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Markov chain Monte Carlo (MCMC) is a widely used sampling method in modern artificial intelligence and probabilistic computing systems. It involves repetitive random number generations and thus often dominates the latency of probabilistic model computing. Hence, we propose a compute-in-memory (CIM) based MCMC design as a hardware acceleration solution. This work investigates SRAM bitcell stochasticity and proposes a novel ``pseudo-read'' operation, based on which we offer a block-wise random number generation circuit scheme for fast random number generation. Moreover, this work proposes a novel multi-stage exclusive-OR gate (MSXOR) design method to generate strictly uniformly distributed random numbers. The probability error deviating from a uniform distribution is suppressed under $10^{-5}$. Also, this work presents a novel in-memory copy circuit scheme to realize data copy inside a CIM sub-array, significantly reducing the use of R/W circuits for power saving. Evaluated in a commercial 28-nm process development kit, this CIM-based MCMC design generates 4-bit$\sim$32-bit samples with an energy efficiency of $0.53$~pJ/sample and high throughput of up to $166.7$M~samples/s. Compared to conventional processors, the overall energy efficiency improves $5.41\times10^{11}$ to $2.33\times10^{12}$ times.

Additional file 1: Table S1. Differentially expressed genes. Table S2. The number of label genes, annotations, and cell numbers of different subgroups in UMAP clustering results. Table S3. Combine annotation cluster cells. Table S4. Gene annotations extracted. Table S5. Statistics of input gene lists.

Memristive in-memory sorting has been proposed recently to improve hardware sorting efficiency. Using iterative in-memory min computations, data movements between memory and external processing units can be eliminated for improved latency and energy efficiency. However, the bit-traversal algorithm to search the min requires a large number of column reads on memristive memory. In this work, we propose a column-skipping algorithm with help of a near-memory circuit. Redundant column reads can be skipped based on recorded states for improved latency and hardware efficiency. To enhance the scalability, we develop a multi-bank management that enables column-skipping for dataset stored in different memristive memory banks. Prototype column-skipping sorters are implemented with a 1T1R memristive memory in 40nm CMOS technology. Experimented on a variety of sorting datasets, the length-1024 32-bit column-skipping sorter with state recording of 2 demonstrates up to 4.08x speedup, 3.14x area efficiency and 3.39x energy efficiency, respectively, over the latest memristive in-memory sorting., Comment: Accepted in ISCAS 2022

Cells and tissues in the human body are subjected to mechanical forces of varying degrees, such as tension or pressure. During tumorigenesis, physical factors, especially mechanical factors, are involved in tumor development. As lung tissue is influenced by movements associated with breathing, it is constantly subjected to cyclical stretching and retraction; therefore, lung cancer cells and lung cancer-associated fibroblasts (CAFs) are constantly exposed to mechanical load. Thus, to better explore the mechanisms involved in lung cancer progression, it is necessary to consider factors involved in cell mechanics, which may provide a more comprehensive analysis of tumorigenesis. The purpose of this review is: 1) to provide an overview of the anatomy and tissue characteristics of the lung and the presence of mechanical stimulation; 2) to summarize the role of mechanical stretching in the progression of lung cancer; and 3) to describe the relationship between mechanical stretching and the lung cancer microenvironment, especially CAFs.

To improve the mechanization of strawberry planting integration and the efficiency of fetching and transplanting seedlings, an integrated transplanting mechanism with protruding, fetching and planting is designed. This new device can realize rapid fetching and pushing bowl movements. The working principle of the slewing mechanism is analyzed, a kinematics model of the mechanism is established, and the optimization goal is established. Visual auxiliary analysis software is developed, optimized parameters are established, and the corresponding theoretical trajectory is provided. A three-dimensional model is established and a virtual simulation design analysis is performed to obtain a simulation trajectory. Three-dimensional printing technology is used to manufacture the test prototype, and the actual working trajectory of the test prototype is extracted using high-speed photography technology, which verifies the consistency of the actual trajectory with the theoretical and simulated trajectories. A prototype transplanting experiment is performed, showing that the success rate of seedling extraction is 91.2% and the rate of excellent planting is 82.8%, which meet the requirements for integrated strawberry harvesting, planting and transplanting and verify the correctness and feasibility of the mechanism design.

This work shows a memristive optimizer based on transient chaos, which is able to solve optimization problems efficiently., Optimization problems are ubiquitous in scientific research, engineering, and daily lives. However, solving a complex optimization problem often requires excessive computing resource and time and faces challenges in easily getting trapped into local optima. Here, we propose a memristive optimizer hardware based on a Hopfield network, which introduces transient chaos to simulated annealing in aid of jumping out of the local optima while ensuring convergence. A single memristor crossbar is used to store the weight parameters of a fully connected Hopfield network and adjust the network dynamics in situ. Furthermore, we harness the intrinsic nonlinearity of memristors within the crossbar to implement an efficient and simplified annealing process for the optimization. Solutions of continuous function optimizations on sphere function and Matyas function as well as combinatorial optimization on Max-cut problem are experimentally demonstrated, indicating great potential of the transiently chaotic memristive network in solving optimization problems in general.

