Binder assisted graphene derivatives as lubricants in copper: Improved tribological performance for industrial application.

Originally derived from graphite, high-quality single-layer graphene is an excellent anti-wear and -friction additive in metal matrix. Here, the tribological performance of 3 different commercialized graphene derivatives (e.g., graphene oxide [GO], reduced graphene oxide [RGO], and graphene nanoplatelet [GNP]) as additives in a Cu matrix, were investigated from an industrial perspective. To increase the interaction of graphene derivatives with Cu particles, and addressing the aggregation problem of the graphene derivatives, different binders (polyvinyl alcohol [PVA] and cellulose nanocrystals [CNC]) were introduced into the system. Benefiting from such a strategy, a uniform distribution of the graphene derivatives in Cu matrix was achieved with graphene loading up to 5 wt %. After high-temperature sintering, the graphene is preserved and well distributed in the Cu matrix. It was found that the GNP-containing sample shows the most stable friction coefficient behavior. However, GO and RGO also improve the tribological performance of Cu under different circumstances.

Vina-FPGA-Cluster: Multi-FPGA Based Molecular Docking Tool with High-Accuracy and Multi-Level Parallelism.

AutoDock Vina (Vina) stands out among numerous molecular docking tools due to its precision and comparatively high speed, playing a key role in the drug discovery process. Hardware acceleration of Vina on FPGA platforms offers a high energy-efficiency approach to speed up the docking process. However, previous FPGA-based Vina accelerators exhibit several shortcomings: 1) Simple uniform quantization results in inevitable accuracy drop; 2) Due to Vina's complex computing process, the evaluation and optimization phase for hardware design becomes extended; 3) The iterative computations in Vina constrain the potential for further parallelization. 4) The system's scalability is limited by its unwieldy architecture. To address the above challenges, we propose Vina-FPGA-cluster, a multi-FPGA-based molecular docking tool enabling high-accuracy and multi-level parallel Vina acceleration. Standing upon the shoulders of Vina-FPGA, we first adapt hybrid fixed-point quantization to minimize accuracy loss. We then propose a SystemC-based model, accelerating the hardware accelerator architecture design evaluation. Next, we propose a novel bidirectional AG module for data-level parallelism. Finally, we optimize the system architecture for scalable deployment on multiple Xilinx ZCU104 boards, achieving task-level parallelism. Vina-FPGA-cluster is tested on three representative molecular docking datasets. The experiment results indicate that in the context of RMSD (for successful docking outcomes with metrics below 2Å), Vina-FPGA-cluster shows a mere 0.2% lose. Relative to CPU and Vina-FPGA, Vina-FPGA-cluster achieves 27.33× and 7.26× speedup, respectively. Notably, Vina-FPGA-cluster is able to deliver the 1.38× speedup as GPU implementation (Vina-GPU), with just the 28.99% power consumption.

Choline Dehydrogenase Contributes to Salt Tolerance in Dunaliella through Betaine Synthesis.

In Dunaliella tertiolecta, a microalga renowned for its extraordinary tolerance to high salinity levels up to 4.5 M NaCl, the mechanisms underlying its stress response have largely remained a mystery. In a groundbreaking discovery, this study identifies a choline dehydrogenase enzyme, termed DtCHDH, capable of converting choline to betaine aldehyde. Remarkably, this is the first identification of such an enzyme not just in D. tertiolecta but across the entire Chlorophyta. A 3D model of DtCHDH was constructed, and molecular docking with choline was performed, revealing a potential binding site for the substrate. The enzyme was heterologously expressed in E. coli Rosetta (DE3) and subsequently purified, achieving enzyme activity of 672.2 U/mg. To elucidate the role of DtCHDH in the salt tolerance of D. tertiolecta, RNAi was employed to knock down DtCHDH gene expression. The results indicated that the Ri-12 strain exhibited compromised growth under both high and low salt conditions, along with consistent levels of DtCHDH gene expression and betaine content. Additionally, fatty acid analysis indicated that DtCHDH might also be a FAPs enzyme, catalyzing reactions with decarboxylase activity. This study not only illuminates the role of choline metabolism in D. tertiolecta's adaptation to high salinity but also identifies a novel target for enhancing the NaCl tolerance of microalgae in biotechnological applications.

