Showing papers by "Qi Liu published in 2023"

Lysosomal lipid peroxidation regulates tumor immunity.

Abstract: Lysosomal inhibition elicited by palmitoyl protein transferase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC), but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12, was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naïve T cells, and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells, engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.

An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression

Abstract: The epigenetic modifier PADI4, which has a role in the immune recognition of proteins, is not transactivated by several p53 hypomorphs, including the African-specific genetic variant Y107H, but plays a key role in tumor suppression by p53.

Speed and Scalability of Ambipolar Deep-Subthreshold TFTs for Ultralow-Power Printed Electronics

Abstract: This work evaluates the speed and scalability potential of ambipolar deep-subthreshold printed-carbon-nanotube thin-film transistors (CNT-TFTs) for the design of ultralow-power CMOS-like circuits. Transistor and circuit simulations are developed based on experimental device measurements. Our simulations allow the assessment of this emerging printed electronics technology in terms of speed, energy/power consumption, and scalability to digital circuits of progressively higher transistor count including elementary logic gates, ring oscillators and other representative digital circuits. It is shown that digital circuits based on this technology are compatible with propagation delays $\le 1$ ms per NOT logic gate, while operating at ultralow supply voltages (0.2 V) and with ultralow static power dissipation (1 pW). Finally, this study develops Monte Carlo simulations to assess the impact of device parameter variations on the viability of large-scale circuit integration based on ambipolar deep-subthreshold printed-CNT-TFTs.

Construction of Diversified Penta-spiro-heterocyclic and Fused-heterocyclic Frameworks with Potent Antitumor Activity.

Abstract: Multiple-spiro/fused-heterocyclic frameworks containing indazolone are structurally unique and represent a class of potentially dominant skeletons. In this work, we successfully fulfilled Rh(III)-catalyst mediated substrate- and pH- controlled strategies to construct four novel types of complicated penta-spiro/fused-heterocyclic frameworks via C-H activation/[4+1] and [4+2] annulation cascades. This method had mild reaction conditions, a broad scope of substrates, moderate to good yields, and valuable applications, which could realize for the first time the generation of the novel di-spiro-heterocyclic and multiple fused-heterocyclic products with unique structures. More importantly, novel spiro[cyclohexane-indazolo[1,2-a]indazole] scaffold constructed by this method exhibited potent antitumor activity against a variety of refractory solid tumors and hematological malignancies in vitro. Overall, our work provided new insights into the construction of complex and diverse multiple spiro/fused-heterocyclic systems and offered novel valuable lead compounds for the discovery of antitumor drugs.

An Emerging NVM CIM Accelerator With Shared-Path Transpose Read and Bit-Interleaving Weight Storage for Efficient On-Chip Training in Edge Devices

Abstract: Computing-in-memory (CIM) helps to improve the energy efficiency of computing by reducing data movement. In edge devices, it is necessary for CIM accelerators to support light-weighted on-chip training for adapting the model to environmental changes and ensuring edge data security. However, most of the previous CIM accelerators for edge devices only realize inference but with training performed on cloud. The support for on-chip training will lead to remarkable area cost and serious performance attenuation. In this brief, a CIM accelerator based on emerging nonvolatile memory (NVM) is presented with shared-path transpose read and bit-interleaving weight storage for efficient on-chip training in edge devices. The shared-path transpose read employs a new biasing scheme to eliminate the influence of body effect on the transpose read, improving both read margin and speed. The bit-interleaving weight storage splits the multi-bit weights into individual bits which are stored in the array alternately, speeding up the calculation of training process remarkably. For 8-bit inputs and weights, the evaluation in the 28nm process shows that the proposed accelerator achieves ~3.34/3.06 TOPS/W energy efficiency for feed-forward/ back-propagation, 4.6X lower computing latency, and reduces at least 20% chip size compared to the baseline design.

Bit-Offsetter: A Bit-serial DNN Accelerator with Weight-offset MAC for Bit-wise Sparsity Exploitation

Abstract: With the rapid evolution of deep neural networks (DNNs), the massive computational burden brings about the difficulty of deploying DNN on edge devices. This situation gives rise to specialized hardware aiming at exploiting the sparsity of DNN parameters. Bit-serial architectures (BSAs) possess great performance potential by leveraging the abundant bit-wise sparsity. However, the distribution of effective bits of weights confines the performance of BSA designs. To improve the efficiency of BSA, we propose a weight-offset multiply-accumulation (MAC) scheme and an associated hardware design called Bit-offsetter in this paper. Weight-offsetting not only significantly boosts bit-wise sparsity but also brings out a more balanced distribution of essential bits. For Bit-offsetter, aside from leveraging the abundant bitwise sparsity induced by weight-offsetting, it’s also equipped with a load-balancing scheduler to reduce idle cycles and mitigate utilization degradation. According to our experiment on a series of DNN models, weight-offsetting can increase bit-wise sparsity for pre-trained weight up to 77.4% on average. The weight-offset MAC scheme associated with Bit-offsetter achieves 3.28×/2.94× speedup/energy efficiency over the baseline.

Investigating material basis and molecular mechanism of Qing Cuo formula in the treatment of acne based on animal experiments, UPLC-LTQ-Orbitrap-MS and network pharmacology

Abstract: Abstract Context Qing Cuo Formula (QCF) is a traditional Chinese medicine for treating acne, but its active compounds and molecular mechanisms are unclear. Objective To investigate the material basis and molecular mechanism of QCF. Materials and methods In vivo experiments were conducted on 60 male golden hamsters with damp-heat acne, with a blank group, a spironolactone group and 3 QCF administration groups (given high, medium and low doses) over a 30-day period. Serum androgen and inflammatory cytokine levels were tested by ELISA. In vitro, chemical compositions of QCF were investigated by UPLC-LTQ-Orbitrap-MS. Network pharmacology approaches were used to analyse the protein–protein interaction (PPI) network and QCF active compounds-intersection targets-acne network. GO enrichment and KEGG pathway analysis was conducted subsequently. Results Low-dose QCF group (11.4 g/kg/day) showed significantly reduced levels of serum T (4.94 ± 0.36; 5.51 ± 0.36 ng/mL), DHT (6.67 ± 0.61; 8.09 ± 0.59 nmol/L), E2 (209.01 ± 20.92; 237.08 ± 13.94 pg/mL), IL-1α (36.84 ± 3.23; 44.07 ± 4.00 pg/mL) and FFA (128.32 ± 10.94; 148.00 ± 12.12 µmol/L) compared to the blank group (p < 0.05). In vitro experiments identified 75 compounds in QCF decoction, with 27 active compounds absorbed in serum. Network pharmacology identified 6 active components connecting 17 targets. GO enrichment and KEGG pathway analysis indicated that QCF’s anti-acne targets mainly regulate extracellular matrix function, inflammatory processes, immune response and endocrine function. Conclusions This study provides evidence of the molecular mechanism and material basis of QCF in treating androgen-related damp-heat acne, paving the way for further research on its potential in treating other conditions related to damp-heat constitution.

Dasatinib Resensitizes MAPK Inhibitor Efficacy in Standard-of-Care Relapsed Melanomas

Abstract: Resistance to combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy arises in nearly every patient with BRAFV600E/K melanoma, despite promising initial responses. Achieving cures in this expanding BRAFi/MEKi-resistant cohort represents one of the greatest challenges to the field; few experience additional durable benefit from immunotherapy and no alternative therapies exist. To better personalize therapy in cancer patients to address therapy relapse, umbrella trials have been initiated whereby genomic sequencing of a panel of potentially actionable targets guide therapy selection for patients; however, the superior efficacy of such approaches remains to be seen. We here test the robustness of the umbrella trial rationale by analyzing relationships between genomic status of a gene and the downstream consequences at the protein level of related pathway, which find poor relationships between mutations, copy number amplification, and protein level. To profile candidate therapeutic strategies that may offer clinical benefit in the context of acquired BRAFi/MEKi resistance, we established a repository of patient-derived xenograft models from heavily pretreated patients with resistance to BRAFi/MEKi and/or immunotherapy (R-PDX). With these R-PDXs, we executed in vivo compound repurposing screens using 11 FDA-approved agents from an NCI-portfolio with pan-RTK, non-RTK and/or PI3K-mTOR specificity. We identify dasatinib as capable of restoring BRAFi/MEKi antitumor efficacy in ∼70% of R-PDX tested. A systems-biology analysis indicates elevated baseline protein expression of canonical drivers of therapy resistance (e.g., AXL, YAP, HSP70, phospho-AKT) as predictive of MAPKi/dasatinib sensitivity. We therefore propose that dasatinib-based MAPKi therapy may restore antitumor efficacy in patients that have relapsed to standard-of-care therapy by broadly targeting proteins critical in melanoma therapy escape. Further, we submit that this experimental PDX paradigm could potentially improve preclinical evaluation of therapeutic modalities and augment our ability to identify biomarker-defined patient subsets that may respond to a given clinical trial. SINGLE SENTENCE SUMMARY Broad target inhibition effective as a salvage strategy in BRAF/MEK inhibitor-acquired resistance PDX

