostic procedure for the evaluation of vesicoureteral reflux with urinary tract infection or congenital renal diseases in children. The procedure is relatively simple and cost-effective, and complications are very rare. The iatrogenic complication of VCUG range from discomfort, urinary tract infection to bacteremia, as well as bladder rupture. Bladder rupture is a rare complication of VCUG, and only a few cases were reported. Bladder rupture among healthy children during VCUG is an especially uncommon event. Bladder rupture associated with VCUG is usually more common in chronically unused bladders like chronic renal failure. Presented is a case of bladder rupture that occurred during a VCUG in a healthy 9-month-old infant, due to instilled action of dye by high pressure. This injury completely healed after 7 days of operation, and it was confirmed with a postoperative cystography. The patient's bladder volume, underlying disease, velocity of the contrast media instilled, catheter size, and styles of instillation are important factors to prevent bladder rupture during VCUG. Management of bladder rupture should be individualized, but the majority of infants are treated with the operation. In conclusion, bladder rupture is a rare complication, however, delicate attention is needed in order to prevent more dire situations

A Proposal for a Standardized Fault Description Format to Study Active Intraplate Tectonics in the Korean Peninsula

Intraplate faulting and the resultant earthquakes are not well understood because of their complex distribution, long period of seismic recurrence, and poor exposure of surface rupture. Pre-existing weaknesses should be studied to understand intraplate faulting and earthquakes. We are developing a long-term project to understand Korean-type intraplate fault behavior and recurrence intervals. As the first step, we will establish an integrated system for production, analysis, and management of fault data related to active crustal deformation. Here we propose a new format for fault data description and management

Perovskite-polymer composite cross-linker approach for highly-stable and efficient perovskite solar cells.

Manipulation of grain boundaries in polycrystalline perovskite is an essential consideration for both the optoelectronic properties and environmental stability of solar cells as the solution-processing of perovskite films inevitably introduces many defects at grain boundaries. Though small molecule-based additives have proven to be effective defect passivating agents, their high volatility and diffusivity cannot render perovskite films robust enough against harsh environments. Here we suggest design rules for effective molecules by considering their molecular structure. From these, we introduce a strategy to form macromolecular intermediate phases using long chain polymers, which leads to the formation of a polymer-perovskite composite cross-linker. The cross-linker functions to bridge the perovskite grains, minimizing grain-to-grain electrical decoupling and yielding excellent environmental stability against moisture, light, and heat, which has not been attainable with small molecule defect passivating agents. Consequently, all photovoltaic parameters are significantly enhanced in the solar cells and the devices also show excellent stability

Cellular and Tissue Selectivity of AAV Serotypes for Gene Delivery to Chondrocytes and Cartilage

Background: Despite several studies on the effect of adeno-associated virus (AAV)-based therapeutics on osteoarthritis (OA), information on the transduction efficiency and applicable profiles of different AAV serotypes to chondrocytes in hard cartilage tissue is still limited. Moreover, the recent discovery of additional AAV serotypes makes it necessary to screen for more suitable AAV serotypes for specific tissues. Here, we compared the transduction efficiencies of 14 conventional AAV serotypes in human chondrocytes, mouse OA models, and human cartilage explants obtained from OA patients. Methods: To compare the transduction efficiency of individual AAV serotypes, green fluorescent protein (GFP) expression was detected by fluorescence microscopy or western blotting. Likewise, to compare the transduction efficiencies of individual AAV serotypes in cartilage tissues, GFP expression was determined using fluorescence microscopy or immunohistochemistry, and GFP-positive cells were counted. Results: Only AAV2, 5, 6, and 6.2 exhibited substantial transduction efficiencies in both normal and OA chondrocytes. All AAV serotypes except AAV6 and rh43 could effectively transduce human bone marrow mesenchymal stem cells. In human and mouse OA cartilage tissues, AAV2, AAV5, AAV6.2, AAV8, and AAV rh39 showed excellent tissue specificity based on transduction efficiency. These results indicate the differences in transduction efficiencies of AAV serotypes between cellular and tissue models. Conclusions: Our findings indicate that AAV2 and AAV6.2 may be the best choices for AAV-mediated gene delivery into intra-articular cartilage tissue. These AAV vectors hold the potential to be of use in clinical applications to prevent OA progression if appropriate therapeutic genes are inserted into the vector

Highly active and stable stepped Cu surface for enhanced electrochemical CO₂ reduction to C₂H₄

Electrochemical CO₂ reduction to value-added chemical feedstocks is of considerable interest for renewable energy storage and renewable source generation while mitigating CO₂ emissions from human activity. Copper represents an effective catalyst in reducing CO₂ to hydrocarbons or oxygenates, but it is often plagued by a low product selectivity and limited long-term stability. Here we report that copper nanowires with rich surface steps exhibit a remarkably high Faradaic efficiency for C₂H₄ that can be maintained for over 200 hours. Computational studies reveal that these steps are thermodynamically favoured compared with Cu(100) surface under the operating conditions and the stepped surface favours C₂ products by suppressing the C₁ pathway and hydrogen production

Highly active and stable stepped Cu surface for enhanced electrochemical CO₂ reduction to C₂H₄

Electrochemical CO₂ reduction to value-added chemical feedstocks is of considerable interest for renewable energy storage and renewable source generation while mitigating CO₂ emissions from human activity. Copper represents an effective catalyst in reducing CO₂ to hydrocarbons or oxygenates, but it is often plagued by a low product selectivity and limited long-term stability. Here we report that copper nanowires with rich surface steps exhibit a remarkably high Faradaic efficiency for C₂H₄ that can be maintained for over 200 hours. Computational studies reveal that these steps are thermodynamically favoured compared with Cu(100) surface under the operating conditions and the stepped surface favours C₂ products by suppressing the C₁ pathway and hydrogen production

Exosomes from Human Adipose Tissue-Derived Mesenchymal Stem Cells Promote Epidermal Barrier Repair by Inducing de Novo Synthesis of Ceramides in Atopic Dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes' effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD