Design techniques for dense embedded memory in advanced CMOS technologies

University of Minnesota Ph.D. dissertation. February 2012. Major: Electrical Engineering. Advisor: Chris H. Kim. 1 computer file (PDF); viii, 116 pages.On-die cache memory is a key component in advanced processors since it can boost micro-architectural level performance at a moderate power penalty. Demand for denser memories only going to increase as the number of cores in a microprocessor goes up with technology scaling. A commensurate increase in the amount of cache memory is needed to fully utilize the larger and more powerful processing units. 6T SRAMs have been the embedded memory of choice for modern microprocessors due to their logic compatibility, high speed, and refresh-free operation. However, the relatively large cell size and conflicting requirements for read and write make aggressive scaling of 6T SRAMs challenging in sub-22 nm. In this dissertation, circuit techniques and simulation methodologies are presented to demonstrate the potential of alternative options such as gain cell eDRAMs and spin-torque-transfer magnetic RAMs (STT-MRAMs) for high density embedded memories.Three unique test chip designs are presented to enhance the retention time and access speed of gain cell eDRAMs. Proposed bit-cells utilize preferential boostings, beneficial couplings, and aggregated cell leakages for expanding signal window between data `1' and `0'. The design space of power-delay product can be further enhanced with various assist schemes that harness the innate properties of gain cell eDRAMs. Experimental results from the test chips demonstrate that the proposed gain cell eDRAMs achieve overall faster system performances and lower static power dissipations than SRAMs in a generic 65 nm low-power (LP) CMOS process. A magnetic tunnel junction (MTJ) scaling scenario and an efficient HSPICE simulation methodology are proposed for exploring the scalability of STT-MRAMs under variation effects from 65 nm to 8 nm. A constant JC0*RA/VDD scaling method is adopted to achieve optimal read and write performances of STT-MRAMs and thermal stabilities for a 10 year retention are achieved by adjusting free layer thicknesses as well as projecting crystalline anisotropy improvements. Studies based on the proposed methodology show that in-plane STT-MRAM will outperform SRAM from 15 nm node, while its perpendicular counterpart requires further innovations in MTJ material properties in order to overcome the poor write performance from 22 nm node

Phase Transition Behavior of Poly(N-isopropylacrylamide-co-N,Ndimethylaminopropylacrylamide) Hydrogels

The copolymer hydrogel of N-isopropylacrylamide (NIPAAm) and N,N-dimethylaminopropylacrylamide (DMAPAA) was synthesized by free radical copolymerization. The phase transition behavior of p(NIPAAmco-DMAPAA) hydrogels as a function of temperature and SDS concentration was studied. The p(NIPAAmco-DMAPAA) hydrogels exhibited larger swelling capacity than the homo p(NIPAAm) hydrogel. The phase transition temperature of p(NIPAAm-co-DMAPAA) hydrogels increased with an increase of DMAPAA content. In aqueous SDS solution, the swelling capacity of p(NIPAAm-co-DMAPAA) hydrogel decreased with an increase of SDS concentration. The phase transition temperature of p(NIPAAm-co-DMAPAA) hydrogels was found to be almost independent of the SDS concentration

β-Glucan enhanced apoptosis in human colon cancer cells SNU-C4

The apoptotic effect of bacteria-derived β-glucan was investigated in human colon cancer cells SNU-C4 using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, reverse transcription-polymerase chain reaction (RT-PCR) expressions of Bcl-2, Bax, and Caspase-3 genes, and assay of caspase-3 enzyme activity. β-Glucan of 10, 50, and 100 µg/mL decreased cell viability in a dose-dependent manner with typical apoptotic characteristics, such as morphological changes of chromatin condensation and apoptotic body formation from TUNEL assay. In addition, β-glucan (100 µg/mL) decreased the expression of Bcl-2 by 0.6 times, whereas the expression of Bax and Caspase-3 were increased by 3.1 and 2.3 times, respectively, compared to untreated control group. Furthermore, the caspase-3 activity in the β-glucan-treated group was significantly increased compared to those in control group (P < 0.05). Bacterial derived β-glucan could be used as an effective compound inducing apoptosis in human colon cancer

Clinical outcomes associated with long-term exposure to airborne particulate pollution in kidney transplant recipients

Background Researchers have yet to investigate the specific association between 10-μm particulate matter (PM10) levels and the risk of graft failure, kidney disease, or the functional decline of transplanted kidneys, in kidney transplant recipients (KTRs). Furthermore, we know very little about the association between PM10 levels and the development of allograft rejection in transplanted kidneys. Identification of air pollution as a potential contributor to kidney disease could help reduce future disease burden, stimulate policy discussions on the importance of reducing air pollution with respect to health and disease, and increase public awareness of the hazards of air pollution. We aimed to evaluate the relationship of PM10 with the risk of graft failure, mortality, and decline of graft function in KTRs. Methods Air pollutant data were obtained from the Korean National Institute of Environmental Research. We then investigated potential associations between these data and the clinical outcomes of 1532 KTRs who underwent kidney transplantation in a tertiary hospital between 2001 and 2015. Survival models were used to evaluate the association between PM10 concentrations and the risk of death-censored graft failure (DCGF), all-cause mortality, and biopsy-proven rejection (BPR), over a median follow-up period of 6.31 years. Results The annual mean PM10 exposure after kidney transplantation was 27.1 ± 8.0 μg/m3. Based on 1-year baseline exposure, 1 μg/m3 increase in PM10 concentration was associated with an increased risk of DCGF (hazard ratio (HR): 1.049; 95% confidence interval (CI): 1.014–1.084) and BPR (HR: 1.053; 95% CI: 1.042–1.063). Fully adjusted models showed that all-cause mortality was significantly associated with 1-year average PM10 concentrations (HR, 1.09; 95% CI, 1.043 to 1.140). Conclusions Long-term PM10 exposure is significantly associated with BPR, DCGF, and all-cause mortality in KTRs.This work was supported by the Seoul National University Research Grant in 2018, the Korean Society of Nephrology Grant in 2018 (BAXTER), and by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1A6A3A01095329) and the Global Research Lab through the NRF, funded by the Ministry of Science and ICT (Information and Communication Technologies) in South Korea (grant number K2100400000110A0500–00710; H Kim)

Urine myo-inositol as a novel prognostic biomarker for diabetic kidney disease: a targeted metabolomics study using nuclear magnetic resonance

Background As a leading cause of chronic kidney disease, clinical demand for noninvasive biomarkers of diabetic kidney disease (DKD) beyond proteinuria is increasing. Metabolomics is a popular method to identify mechanisms and biomarkers. We investigated urinary targeted metabolomics in DKD patients. Methods We conducted a targeted metabolomics study of 26 urinary metabolites in consecutive patients with DKD stage 1 to 5 (n = 208) and healthy controls (n = 26). The relationships between estimated glomerular filtration rate (eGFR) or urine protein-creatinine ratio (UPCR) and metabolites were evaluated. Multivariate Cox analysis was used to estimate relationships between urinary metabolites and the target outcome, end-stage renal disease (ESRD). C statistics and time-dependent receiver operating characteristics (ROC) were used to assess diagnostic validity. Results During a median 4.5 years of follow-up, 103 patients (44.0%) progressed to ESRD and 65 (27.8%) died. The median fold changes of nine metabolites belonged to monosaccharide and tricarboxylic acid (TCA) cycle metabolites tended to increase with DKD stage. Myo-inositol, choline, and citrates were correlated with eGFR and choline, while mannose and myo-inositol were correlated with UPCR. Elevated urinary monosaccharide and TCA cycle metabolites showed associations with increased morality and ESRD progression. The predictive power of ESRD progression was high, in the order of choline, myo-inositol, and citrate. Although urinary metabolites alone were less predictive than serum creatinine or UPCR, myo-inositol had additive effect with serum creatinine and UPCR. In time-dependent ROC, myo-inositol was more predictive than UPCR of 1-year ESRD progression prediction. Conclusion Myo-inositol can be used as an additive biomarker of ESRD progression in DKD