Cyclin-dependent kinases (CDKs) 7 and 9 are deregulated in various types of human cancer and are thus viewed as therapeutic targets. Accordingly, small-molecule inhibitors of both CDKs are highly sought-after. Capitalising on our previous discovery of CDKI-73, a potent CDK9 inhibitor, medicinal chemistry optimisation was pursued. A number of N-pyridinylpyrimidin-2-amines were rationally designed, chemically synthesised and biologically assessed. Among them, N-(6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl)-4-(imidazo[1,2-a]pyrimidin-3-yl)pyrimidin-2-amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti-proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4-11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub-G1 phase and induced apoptosis. Refereed/Peer-reviewed

CDK8 is deregulated in multiple types of human cancer and is viewed as a therapeutic target for the treatment of the disease. Accordingly, the search for small-molecule inhibitors of CDK8 is being intensified. Capitalising on our initial discovery of AU1-100, a potent CDK8 inhibitor yet with a limited degree of kinase selectivity, a structure-based optimisation was carried out, with a series of new multi-substituted pyridines rationally designed, chemically prepared and biologically evaluated. Such endeavour has culminated in the identification of 42, a more potent CDK8 inhibitor with superior kinomic selectivity and oral bioavailability. The mechanism underlying the anti-proliferative effect of 42 on MV4-11 cells was studied, revealing that the compound arrested the G1 cell cycle and triggered apoptosis. The low risk of hepato- and cardio-toxicity of 42 was estimated. These findings merit further investigation of 42 as a targeted cancer therapeutic. Refereed/Peer-reviewed

CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent. Refereed/Peer-reviewed

The Ras/Raf/MAPK and PI3K/Akt/mTOR pathways are key signaling cascades involved in the regulation of cell proliferation and survival, and have been implicated in the pathogenesis of several types of cancers, including acute myeloid leukemia (AML). The oncogenic activity of eIF4E driven by the Mnk kinases is a convergent determinant of the two cascades, suggesting that targeting the Mnk/eIF4E axis may provide therapeutic opportunity for the treatment of cancer. Herein, a potent and selective Mnk2 inhibitor (MNKI-85) and a dual-specific Mnk1 and Mnk2 inhibitor (MNKI-19), both derived from a thienopyrimidinyl chemotype, were selected to explore their antileukemic properties. MNKI-19 and MNKI-85 are effective in inhibiting the growth of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation. Further mechanistic studies show that the downstream effects with respect to the selective Mnk1/2 kinase inhibition in AML cells causes G1 cell cycle arrest followed by induction of apoptosis. MNKI-19 and MNKI-85 demonstrate similar Mnk2 kinase activity and cellular antiproliferative activity but exhibit different time-dependent effects on cell cycle progression and apoptosis. Collectively, this study shows that pharmacologic inhibition of both Mnk1 and Mnk2 can result in a more pronounced cellular response than targeting Mnk2 alone. However, MNKI-85, a first-in-class inhibitor of Mnk2, can be used as a powerful pharmacologic tool in studying the Mnk2/eIF4E-mediated tumorigenic mechanism. In conclusion, this study provides a better understanding of the mechanism underlying the inhibition of AML cell growth by Mnk inhibitors and suggests their potential utility as a therapeutic agent for AML. Refereed/Peer-reviewed

The Ras/Raf/MAPK and PI3K/Akt/mTORC1 cascades are two most aberrantly regulated pathways in cancers. As MAPK-interacting kinases (Mnks) are part of the convergent node of these two pathways, and play a pivotal role in cellular transformation, targeting Mnks has emerged as a potential therapeutic strategy. Herein, a dual-specific Mnk1/2 inhibitor MNKI-57 and a potent Mnk2-specific inhibitor MNKI-4 were selected for a panel screen against 28 human cancer cell lines. The study reveals that MNKI-57 and MNKI-4 are most potent against leukemia cells KYO-1 (i.e. BC-CML) and KG-1 (i.e. AML). Interestingly, we found that sensitivity of selected leukemia cells to Mnk inhibitors is correlated with the level of phosphorylated 4E-BP1 at Thr70. The anti-proliferative effects of Mnk inhibitors are cytostatic in the sensitive KYO-1 cells, inducing significant G1 arrest via down-regulation of cyclin D1 expression. In KYO-1 cells where Akt is not constitutively active, Mnk inhibitors increase the sensitivity of cells to rapamycin, resulting in a more pronounced anti-proliferative activity. Remarkably, the synergistic anti-proliferative effects are associated with a marked de-phosphorylation of 4E-BP1 at Thr70. Collectively, these data highlight the importance of 4E-BP1 as a key integrator in the MAPK and mTORC1 cascades, and suggest that a combined pharmacologic inhibition of mTORC1 and Mnk kinases offers an innovative therapeutic opportunity in BC-CML. Refereed/Peer-reviewed