A NEW PIEZOELECTRIC MICROACTUATOR WITH TRANSVERSE AND LATERAL CONTROL OF HEAD POSITIONING SYSTEMS FOR HIGH DENSITY HARD DISK DRIVES

In high density magnetic hard disk drives, both fast track seeking and extremely accurate positioning of the read/write head are required. A new piezoelectric microactuator with transverse and lateral control of the head positioning system for high density hard disk drives is proposed. First, the structure of the new piezoelectric microactuator is illustrated. Design of the new microactuator is based on the axial deformation of piezoelectric elements for lateral motion and the bimorph actuation of piezoelectric elements for transverse motion. Next, a mathematical model of the microactuator system is defined. Static properties associated with the displacement of the system are evaluated and then dynamic system equations of the system are evaluated. Frequency response of the system is studied based on the dynamic system equations of the actuator system. Dynamic properties of the system with a variety of system parameters are evaluated. Finally, the controller design for the actuator is presented. Simulation results show that the new actuator achieves a maximum stroke of displacement of more than 0.2m with servo bandwidth of more than 5 kHz in the lateral direction and the flying height is decreased to less than 6 nm with resonance frequency of more than 100 kHz under the 0.5 % damping assumption. The new piezoelectric microactuator improves performance of high density hard disk drives by increasing servo bandwidth and decreasing flying height

Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation

Genetic variation affecting exon skipping contributes to brain structural atrophy in Alzheimer's disease

Genetic variation in cis-regulatory elements related to splicing machinery and splicing regulatory elements (SREs) results in exon skipping and undesired protein products. We developed a splicing decision model to identify actionable loci among common SNPs for gene regulation. The splicing decision model identified SNPs affecting exon skipping by analyzing sequence-driven alternative splicing (AS) models and by scanning the genome for the regions with putative SRE motifs. We used non-Hispanic Caucasians with neuroimaging, and fluid biomarkers for Alzheimer's disease (AD) and identified 17,088 common exonic SNPs affecting exon skipping. GWAS identified one SNP (rs1140317) in HLA-DQB1 as significantly associated with entorhinal cortical thickness, AD neuroimaging biomarker, after controlling for multiple testing. Further analysis revealed that rs1140317 was significantly associated with brain amyloid-f deposition (PET and CSF). HLA-DQB1 is an essential immune gene and may regulate AS, thereby contributing to AD pathology. SRE may hold potential as novel therapeutic targets for AD

Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer's Disease by Splicing-Based Aggregation

TREM2 is among the most well-known Alzheimer’s disease (AD) risk genes; however, the functional roles of its AD-associated variants remain to be elucidated, and most known risk alleles are low-frequency variants whose investigation is challenging. Here, we utilized a splicing-guided aggregation method in which multiple low-frequency TREM2 variants were bundled together to investigate the functional impact of those variants on alternative splicing in AD. We analyzed whole genome sequencing (WGS) and RNA-seq data generated from cognitively normal elderly controls (CN) and AD patients in two independent cohorts, representing three regions in the frontal lobe of the human brain: the dorsolateral prefrontal cortex (CN = 213 and AD = 376), frontal pole (CN = 72 and AD = 175), and inferior frontal (CN = 63 and AD = 157). We observed an exon skipping event in the second exon of TREM2, with that exon tending to be more frequently skipped (p = 0.0012) in individuals having at least one low-frequency variant that caused loss-of-function for a splicing regulatory element. In addition, genes differentially expressed between AD patients with high vs. low skipping of the second exon (i.e., loss of a TREM2 functional domain) were significantly enriched in immune-related pathways. Our splicing-guided aggregation method thus provides new insight into the regulation of alternative splicing of the second exon of TREM2 by low-frequency variants and could be a useful tool for further exploring the potential molecular mechanisms of multiple, disease-associated, low-frequency variants

ADAS-viewer: web-based application for integrative analysis of multi-omics data in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder and is represented by complicated biological mechanisms and complexity of brain tissue. Our understanding of the complicated molecular architecture that contributes to AD progression benefits from performing comprehensive and systemic investigations with multi-layered molecular and biological data from different brain regions. Since recently different independent studies generated various omics data in different brain regions of AD patients, multi-omics data integration can be a useful resource for better comprehensive understanding of AD. Here we present a web platform, ADAS-viewer, that provides researchers with the ability to comprehensively investigate and visualize multi-omics data from multiple brain regions of AD patients. ADAS-viewer offers means to identify functional changes in transcript and exon expression (i.e., alternative splicing) along with associated genetic or epigenetic regulatory effects. Specifically, it integrates genomic, transcriptomic, methylation, and miRNA data collected from seven different brain regions (cerebellum, temporal cortex, dorsolateral prefrontal cortex, frontal pole, inferior frontal gyrus, parahippocampal gyrus, and superior temporal gyrus) across three independent cohort datasets. ADAS-viewer is particularly useful as a web-based application for analyzing and visualizing multi-omics data across multiple brain regions at both transcript and exon level, allowing the identification of candidate biomarkers of Alzheimer’s disease