A Scalable Die-to-Die Interconnect with Replay and Repair Schemes for 2.5D/3D Integration

Abstract: Chiplet is a critical technology in the post-Moore era, and the die-to-die (D2D) interconnect is essential for communication between chiplets. Meanwhile, several edge-computing devices based on 2.5D/3D chiplet have recently emerged. However, a lightweight D2D interconnect for 2.5D/3D edge-computing systems is lacking. Given the differences between 2.5D/3D integration, a scalable D2D interconnect with replay and repair schemes is presented in this paper. A credit-based flow control scheme and a custom replay scheme are presented for high efficiency. An effective detection and repair scheme is proposed to enhance fault tolerance for the D2D interconnect. Compared with a previous D2D interconnect design, the proposed D2D interconnect delivers 1.07/1.09Gbps throughput ($\sim 2.4\times/\sim 3.9\times \text{for}\ \text{write}/\text{read}$) and significantly reduced energy/bit with only ∼1.7× increased hardware cost. Additionally, compared with a previous chip-to-chip interconnect design, the proposed D2D interconnect can be configured down to power consumption as low as 0.55pJ/bit and 38.40Gbps throughput, achieving ∼2.5× throughput and significantly reduced latency with a negligible increase in hardware cost.

A $2.53 \mu \mathrm{W}/\text{channel}$ Event-Driven Neural Spike Sorting Processor with Sparsity-Aware Computing-In-Memory Macros

Abstract: Spike sorting processors with high energy efficiency are widely used in large-scale neural signal processing tasks to monitor the activity of neurons in brains. This paper presents a low-power processor for high-accuracy spike sorting and on-chip incremental learning using an algorithm-hardware co-design approach. The processor introduces an event-driven mechanism with adaptive-threshold detection to conditionally activate the system in order to reduce power consumption. Sparsity-aware computing-in-memory (CIM) macros are also developed in our design to store templates and perform complicated computations efficiently. The prototype is designed using 28nm technology with an area of 0.018 mm2/channel and an overall power efficiency of $\mathbf{2.53} \mu \mathbf{W}/\mathbf{channel}$ and 84nW/(channel.cluster) at the voltage of 0.72V. Moreover, the accuracy of the whole design can reach 94.5% in a 32-channel scenario.

A 9Mb HZO-Based Embedded FeRAM with 1012-Cycle Endurance and 5/7ns Read/Write using ECC-Assisted Data Refresh and Offset-Canceled Sense Amplifier

Abstract: The growing demand for data and code storage has driven the development of emerging embedded nonvolatile memory (eNVM) technologies [1–6]. HZO-based $(\text{Hf}_{0.5}\text{Zr}_{0.5}0_{2})$ ferroelectric random-access memory (FeRAM) is a good candidate because of its high reliability, high speed, good scalability, and CMOS process compatibility [3], [4]. However, challenges still exist in designing robust read/write circuits for high endurance and improved sense margins. In this work, we present a 9-Mb (including ECC) HZO-based nonvolatile FeRAM chip aimed at mass scale production. A TiN/HZO/TiN ferroelectric capacitor (FeCAP) is integrated in the back-end-of-line of a 130nm CMOS process with a 700nm diameter capacitor and a mega-level capacity. A temperature-aware write-voltage driver, with ECC-assisted refresh (ECC-WD), is designed to improve the endurance of FeCAP. The offset-canceled sense amplifier is designed to tolerate a small BL signal margin and to reduce the read bit-error rate (BER). Measurement results show a $2\times$ remnant polarization $(\mathrm{P}_{\mathrm{R}}) > 30\mu\mathrm{C}/\text{cm}^{2}, \mathrm{a} > 10^{12}$-cycle endurance, a 7ns write and a 5ns read time, a sub-3V operating voltage, and 10-year data retention at $85^{\circ}\mathrm{C}$.

[Rapid screening of Chemical Weapons Convention-related chemicals in oil matrix by headspace solid-phase microextraction and gas chromatography-mass spectrometry].