Vesicular translocation of PARP-1 to cytoplasm causes ADP-ribosylation and disassembly of vimentin filaments during microglia activation induced by LPS.

ADP-ribosylation plays a significant role in various biological processes including genomic stability maintenance, transcriptional regulation, energy metabolism, and cell death. Using macrodomain pull-down assay with microglia lysates and MALDI-TOF-MS analysis, we identified vimentin as a major protein highly ADP-ribosylated by the poly(ADP-ribose) polymerases-1 (PARP-1) in response to LPS. ABT-888, a potent inhibitor of PARP-1/2 blocks the disassembly and ADP-ribosylation of vimentin. PARP-1 is a highly abundant nuclear protein. Its nuclear functions in repairing DNA damages induced by various stress signals, such as inflammatory stresses, have been well studied. In contrast, limited studies have been done on the cytoplasmic role(s) of PARP-1. Our study focuses on the cytoplasmic role of PARP-1 during microglia activation. Using immunofluorescence microscopy and Western blotting, we showed that a significant amount of PARP-1 is present in the cytosol of microglia cells stimulated and activated by LPS. Live cell imaging showed the translocation of nuclear PARP-1-EGFP to the cytoplasm in vesicular structures upon LPS stimulation. ABT-888 and U0126 can block this translocation. Immunofluorescence staining with various organelle marker antibodies revealed that PARP-1 vesicles show colocalization with Lamin A/C, suggesting they might be derived from the nuclear envelope through nuclear envelope budding. In conclusion, we demonstrated that PARP-1 is translocated from the nucleus to cytoplasm via vesicles upon LPS stimulation and that cytoplasmic PARP-1 causes ADP-ribosylation and disassembly of vimentin filaments during microglia activation induced by LPS.

Phenome-wide causal associations between osteoarthritis and other complex traits through the latent causal variable analysis.

BACKGROUND: Individuals with osteoarthritis present with comorbidities, and the potential causal associations remain incompletely elucidated. The present study undertook a large-scale investigation about the causality between osteoarthritis and variable traits, using the summary-level data of genome-wide association studies (GWAS). METHODS: The present study included the summary-level GWS data of knee osteoarthritis, hip osteoarthritis, hip or knee osteoarthritis, hand osteoarthritis, and other 1355 traits. Genetic correlation analysis was conducted between osteoarthritis and other traits through cross-trait bivariate linkage disequilibrium score regression. Subsequently, latent causal variable analysis was performed to explore the causal association when there was a significant genetic correlation. Genetic correlation and latent causal variable analysis were conducted on the Complex Traits Genomics Virtual Lab platform ( https://vl.genoma.io/ ). RESULTS: We found 133 unique phenotypes showing causal relationships with osteoarthritis. Our results confirmed several well-established risk factors of osteoarthritis, such as obesity, weight, BMI, and meniscus derangement. Additionally, our findings suggested putative causal links between osteoarthritis and multiple factors. Socioeconomic determinants such as occupational exposure to dust and diesel exhaust, extended work hours exceeding 40 per week, and unemployment status were implicated. Furthermore, our analysis revealed causal associations with cardiovascular and metabolic disorders, including heart failure, deep venous thrombosis, type 2 diabetes mellitus, and elevated cholesterol levels. Soft tissue and musculoskeletal disorders, such as hallux valgus, internal derangement of the knee, and spondylitis, were also identified to be causally related to osteoarthritis. The study also identified the putative causal associations of osteoarthritis with digestive and respiratory diseases, such as Barrett's esophagus, esophagitis, and asthma, as well as psychiatric conditions including panic attacks and manic or hyperactive episodes. Additionally, we observed osteoarthritis causally related to pharmacological treatments, such as the use of antihypertensive medications, anti-asthmatic drugs, and antidepressants. CONCLUSION: Our study uncovered a wide range of traits causally associated with osteoarthritis. Further studies are needed to validate and illustrate the detailed mechanism of those causal associations.

