Re-designing Main Memory Subsystems with Emerging Monolithic 3D (M3D) Integration and Phase Change Memory Technologies

Over the past two decades, Dynamic Random-Access Memory (DRAM) has emerged as the dominant technology for implementing the main memory subsystems of all types of computing systems. However, inferring from several recent trends, computer architects in both the industry and academia have widely accepted that the density (memory capacity per chip area) and latency of DRAM based main memory subsystems cannot sufficiently scale in the future to meet the requirements of future data-centric workloads related to Artificial Intelligence (AI), Big Data, and Internet-of-Things (IoT). In fact, the achievable density and access latency in main memory subsystems presents a very fundamental trade-off. Pushing for a higher density inevitably increases access latency, and pushing for a reduced access latency often leads to a decreased density. This trade-off is so fundamental in DRAM based main memory subsystems that merely looking to re-architect DRAM subsystems cannot improve this trade-off, unless disruptive technological advancements are realized for implementing main memory subsystems. In this thesis, we focus on two key contributions to overcome the density (represented as the total chip area for the given capacity) and access latency related challenges in main memory subsystems. First, we show that the fundamental area-latency trade-offs in DRAM can be significantly improved by redesigning the DRAM cell-array structure using the emerging monolithic 3D (M3D) integration technology. A DRAM bank structure can be split across two or more M3D-integrated tiers on the same DRAM chip, to consequently be able to significantly reduce the total on-chip area occupancy of the DRAM bank and its access peripherals. This approach is fundamentally different from the well known approach of through-silicon vias (TSVs)-based 3D stacking of DRAM tiers. This is because the M3D integration based approach does not require a separate DRAM chip per tier, whereas the 3D-stacking based approach does. Our evaluation results for PARSEC benchmarks show that our designed M3D DRAM cellarray organizations can yield up to 9.56% less latency and up to 21.21% less energy-delay product (EDP), with up to 14% less DRAM die area, compared to the conventional 2D DDR4 DRAM. Second, we demonstrate a pathway for eliminating the write disturbance errors in single-level-cell PCM, thereby positioning the PCM technology, which has inherently more relaxed density and latency trade-off compared to DRAM, as a more viable option for replacing the DRAM technology. We introduce low-temperature partial-RESET operations for writing ‘0’s in PCM cells. Compared to traditional operations that write \u270\u27s in PCM cells, partial-RESET operations do not cause disturbance errors in neighboring cells during PCM writes. The overarching theme that connects the two individual contributions into this single thesis is the density versus latency argument. The existing PCM technology has 3 to 4× higher write latency compared to DRAM; nevertheless, the existing PCM technology can store 2 to 4 bits in a single cell compared to one bit per cell storage capacity of DRAM. Therefore, unlike DRAM, it becomes possible to increase the density of PCM without consequently increasing PCM latency. In other words, PCM exhibits inherently improved (more relaxed) density and latency trade-off. Thus, both of our contributions in this thesis, the first contribution of re-designing DRAM with M3D integration technology and the second contribution of making the PCM technology a more viable replacement of DRAM by eliminating the write disturbance errors in PCM, connect to the common overarching goal of improving the density and latency trade-off in main memory subsystems. In addition, we also discuss in this thesis possible future research directions that are aimed at extending the impacts of our proposed ideas so that they can transform the performance of main memory subsystems of the future

Binding of Features and Responses in Inhibition of Return: The Effects of Task Demand

Binding of target’s location and response has been demonstrated in inhibition of return (IOR). This study further investigated the effects of task demand on the binding of the target’s form to the target’s location and response in the target-target paradigm of IOR. Experiments 1 (detection task) and 2 (localization task), in which the target’s form was task irrelevant, suggested the binding of location and response. Experiment  3 (discrimination task), in which the target’s form was task relevant, showed the binding of target’s form, location, and response. These findings support the concept that the features and responses associated with a target are integrated into episodic representations or event files for the target event. Furthermore, task demand modulates the binding or retrieval of the event files

Enhanced-Surface-Area TiO2-Based Nanotube for Photocatalytic Applications

This study utilized chemical method to reform titania nanopowder into larger surface area titania-based nanotubes (NTs). Various factors, such as reaction temperature, concentration, time, and aging time were investigated to determine their effects toward NT properties. The formation of the titania-based NTs was carried out under the conditions of 10N NaOH reaction medium, at reaction temperature and time of 116°C and 23 hours, respectively. Subsequent aging was done at 40°C for 24 hours. The NTs were further resintered at 400°C for 1 hour to improve their crystallinity and photocatalytic efficiency. Result indicates that the aging process is significant for the NT synthesis process. The treated titania-based NTs have an average surface area of 247.91 m2/g with nearly 100% photodecomposition of methylene blue in 15 minutes

Seismology-based early identification of dam-formation landquake events

Flooding resulting from the bursting of dams formed by landquake events such as rock avalanches, landslides and debris flows can lead to serious bank erosion and inundation of populated areas near rivers. Seismic waves can be generated by landquake events which can be described as time-dependent forces (unloading/reloading cycles) acting on the Earth. In this study, we conduct inversions of long-period (LP, period ≥20 s) waveforms for the landquake force histories (LFHs) of ten events, which provide quantitative characterization of the initiation, propagation and termination stages of the slope failures. When the results obtained from LP waveforms are analyzed together with high-frequency (HF, 1–3 Hz) seismic signals, we find a relatively strong late-arriving seismic phase (dubbed Dam-forming phase or D-phase) recorded clearly in the HF waveforms at the closest stations, which potentially marks the time when the collapsed masses sliding into river and perhaps even impacting the topographic barrier on the opposite bank. Consequently, our approach to analyzing the LP and HF waveforms developed in this study has a high potential for identifying five dam-forming landquake events (DFLEs) in near real-time using broadband seismic records, which can provide timely warnings of the impending floods to downstream residents