Abstract: The Chemical Weapons Convention (CWC) requires verification of a large number of compounds with different types and properties. The results of the verification are of great political and military sensitivity. However, the sources of verification samples are complex and diverse, and the contents of the target compounds in these samples are usually very low. These issues increase the likelihood of missed or false detection. Thus, establishing rapid and effective screening methods for the accurate identification of CWC-related compounds in complex environmental samples are of great importance. In this study, a fast and simple procedure based on headspace solid-phase microextraction (HS-SPME) followed by gas chromatography-electron ionization mass spectrometry (GC-EI/MS) in full-scan mode was developed to determine CWC-related chemicals in oil matrix. A total of 24 CWC-related chemicals with different chemical characteristics were selected to simulate the screening procedure. The selected compounds were divided into three groups based on their properties. The first group included volatile and semi-volatile CWC-related compounds with relatively low polarity, which could be extracted by HS-SPME and directly analyzed by GC-MS. The second group included moderately polar compounds with hydroxyl or amino groups; such compounds are related to nerve, blister, and incapacitating agents. The compounds in the third group included non-volatile CWC-related chemicals with relatively strong polarity, such as alkyl methylphosphonic acids and diphenyl hydroxyacetic acid. These compounds must be derivatized into vaporizable derivatives prior to extraction by HS-SPME and analysis by GC-MS. Variables that influence the SPME process, such as fiber type, extraction temperature and time, desorption time, and derivatization protocol, were optimized to improve the sensitivity of the method. The screening procedure for CWC-related compounds in the oil matrix samples included two main steps. First, low-polarity volatile and semi-volatile compounds (i. e. the first group) were extracted by HS-SPME with divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) fibers and analyzed in split-injection mode (split ratio, 10∶1) using GC-MS. The use of a large split ratio can reduce the solvent effect, which is conducive to the detection of low-boiling-point compounds. If necessary, the sample could be extracted once more and analyzed in splitless mode. The derivatization agent bis(trimethylsilyl)trifluoroacetamide (BSTFA) was then added to the sample. Mid- and high-polarity compounds (i. e. the second and third groups) were extracted with polydimethylsiloxane/divinylbenzene (PDMS/DVB) fibers after derivatization and analyzed in splitless mode using GC-MS. The established method exhibited good repeatability and sensitivity. The detection limits for the compounds in the first group ranged from 0.5 ng/mL to 100 ng/mL, whereas the detection limits for the compounds in the second and third groups ranged from 20 ng/mL to 300 ng/mL. Except for compounds with extremely high boiling points and a few compounds that are not suitable for derivatization with BSTFA, the method can be used to analyze most CWC-related compounds in oil matrix samples. In particular, it greatly shortened the preparation time of the oil matrix samples and reduced the loss of low-boiling-point compounds owing to the sample concentration process, thereby avoiding missed detection. The method was successfully applied to the Organization for the Prohibition of Chemical Weapons (OPCW) proficiency tests and proved to be a useful technique for the rapid screening of trace levels of CWC-related chemicals in oil matrix.

Straightforward data transfer in a blockwise dataflow for an analog RRAM-based CIM system

Abstract: Analog resistive random-access memory (RRAM)-based computation-in-memory (CIM) technology is promising for constructing artificial intelligence (AI) with high energy efficiency and excellent scalability. However, the large overhead of analog-to-digital converters (ADCs) is a key limitation. In this work, we propose a novel LINKAGE architecture that eliminates PE-level ADCs and leverages an analog data transfer module to implement inter-array data processing. A blockwise dataflow is further proposed to accelerate convolutional neural networks (CNNs) to speed up compute-intensive layers and solve the unbalanced pipeline problem. To obtain accurate and reliable benchmark results, key component modules, such as straightforward link (SFL) modules and Tile-level ADCs, are designed in standard 28 nm CMOS technology. The evaluation shows that LINKAGE outperforms the conventional ADC/DAC-based architecture with a 2.07×∼11.22× improvement in throughput, 2.45×∼7.00× in energy efficiency, and 22%–51% reduction in the area overhead while maintaining accuracy. Our LINKAGE architecture can achieve 22.9∼24.4 TOPS/W energy efficiency (4b-IN/4b-W) and 1.82 ∼4.53 TOPS throughput with the blockwise method. This work demonstrates a new method for significantly improving the energy efficiency of CIM chips, which can be applied to general CNNs/FCNNs.