Catalytic Mechanism and Heterologous Biosynthesis Application of Sesquiterpene Synthases.

Sesquiterpenes comprise a diverse group of natural products with a wide range of applications in cosmetics, food, medicine, agriculture, and biofuels. Heterologous biosynthesis is increasingly employed for sesquiterpene production, aiming to overcome the limitations associated with chemical synthesis and natural extraction. Sesquiterpene synthases (STSs) play a crucial role in the heterologous biosynthesis of sesquiterpene. Under the catalysis of STSs, over 300 skeletons are produced through various cyclization processes (C1-C10 closure, C1-C11 closure, C1-C6 closure, and C1-C7 closure), which are responsible for the diversity of sesquiterpenes. According to the cyclization types, we gave an overview of advances in understanding the mechanism of STSs cyclization from the aspects of protein crystal structures and site-directed mutagenesis. We also summarized the applications of engineering STSs in the heterologous biosynthesis of sesquiterpene. Finally, the bottlenecks and potential research directions related to the STSs cyclization mechanism and application of modified STSs were presented.

Heterologous Biosynthesis of Kauralexin A1 in Saccharomyces cerevisiae through Metabolic and Enzyme Engineering.

Kauralexin A1 (KA1) is a key intermediate of the kauralexin A series metabolites of maize phytoalexins. However, their application is severely limited by their low abundance in maize. In this study, an efficient biosynthetic pathway was constructed to produce KA1 in Saccharomyces cerevisiae. Also, metabolic and enzyme engineering strategies were applied to construct the high-titer strains, such as chassis modification, screening synthases, the colocalization of enzymes, and multiple genomic integrations. First, the KA1 precursor ent-kaurene was synthesized using the efficient diterpene synthase GfCPS/KS from Fusarium fujikuroi, and optimized to reach 244.36 mg/L in shake flasks, which displayed a 200-fold increase compared to the initial strain. Then, the KA1 was produced under the catalysis of ZmCYP71Z18 from Zea mays and SmCPR1 from Salvia miltiorrhiza, and the titer was further improved by integrating the fusion protein into the genome. Finally, an ent-kaurene titer of 763.23 mg/L and a KA1 titer of 42.22 mg/L were achieved through a single-stage fed-batch fermentation in a 5 L bioreactor. This is the first report of the heterologous biosynthesis of maize diterpene phytoalexins in S. cerevisiae, which lays a foundation for further pathway reconstruction and biosynthesis of the kauralexin A series maize phytoalexins.

Decoding the Cell Atlas and Inflammatory Features of Human Intracranial Aneurysm Wall by Single-Cell RNA Sequencing.

BACKGROUND: Intracranial aneurysm (IA) is common and occasionally results in life-threatening hemorrhagic strokes. However, the cell architecture and inflammation in the IA dome remain less understood. METHODS AND RESULTS: Single-cell RNA sequencing was performed on ruptured and unruptured human IA domes for delineating the cell atlas, gene expression perturbations, and inflammation features. Two external bulk mRNA sequencing-based data sets and serological results of 126 patients were collected for validation. As a result, a total of 21 332 qualified cells were captured. Vascular cells, including endothelial cells, smooth muscle cells, fibroblasts, and pericytes, were assigned in extremely sparse numbers (4.84%), and were confirmed by immunofluorescence staining. Pericytes, characterized by ABCC9 and HIGD1B, were identified in the IA dome for the first time. Abundant immune cells were identified, with the proportion of monocytes/macrophages and neutrophils being remarkably higher in ruptured IA. The lymphocyte compartment was also thoroughly categorized. By leveraging external data sets and machine learning algorithms, macrophages were robustly associated with IA rupture, irrespective of their polarization status. The single nucleotide polymorphism rs2280543, which is identified in East Asian populations, was associated with macrophage metabolic reprogramming through regulating TALDO1 expression. CONCLUSIONS: This study provides insights into the cellular architecture and inflammatory features in the IA dome and may enlighten novel therapeutics for unruptured IA.