Safety and efficacy of PG102P for the control of pruritus in patients undergoing hemodialysis (SNUG trial): study protocol for a randomized controlled trial

Background Pruritus in patients undergoing hemodialysis is a highly prevalent complication that affects quality of life. Several medications are currently used for the treatment of uremic pruritus, but these are not satisfactory. PG102P, which is prepared from Actinidia arguta, has an immune-modulating effect on pruritus. This trial is designed to assess the antipruritic effect of PG102P compared with placebo. Methods This multicenter, randomized, double-blind, placebo-controlled clinical trial will include 80 patients undergoing hemodialysis. The patients will be randomized in a 1:1 ratio to a treatment group (PG102P 1.5 g/day) or a control group (placebo). The treatment will last for 8 weeks, followed by a 2-week observational period. During the observational period, all of the patients will maintain the antipruritic treatment previously used. The primary endpoint will be measured as the difference in visual analog scale between the groups before and after treatment. Secondary outcomes include serum levels of total immunoglobulin E, eosinophil cationic protein, potassium, calcium, phosphorus, intact parathyroid hormone, and blood eosinophil count between weeks 0 and 8. Kidney Disease and Quality of Life and Becks Depression Inventory questionnaires will be conducted. Safety assessments and any adverse events that occur will also be evaluated. Discussion The SNUG is a clinical study that aims to investigate the antipruritic effect of PG102P to ameliorate itching in patients undergoing hemodialysis. Trial registration Clinical Trials.gov, NCT03576235. Registered on 4 July 2018.This work was initiated and financially supported by Viromed Co. Ltd., Seoul, Republic of Korea, and Jinyangpharm. Co. Ltd., Seoul, Republic of Korea. The sponsors supported the expenses for the investigational products, laboratory tests, and clinical research coordinator. The funding body had no role in the writing of the manuscript based on the study protocol (Project No. VM_PG102P)

Sodium-activated Potassium Current in Guinea pig Gastric Myocytes

This study was designed to identify and characterize Na+-activated K+ current (IK(Na)) in guinea pig gastric myocytes under whole-cell patch clamp. After whole-cell configuration was established under 110 mM intracellular Na+ concentration ([Na+]i) at holding potential of -60 mV, a large inward current was produced by external 60 mM K+ ([K+]o). This inward current was not affected by removal of external Ca2+. K+ channel blockers had little effects on the current (p>0.05). Only TEA (5 mM) inhibited steady-state current to 68±2.7% of the control (p<0.05). In the presence of K+ channel blocker cocktail (mixture of Ba2+, glibenclamide, 4-AP, apamin, quinidine and TEA), a large inward current was activated. However, the amplitude of the steadystate current produced under [K+]o (140 mM) was significantly smaller when Na+ in pipette solution was replaced with K+- and Li+ in the presence of K+ channel blocker cocktail than under 110 mM [Na+]i. In the presence of K+ channel blocker cocktail under low Cl- pipette solution, this current was still activated and seemed K+-selective, since reversal potentials (Erev) of various concentrations of [K+]o-induced current in current/voltage (I/V) relationship were nearly identical to expected values. R-56865 (10-20 µM), a blocker of IK(Na), completely and reversibly inhibited this current. The characteristics of the current coincide with those of IK(Na) of other cells. Our results indicate the presence of IK(Na) in guinea pig gastric myocytes

Genetic variations in HMGCR and PCSK9 and kidney function: a Mendelian randomization study