EBV-encoded small RNA1 and nonresolving inflammation in rheumatoid arthritis

AbstractRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by perpetuated inflammation in multiple joints. To date, there is no cure for RA, and the causal factor for non-resolving inflammation in RA remains unclear. In this study, we initially observed expression of Epstein–Barr virus-encoded small RNA1 (EBER1) in the synovial tissue of all five patients who showed nonresolving RA inflammation. By contrast, EBER1 was detected in the synovial tissue of only one out of seven patients with advanced osteoarthritis (OA; p < 0.01, Fisher’s exact test). To confirm this finding, we conducted a second study on synovial tissue samples taken from 23 patients with nonresolving RA inflammation and 13 patients with OA. All synovial samples from patients with nonresolving inflammation of RA showed positive expression of EBER1 (23/23, 100%), whereas none of the synovial samples from patients with OA showed expression of EBER1 (0/13, 0%; p < 0.001, by Fisher’s exact test). In vitro, transfection of RA synovial fibroblasts with EBER1 induced the production of interleukin-6. Taken together, these data strongly suggest that nonresolving RA inflammation is strongly related to the presence of EBER1, which might be, at least partially, responsible for synovial fibroblast interleukin-6 production

Omics approach for generating a high-yield CHO cell line producing monoclonal antibodies

Chinese hamster ovary (CHO) cells are extensively used for the industrial manufacture of therapeutic antibodies. Generating high producing cell lines for secretory protein production requires knowing the bottleneck in the cellular machinery for protein expression. Integration site of gene of interest (GOI) is one of the important factors that influence the protein productivity. Even though screening of cells randomly integrated GOI can select high producing cells, the selected cell might not stable due to the chromosome instability. Here, we would like to look for host integration sites where GOI is high yield and stable by screening a single copy integration system. We developed several methods to identify integration sites including PCR based, whole genome sequencing based, and a platform to integrate a single copy of GOI into host genome. By determining the integration sites of the high producing clones, we can elucidate the major high yield sites for target gene expression. We have also employed the genome-editing tool, TALEN and CRISPR/cas9 to specifically integrate the vector with an antibody gene into two integration sites of CHO genome. Our data showed, IS1 and IS2 integration sites can be actively edited and specifically integrated an antibody expression vector of 15kb by either TALEN or CRISPR/Cas9. We successfully established site specifically integrated cell pools and expanded the FACS-sorted single cell into a cell line. Each single cell derived cell lines was confirmed by junction-PCR and sequence analysis. Furthermore, these single cells derived CHO cell lines are shown to express antibody gene with high titer. With the combination of omics knowledge and toolbox, including CHO genomics, transcriptomics and CHO specific microarray, GOI can be stably and highly produced

Highly reliable GIGA-sized synthetic human therapeutic antibody library construction

BackgroundMonoclonal antibodies (mAbs) and their derivatives are the fastest expanding category of pharmaceuticals. Efficient screening and generation of appropriate therapeutic human antibodies are important and urgent issues in the field of medicine. The successful in vitro biopanning method for antibody screening largely depends on the highly diverse, reliable and humanized CDR library. To rapidly obtain potent human antibodies, we designed and constructed a highly diverse synthetic human single-chain variable fragment (scFv) antibody library greater than a giga in size by phage display. Herein, the novel TIM-3-neutralizing antibodies with immunomodulatory functions derived from this library serve as an example to demonstrate the library’s potential for biomedical applications.MethodsThe library was designed with high stability scaffolds and six complementarity determining regions (CDRs) tailored to mimic human composition. The engineered antibody sequences were optimized for codon usage and subjected to synthesis. The six CDRs with variable length CDR-H3s were individually subjected to β-lactamase selection and then recombined for library construction. Five therapeutic target antigens were used for human antibody generation via phage library biopanning. TIM-3 antibody activity was verified by immunoactivity assays.ResultsWe have designed and constructed a highly diverse synthetic human scFv library named DSyn-1 (DCB Synthetic-1) containing 2.5 × 1010 phage clones. Three selected TIM-3-recognizing antibodies DCBT3-4, DCBT3-19, and DCBT3-22 showed significant inhibition activity by TIM-3 reporter assays at nanomolar ranges and binding affinities in sub-nanomolar ranges. Furthermore, clone DCBT3-22 was exceptionally superior with good physicochemical property and a purity of more than 98% without aggregation.ConclusionThe promising results illustrate not only the potential of the DSyn-1 library for biomedical research applications, but also the therapeutic potential of the three novel fully human TIM-3-neutralizing antibodies

RNA Editing and Drug Discovery for Cancer Therapy

RNA editing is vital to provide the RNA and protein complexity to regulate the gene expression. Correct RNA editing maintains the cell function and organism development. Imbalance of the RNA editing machinery may lead to diseases and cancers. Recently, RNA editing has been recognized as a target for drug discovery although few studies targeting RNA editing for disease and cancer therapy were reported in the field of natural products. Therefore, RNA editing may be a potential target for therapeutic natural products. In this review, we provide a literature overview of the biological functions of RNA editing on gene expression, diseases, cancers, and drugs. The bioinformatics resources of RNA editing were also summarized