Thin-film transistor for temporal self-adaptive reservoir computing with closed-loop architecture.

Reservoir computing is a powerful neural network-based computing paradigm for spatiotemporal signal processing. Recently, physical reservoirs have been explored based on various electronic devices with outstanding efficiency. However, the inflexible temporal dynamics of these reservoirs have posed fundamental restrictions in processing spatiotemporal signals with various timescales. Here, we fabricated thin-film transistors with controllable temporal dynamics, which can be easily tuned with electrical operation signals and showed excellent cycle-to-cycle uniformity. Based on this, we constructed a temporal adaptive reservoir capable of extracting temporal information of multiple timescales, thereby achieving improved accuracy in the human-activity-recognition task. Moreover, by leveraging the former computing output to modify the hyperparameters, we constructed a closed-loop architecture that equips the reservoir computing system with temporal self-adaptability according to the current input. The adaptability is demonstrated by accurate real-time recognition of objects moving at diverse speed levels. This work provides an approach for reservoir computing systems to achieve real-time processing of spatiotemporal signals with compound temporal characteristics.

Naringenin attenuated airway cilia structural and functional injury induced by cigarette smoke extract via IL-17 and cAMP pathways.

BACKGROUND: Cigarette smoke impairs mucociliary clearance via mechanisms such as inflammatory response and oxidative injury, which in turn induces various respiratory diseases. Naringenin, a naturally occurring flavonoid in grapes and grapefruit, has exhibited pharmacological properties such as anti-inflammatory, expectorant, and antioxidant properties. However, it is still unclear whether naringenin protects airway cilia from injury caused by cigarette smoke. PURPOSE: This study aimed to investigate the effect of naringenin on cigarette smoke extract (CSE)-induced structural and functional abnormalities in airway cilia and highlight the potential regulatory mechanism. METHODS: Initially, network pharmacology was used to predict the mechanism of action of naringenin in ciliary disease. Next, HE staining, immunofluorescence, TEM, qRT-PCR, western blot, and ELISA were performed to assess the effects of naringenin on airway cilia in tracheal rings and air-liquid interface (ALI) cultures of Sprague Dawley rats after co-exposure to CSE (10% or 20%) and naringenin (0, 25, 50, 100 µM) for 24 h. Finally, transcriptomics and molecular biotechnology methods were conducted to elucidate the mechanism by which naringenin protected cilia from CSE-induced damage in ALI cultures. RESULTS: The targets of ciliary diseases regulated by naringenin were significantly enriched in inflammation and oxidative stress pathways. Also, the CSE decreased the number of cilia in the tracheal rings and ALI cultures and reduced the ciliary beat frequency (CBF). However, naringenin prevented CSE-induced cilia damage via mechanisms such as the downregulation of cilia-related genes (e.g., RFX3, DNAI1, DNAH5, IFT88) and ciliary marker proteins such as DNAI2, FOXJ1, and ß-tubulin IV, the upregulation of inflammatory factors (e.g., IL-6, IL-8, IL-13), ROS and MDA. IL-17 signaling pathway might be involved in the protective effect of naringenin on airway cilia. Additionally, the cAMP signaling pathway might also be related to the enhancement of CBF by naringenin. CONCLUSION: In this study, we first found that naringenin reduces CSE-induced structural disruption of airway cilia in part via modulation of the IL-17 signaling pathway. Furthermore, we also found that naringenin enhances CBF by activating the cAMP signaling pathway. This is the first report to reveal the beneficial effects of naringenin on airway cilia and the potential underlying mechanisms.

Emerging role of SENP1 in tumorigenesis and cancer therapy.

Acting as a cysteine protease, small ubiquitin-like modifier (SUMO)/sentrin-specific protease1 (SENP1) involved in multiple physiological and pathological processes through processing the precursor SUMO protein into mature form and deSUMOylating target protein. It has been reported that SENP1 is highly expressed and plays a carcinogenic role in various cancers. In this paper, we mainly explore the function and mechanism of SENP1 in tumor cell proliferation, apoptosis, invasion, metastasis, stemness, angiogenesis, metabolism and drug resistance. Furthermore, the research progress of SENP1 inhibitors for cancer treatment is introduced. This study aims to provide theoretical references for cancer therapy by targeting SENP1.