A 28-nm RRAM Computing-in-Memory Macro Using Weighted Hybrid 2T1R Cell Array and Reference Subtracting Sense Amplifier for AI Edge Inference

Abstract: Non-volatile computing-in-memory (nvCIM) can potentially meet the ever-increasing demands on improving the energy efficiency (EF) for intelligent edge devices. However, it still suffers from limited input parallelism due to the parasitic effects, signal margin degradation due to device non-idealities, and large hardware cost for analog readout. In this work, we present a two-transistor-one-resistor (2T1R) resistive memory (RRAM) nvCIM macro featuring: 1) a macro structure with decoupled memory and computing data paths; 2) the weighted hybrid 2T1R (WH-2T1R) cell array; 3) the redundant sub-array mapping scheme of the most-significant-bit (RSM-MSB); and 4) reference-subtracting current sense amplifier (RS-CSA). A test-chip is silicon-verified using the 28-nm high-k/metal-gate (HKMG) logic process with foundry-developed RRAM. The test-chip performs linear analog multiply-and-accumulate (MAC) operations over 32 accumulation channels and achieves 30.34–154.04 TOPS/W with 1-bit input (IN), 3-bit weight (W), and 4-bit output (O). Evaluations with the ResNet-18 model show that the MSB-RSM scheme results in 0.96% and 2.83% improvement on CIFAR-10 and CIFAR-100 inference accuracy, respectively.

Molecular mechanism and research progress on pharmacology of ferulic acid in liver diseases

Abstract: Ferulic acid (FA) is a natural polyphenol, a derivative of cinnamic acid, widely found in Angelica, Chuanxiong and other fruits, vegetables and traditional Chinese medicine. FA contains methoxy, 4-hydroxy and carboxylic acid functional groups that bind covalently to neighbouring adjacent unsaturated Cationic C and play a key role in many diseases related to oxidative stress. Numerous studies have shown that ferulic acid protects liver cells and inhibits liver injury, liver fibrosis, hepatotoxicity and hepatocyte apoptosis caused by various factors. FA has protective effects on liver injury induced by acetaminophen, methotrexate, antituberculosis drugs, diosbulbin B and tripterygium wilfordii, mainly through the signal pathways related to TLR4/NF-κB and Keap1/Nrf2. FA also has protective effects on carbon tetrachloride, concanavalin A and septic liver injury. FA pretreatment can protect hepatocytes from radiation damage, protects the liver from damage caused by fluoride, cadmium and aflatoxin b1. At the same time, FA can inhibit liver fibrosis, inhibit liver steatosis and reduce lipid toxicity, improve insulin resistance in the liver and exert the effect of anti-liver cancer. In addition, signalling pathways such as Akt/FoxO1, AMPK, PPAR γ, Smad2/3 and Caspase-3 have been shown to be vital molecular targets for FA involvement in improving various liver diseases. Recent advances in the pharmacological effects of ferulic acid and its derivatives on liver diseases were reviewed. The results will provide guidance for the clinical application of ferulic acid and its derivatives in the treatment of liver diseases.

A 14b 500 MS/s Single-Channel Pipelined-SAR ADC With Reference Ripple Mitigation Techniques and Adaptively Biased Floating Inverter Amplifier

Abstract: This work presents a 14-bit 500 MS/s single-channel pipelined-successive-approximation-register (SAR) analog-to-digital converter (ADC) with an adaptively biased floating inverter amplifier (AB-FIA) as the residue amplifier (RA) and a hybrid reference ripple mitigation (H-RRM) technique to relax the power and area burden on the reference stabilization. Leveraging the adaptively biased architecture in the last stage FIA, the speed and open-loop gain of the proposed two-stage FIA are enhanced compared with the conventional cascode counterpart. Besides, the impact of the reference error on the pipelined-SAR conversion accuracy is alleviated by hybridizing the improved reference ripple cancellation (RRC), reference ripple neutralization (RRN), and reference buffer (RBUF). The improved RRC removes the potential noise coupled from the floating capacitor to counter the decision error during the sub-SAR conversion in the first stage. Meanwhile, the RRN facilitates a rapid reference recovery. These acts constitute the H-RRM, which assists a high-speed and high-resolution pipelined-SAR process with a relaxed integrated reference RBUF with low-power and compact area. The prototype ADC was fabricated in a 28 nm CMOS process; it consumes 6.34 mW total power at 500 MS/s, including 2.4 mW dynamic power of RBUF. It occupies an active area of 0.018 mm $^{2}$ , which the ADC core area of 0.0168 mm $^{2}$ and the area of RBUF with a 2.3 pF decoupling capacitor is 0.00105 mm $^{2}$ . The measured signal to noise and distortion ratio (SNDR) and spurious free dynamic range (SFDR) are 64.2 dB and 80.55 dB with a Nyquist input, respectively, leading to a 170.2 dB Schreier figure-of-merit (FoM) (FoM $_{\mathrm{S}}$ ) and 9.6 fJ/conversion-step Walden FoM (FoM $_{\mathrm{W}}$ ).