Nutritional Status of Vitamin D and the Effect of Vitamin D Supplementation in Korean Breast-fed Infants

We investigated the vitamin D status and the effect of vitamin D supplementation in Korean breast-fed infants. The healthy term newborns were divided into 3 groups; A, formula-fed; B, breast-fed only; S, breast-fed with vitamin D supplementation. We measured serum concentrations of vitamin D (25OHD3), calcium (Ca), phosphorus (P), alkaline phosphatase (AP), intact parathyroid hormone (iPTH) and bone mineral density (BMD) at 6 and 12 months of age. Using questionnaires, average duration of sun-light exposure and dietary intake of vitamin D, Ca and P were obtained. At 6 and 12 months of age, 25OHD3 was significantly higher in group S than in group B (P<0.001). iPTH was significantly lower in group S than in group B at 6 months (P=0.001), but did not differ at 12 months. Regardless of vitamin D supplementation, BMD was lower in group B and S than in group A (P<0.05). Total intake of vitamin D differed among 3 groups (P<0.001, A>S>B), but total intake of Ca and P were higher in group A than in group B and S (P<0.001). In conclusion, breast-fed infants show lower vitamin D status and bone mineralization than formula-fed infants. Vitamin D supplementation (200 IU/day) in breast-fed infants increases serum 25-OH vitamin D3, but not bone mineral density

A standardized pathology report for gastric cancer: 2nd edition

The first edition of ‘A Standardized Pathology Report for Gastric Cancer’ was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies

Block-oriented nonlinear system identification using semidenite programming

Identification of block-oriented nonlinear systems has been an active research area for the last several decades. A block-oriented nonlinear system represents a nonlinear dynamical system as a combination of linear dynamic systems and static nonlinear blocks. In block-oriented nonlinear systems, each block (linear dynamic systems and static nonlinearity) can be connected in many different ways (series, parallel, feedback) and this flexibility provides the block-oriented modeling approach with an ability to capture a large class of nonlinear systems. However, intermediate signals in such block-oriented systems are not measurable and the inaccessibility of such measurements is the main difficulty in block-oriented nonlinear system identification. Recently a system identification method using rank minimization has been introduced for linear system identification. Finding the simplest model within a feasible model set restricted by convex constraints can often be formulated as a rank minimization problem. In this research, the rank minimization approach is extended to block-oriented nonlinear system identification. The system parameter estimation problem is formulated as a rank minimization problem or the combination of prediction error and rank minimization problems by constraining a finite dimensional time dependency of a linear dynamic system and by using the monotonicity of static nonlinearity. This allows us to reconstruct non-measurable intermediate signals and once the intermediate signals have been reconstructed, the identification of each block can be solved with the standard Prediction Error method or Least Squares method. The research work presented in this dissertation proposes a new approach for block-oriented system identification by tackling the inaccessibility of measurement of intermediate signals in block-oriented nonlinear systems via rank minimization. Since the rank minimization problem is non-convex, the rank minimization problem is relaxed to a semidefinite programming problem by minimizing the nuclear norm instead of the rank. The research contributes to advances in block-oriented nonlinear system identificatio

Proteasome inhibitor-induced cleavage of HSP90 is mediated by ROS generation and caspase 10-activation in human leukemic cells

Heat shock protein 90 (HSP90) is a molecular chaperone that supports the stability of client proteins. The proteasome is one of the targets for cancer therapy, and studies are underway to use proteasome inhibitors as anti-cancer drugs. In this study, we found that HSP90 was cleaved to a 55 kDa protein after treatment with proteasome inhibitors including MG132 in leukemia cells but was not cleaved in other tissue-derived cells. HSP90 has two major isoforms (HSP90α and HSP90β), and both were cleaved by MG132 treatment. MG132 treatment also induced a decrease in HSP90 client proteins. MG132 treatment generated ROS, and the cleavage of HSP90 was blocked by a ROS scavenger, N-acetylcysteine (NAC). MG132 activated several caspases, and the activation was reduced by pretreatment with NAC. Based on an inhibitor study, the cleavage of HSP90 induced by MG132 was dependent on caspase 10 activation. Furthermore, active recombinant caspase 10 induced HSP90 cleavage in vitro. MG132 upregulated VDUP-1 expression and reduced the GSH levels implying that the regulation of redox-related proteins is involved. Taken all together, our results suggest that the cleavage of HSP90 by MG132 treatment is mediated by ROS generation and caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in the anti-cancer effects of proteasome inhibitors