Molecular identification and functional characterization of a transcription factor GeRAV1 from Gelsemium elegans.

BACKGROUND: Gelsemium elegans is a traditional Chinese medicinal plant and temperature is one of the key factors affecting its growth. RAV (related to ABI3/VP1) transcription factor plays multiple roles in higher plants, including the regulation of plant growth, development, and stress response. However, RAV transcription factor in G. elegans has not been reported. RESULTS: In this study, three novel GeRAV genes (GeRAV1-GeRAV3) were identified from the transcriptome of G. elegans under low temperature stress. Phylogenetic analysis showed that GeRAV1-GeRAV3 proteins were clustered into groups II, IV, and V, respectively. RNA-sequencing (RNA-seq) and real-time quantitative PCR (qRT-PCR) analyses indicated that the expression of GeRAV1 and GeRAV2 was increased in response to cold stress. Furthermore, the GeRAV1 gene was successfully cloned from G. elegans leaf. It encoded a hydrophilic, unstable, and non-secretory protein that contained both AP2 and B3 domains. The amino acid sequence of GeRAV1 protein shared a high similarity of 81.97% with Camptotheca acuminata CaRAV. Subcellular localization and transcriptional self-activation experiments demonstrated that GeRAV1 was a nucleoprotein without self-activating activity. The GeRAV1 gene was constitutively expressed in the leaves, stems, and roots of the G. elegans, with the highest expression levels in roots. In addition, the expression of the GeRAV1 gene was rapidly up-regulated under abscisic acid (ABA), salicylic acid (SA), and methyl jasmonate (MeJA) stresses, suggesting that it may be involved in hormonal signaling pathways. Moreover, GeRAV1 conferred improved cold and sodium chloride tolerance in Escherichia coli Rosetta cells. CONCLUSIONS: These findings provided a foundation for further understanding on the function and regulatory mechanism of the GeRAV1 gene in response to low-temperature stress in G. elegans.

Dynamical models reveal anatomically reliable attractor landscapes embedded in resting state brain networks.

Analyses of functional connectivity (FC) in resting-state brain networks (RSNs) have generated many insights into cognition. However, the mechanistic underpinnings of FC and RSNs are still not well-understood. It remains debated whether resting state activity is best characterized as noise-driven fluctuations around a single stable state, or instead, as a nonlinear dynamical system with nontrivial attractors embedded in the RSNs. Here, we provide evidence for the latter, by constructing whole-brain dynamical systems models from individual resting-state fMRI (rfMRI) recordings, using the Mesoscale Individualized NeuroDynamic (MINDy) platform. The MINDy models consist of hundreds of neural masses representing brain parcels, connected by fully trainable, individualized weights. We found that our models manifested a diverse taxonomy of nontrivial attractor landscapes including multiple equilibria and limit cycles. However, when projected into anatomical space, these attractors mapped onto a limited set of canonical RSNs, including the default mode network (DMN) and frontoparietal control network (FPN), which were reliable at the individual level. Further, by creating convex combinations of models, bifurcations were induced that recapitulated the full spectrum of dynamics found via fitting. These findings suggest that the resting brain traverses a diverse set of dynamics, which generates several distinct but anatomically overlapping attractor landscapes. Treating rfMRI as a unimodal stationary process (i.e., conventional FC) may miss critical attractor properties and structure within the resting brain. Instead, these may be better captured through neural dynamical modeling and analytic approaches. The results provide new insights into the generative mechanisms and intrinsic spatiotemporal organization of brain networks.

Relationships between protein and other chemical composition and texture of tofu made from soybeans grown in different locations.