Background The genetically predicted lipid-lowering effect of HMGCR or PCSK9 variant can be used to assess drug proxy effects on kidney function. Methods Mendelian randomization (MR) analysis-identified HMGCR and PCSK9 genetic variants were used to predict the low-density lipoprotein (LDL) cholesterol-lowering effects of medications targeting related molecules. Primary summary-level outcome data for log-estimated glomerular filtration rate (eGFR; creatinine) were provided by the CKDGen Consortium (n = 1,004,040 European) from a meta-analysis of CKDGen and UK Biobank data. We also conducted a separate investigation of summary-level data from CKDGen (n = 567,460, log-eGFR [creatinine]) and UK Biobank (n = 436,581, log-eGFR [cystatin C]) samples. Summary-level MRs using an inverse variance weighted method and pleiotropy-robust methods were performed. Results Summary-level MR analysis indicated that the LDL-lowering effect predicted genetically by HMGCR variants (50-mg/dL decrease) was significantly associated with a decrease in eGFR (–1.67%; 95% confidence interval [CI], –2.20% to –1.13%). Similar significance was found in results from the pleiotropy-robust MR methods when the CKDGen and UK Biobank data were analyzed separately. However, the LDL-lowering effect predicted genetically by PCSK9 variants was significantly associated with an increase in eGFR (+1.17%; 95% CI, 0.10%–2.25%). The results were similarly supported by the weighted median method and in each CKDGen and UK Biobank dataset, but the significance obtained by MR-Egger regression was attenuated. Conclusion Genetically predicted HMG-CoA reductase inhibition was associated with low eGFR, while genetically predicted PCSK9 inhibition was associated with high eGFR. Clinicians should consider that the direct effect of different types of lipid-lowering medication on kidney function can vary

Health Indicators Related to Disease, Death, and Reproduction

One of the primary goals of epidemiology is to quantify various aspects of a population’s health, illness, and death status and the determinants (or risk factors) thereof by calculating health indicators that measure the magnitudes of various conditions. There has been some confusion regarding health indicators, with discrepancies in usage among organizations such as the World Health Organization the, Centers for Disease Control and Prevention (CDC), and the CDC of other countries, and the usage of the relevant terminology may vary across papers. Therefore, in this review, we would like to propose appropriate terminological definitions for health indicators based on the most commonly used meanings and/or the terms used by official agencies, in order to bring clarity to this area of confusion. We have used appropriate examples to make each health indicator easy for the reader to understand. We have included practical exercises for some health indicators to help readers understand the underlying concepts

Causal effects of atrial fibrillation on brain white and gray matter volume: a Mendelian randomization study

Background Atrial fibrillation (AF) and brain volume loss are prevalent in older individuals. We aimed to assess the causal effect of atrial fibrillation on brain volume phenotypes by Mendelian randomization (MR) analysis. Methods The genetic instrument for AF was constructed from a previous genome-wide association study (GWAS) meta-analysis (15,993 AF patients and 113,719 controls of European ancestry). The outcome summary statistics for head-size-normalized white or gray matter volume measured by magnetic resonance imaging were provided by a previous GWAS of 33,224 white British participants in the UK Biobank. Two-sample MR by the inverse variance–weighted method was performed, supported by pleiotropy-robust MR sensitivity analysis. The causal estimates for the effect of AF on ischemic stroke were also investigated in a dataset that included the findings from the MEGASTROKE study (34,217 stroke patients and 406,111 controls of European ancestry). The direct effects of AF on brain volume phenotypes adjusted for the mediating effect of ischemic stroke were studied by multivariable MR. Results A higher genetic predisposition for AF was significantly associated with lower grey matter volume [beta −0.040, standard error (SE) 0.017, P=0.017], supported by pleiotropy-robust MR sensitivity analysis. Significant causal estimates were identified for the effect of AF on ischemic stroke (beta 0.188, SE 0.026, P=1.03E−12). The total effect of AF on lower brain grey matter volume was attenuated by adjusting for the effect of ischemic stroke (direct effects, beta −0.022, SE 0.033, P=0.528), suggesting that ischemic stroke is a mediator of the identified causal pathway. The causal estimates were nonsignificant for effects on brain white matter volume as an outcome. Conclusions This study identified that genetic predisposition for AF is significantly associated with lower gray matter volume but not white matter volume. The results indicated that the identified total effect of AF on gray matter volume may be mediated by ischemic stroke.This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HW20C2066). The funder played no role in the conduct of the study, and the study was performed independently by the authors