Understanding quantitative relationships between protein and other chemical components in diverse soybean genotypes (lines) grown in different locations and the firmness of tofu can provide scientific insight for selecting soybean suitable for tofu making. Locations showed significant effects on seed components, including total protein, major storage proteins, subunits and polypeptides of the major storage proteins, and calcium, but not magnesium or phytic acid. Results showed that 11S content, but not 11S/7S ratio, was only correlated with filled tofu firmness when analyzed over all locations. A strong and positive correlation between firmness and A3 polypeptide of the 11S protein content was found for both pressed tofu (r = 0.80, p < 0.001) and filled tofu (r = 0.76, p < 0.001) over three locations (overall pooled data) and within most individual locations. The correlation of filled tofu firmness and A3 polypeptide was significant for each of the three individual locations. However, the correlation of pressed tofu firmness and A3 polypeptide content was significant at two of three locations. Mean calcium content was positively correlated with mean pressed and filled tofu firmness over all locations, but calcium was not correlated with pressed tofu firmness at any individual location, and only one location showed a significant correlation of calcium and filled tofu firmness. In addition, pressed tofu firmness was found to be negatively correlated with tofu yield. The findings that A3 polypeptide's strong relationship with tofu firmness within certain locations may be used by the food industry to select proper soybean for manufacturing tofu and to facilitate tofu soybean breeding for tofu making.

Hypergravity stimulates mechanical behavior and micro-architecture of tibia in rats.

INTRODUCTION: The bone tissue is susceptible to hypergravity (+ G) environment. It is necessary to discuss the extent to which specific + G values are beneficial or detrimental to bone tissue. The objective of this study was to characterize the effects of high + G values on mechanical properties, microstructures, and cellular metabolism of bone. MATERIALS AND METHODS: 30 male Wistar rats aged 12 weeks were randomly divided into 5 groups, and bore different + G (namely + 1G, + 4G, + 8G, + 10G and + 12G) environments respectively for 4 weeks, 5 days each week, and 3 minutes each day. The macro-mechanical parameters, microstructure parameters, and mRNA transcription levels of the tibia were determined through the three-point bending method, micro-CT detection, and q-PCR analysis, respectively. RESULTS: As the + G value increases, hypergravity becomes increasingly detrimental to the macro-mechanical performance of rat tibia. Concerning the microstructure of cancellous bone, there appears to be a favorable trend at + 4G, followed by a progressively detrimental trend at higher G values. In addition, the mRNA transcription levels of OPG and RANKL show an initial tendency of enhanced bone absorption at +4G, followed by an increase in bone remodeling capacity as G value increases. CONCLUSION: The higher G values correspond to poorer macro-mechanical properties of the tibia, and a + 4G environment benefits the microstructure of the tibia. At the cellular level, bone resorption is enhanced in the + 4G group, but the bone remodeling capability gradually increases with further increments in G values.

Glimpsing the Future of Animal Welfare through a Bottle of Milk: Insights from Chinese University Students.

The consumption patterns of university students hold the power to significantly influence market trends. This study illuminates the escalating emphasis on animal welfare in these students' purchasing choices, specifically concerning milk products. Utilizing a discrete choice experiment, we identified a pronounced preference among students for milk products with animal welfare certifications. Students were segmented into three categories based on their motivations: "Quality-Oriented" (20.55%), "Emotionally Intuitive" (30.67%), and "Quality-Emotion Balanced" (48.77%). The "Emotionally Intuitive" group manifested the most robust inclination toward such certifications. Based on these findings, we recommend tailored market strategies targeting these distinct segments. Moreover, our findings emphasize the importance of intensifying animal welfare education, shaping a market aligned with animal welfare principles, and fostering a broader societal environment attuned to animal welfare.

Pathological complete response to neoadjuvant lorlatinib in a patient with unresectable ALK-Positive locally advanced non-small cell lung cancer: A case report.

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) have demonstrated substantial effectiveness in individuals with advanced ALK-positive non-small cell lung cancer (NSCLC). However, the controversy over using ALK-TKIs for neoadjuvant therapy in ALK-positive NSCLC has not been fully explored. This case study describes the clinical progression of a patient initially diagnosed with unresectable stage III (cT1bN2M0) lung adenocarcinoma, who was later discovered to harbor an ALK mutation through next-generation sequencing. The patient underwent surgery to achieve a radical resection of the right upper lung lesion after neoadjuvant therapy with lorlatinib and a pathological complete response (pCR) was confirmed by pathological analysis. To our knowledge, it has never been reported that neoadjuvant therapy with lorlatinib resulted in pCR for an ALK-positive patient with stage III NSCLC who was initially unresectable. Therefore, our findings indicate that utilizing ALK-TKIs as neoadjuvant therapy could be considered a viable choice for ALK-positive NSCLC patients.

Adjustable short-term memory of SiOx:Ag-based memristor for reservoir computing.

Temporal information processing is critical for a wide spectrum of applications, such as finance, biomedicine, and engineering. Reservoir computing (RC) can efficiently process temporal information with low training costs. Various memristors have been explored to demonstrate RC systems leveraging the short-term memory and nonlinear dynamic behaviours. However, the short-term memory is fixed after the device fabrication, limiting the applications to diverse temporal analysis tasks. In this work, we propose the approaches to modulating the short-term memory of Pt/SiOx:Ag/Pt memristor for the performance improvement of the RC systems. By controlling the read voltage, pulse amplitude and pulse width applied to the devices, the obtainable range of the characteristic time reaches three orders of magnitude from microseconds to around milliseconds. Based on the fabricated memristor, the classification of 4-bit pulse streams is demonstrated. Memristor-based RC systems with adjustable short-term memory are constructed for time-series prediction and pattern recognition tasks with different requirements for the characteristic times. The simulation results show that low normalized root mean square error of 0.003 (0.27) in Hénon map (Mackey-Glass time series) and excellent classification accuracy of 99.6% (91.7%) in spoken-digit recognition (MNIST image recognition) are achieved, which outperforms most memristor-based RC systems recently reported. Furthermore, the RC networks with diverse short-term memories are constructed to address more complicated tasks with low prediction errors. This work proves the high controllability of memristor-based RC systems to handle multiple temporal processing tasks.

The potential of swine pseudorabies virus attenuated vaccine for oncolytic therapy against malignant tumors.

BACKGROUND: Oncolytic viruses are now well recognized as potential immunotherapeutic agents against cancer. However, the first FDA-approved oncolytic herpes simplex virus 1 (HSV-1), T-VEC, showed limited benefits in some patients in clinical trials. Thus, the identification of novel oncolytic viruses that can strengthen oncolytic virus therapy is warranted. Here, we identified a live-attenuated swine pseudorabies virus (PRV-LAV) as a promising oncolytic agent with broad-spectrum antitumor activity in vitro and in vivo. METHODS: PRV cytotoxicity against tumor cells and normal cells was tested in vitro using a CCK8 cell viability assay. A cell kinase inhibitor library was used to screen for key targets that affect the proliferation of PRV-LAV. The potential therapeutic efficacy of PRV-LAV was tested against syngeneic tumors in immunocompetent mice, and against subcutaneous xenografts of human cancer cell lines in nude mice. Cytometry by time of flight (CyTOF) and flow cytometry were used to uncover the immunological mechanism of PRV-LAV treatment in regulating the tumor immune microenvironment. RESULTS: Through various tumor-specific analyses, we show that PRV-LAV infects cancer cells via the NRP1/EGFR signaling pathway, which is commonly overexpressed in cancer. Further, we show that PRV-LAV kills cancer cells by inducing endoplasmic reticulum (ER) stress. Moreover, PRV-LAV is responsible for reprogramming the tumor microenvironment from immunologically naïve ("cold") to inflamed ("hot"), thereby increasing immune cell infiltration and restoring CD8+ T cell function against cancer. When delivered in combination with immune checkpoint inhibitors (ICIs), the anti-tumor response is augmented, suggestive of synergistic activity. CONCLUSIONS: PRV-LAV can infect cancer cells via NRP1/EGFR signaling and induce cancer cells apoptosis via ER stress. PRV-LAV treatment also restores CD8+ T cell function against cancer. The combination of PRV-LAV and immune checkpoint inhibitors has a significant synergistic effect. Overall, these findings point to PRV-LAV as a serious potential candidate for the treatment of NRP1/EGFR pathway-associated tumors.