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Zero-knowledge proof (ZKP) is a cryptographic primitive that enables a prover to convince a verifier that a statement is true, without revealing any other information beyond the correctness of the statement itself. Due to its powerful capabilities, its most practical type, called zero-knowledge Succinct Non-interactive ARgument of Knowledge (zkSNARK), has been widely deployed in various privacypreserving applications such as cryptocurrencies and verifiable computation. Although state-of-the-art zkSNARKs are highly efficient for the verifier, the computational overhead for the prover is still orders of magnitude too high to warrant use in many applications. This overhead arises from several time-consuming operations, including large-scale matrix-vector multiplication (MUL), number-theoretic transform (NTT), and especially the multi-scalar multiplication (MSM) which constitutes the largest proportion. Therefore, further efficiency improvements are needed. In this paper, we focus on comprehensive optimization of running time and storage space required by the MSM algorithm on GPUs. Specifically, we propose a novel, modular and adaptive parameter configuration technique—elastic MSM to enable us to adjust the scale of MSM according to our own wishes by performing a corresponding amount of preprocessing. This technique enables us to fully unleash the potential of various efficient parallel MSM algorithms. We have implemented and tested elastic MSM over three prevailing parallel Pippenger algorithms on GPUs. Across various preprocessing space limitations (across various MSM scales), our constructions achieve up to about 1.90×, 1.08× and 1.36× (2.58×, 1.39× and 1.91×) speedup versus three state-of-the-art parallel Pippenger algorithms on GPUs, respectively. From another perspective, elastic MSM could also be regarded as a preprocessing technique over the well-known Pippenger algorithm, which is modular and could be used to accelerate almost all the most advanced parallel Pippenger algorithms on GPUs. Meanwhile, elastic MSM provides an adaptive trade-off between the running time and the extra storage space needed by parallel Pippenger algorithms on GPUs. This is the first preprocessing technique to retain the improved MSM computation brought by preprocessing under varying storage space limitations. Specifically, across various preprocessing space limitations (across various MSM scales), our constructions achieve up to about 192× and 223× (159× and 174×) speedup versus two state-ofthe- art preprocessing parallel Pippenger algorithms on GPUs, respectively.

Abstract Ulcerative colitis (UC) faces some barriers in oral therapy, such as how to safely deliver drugs to the colon and accumulate in the colon lesions. Hence, we report an advanced yeast particles system loaded with supramolecular nanoparticles with ROS scavenger (curcumin) to treat UC by reducing oxidative stress state and inflammatory response and accelerating the reprogramming of macrophages. In this study, the dual-sensitive materials are bonded on β-cyclodextrin (β-CD), the D-mannose (Man) is modified to adamantane (ADA), and then loaded with curcumin (CUR), to form a functional supramolecular nano-delivery system (Man-CUR NPs) through the host-guest interaction. To improve gastrointestinal stability and colonic accumulation of Man-CUR NPs, yeast cell wall microparticles (YPs) encapsulated Man-CUR NPs to form Man-CUR NYPs via electrostatic adsorption and vacuum extrusion technologies. As expected, the YPs showed the strong stability in complex gastrointestinal environment. In addition, the Man modified supramolecular nanoparticles demonstrated excellent targeting ability to macrophages in the in vitro cellular uptake study and the pH/ROS sensitive effect of Man-CUR NPs was confirmed by the pH/ROS-dual stimulation evaluation. They also enhanced lipopolysaccharide (LPS)-induced inflammatory model in macrophages through downregulation of pro-inflammatory factors, upregulation of anti-inflammatory factors, M2 macrophage polarization, and scavenging the excess ROS. Notably, in DSS-induced mice colitis model, Man-CUR NYPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways, alleviate oxidative stress by Nrf2/HO-1 signaling pathway, promote macrophages reprogramming and improve the favorable recovery of the damaged colonic tissue. Taken together, this study not only provides strategy for “supramolecular curcumin nanoparticles with pH/ROS sensitive and multistage therapeutic effects” in “advanced yeast particles”, but also provided strong theoretical support multi-effect therapy for UC.

As a viable substitute for bisphenol A (BPA), BPF has been widely used in the plastic industry and daily consumer goods, resulting in its detection in humans at a comparable concentration. Evidence reveals that BPF and BPA may have similar toxic effects due to their similar structures. However, there is less information about BPF and its latent implications on the immune system, which is associated with many disorders. In this study, the in vitro toxicity of BPF on RAW264.7 macrophages was explored. The cells were treated with different concentrations of BPF (5, 10, 20, 50, 100, and 200 μM), the cell viability and apoptosis were detected, the gene expression profile was analyzed by whole-transcriptome sequencing, and the mRNA levels were detected by qRT-PCR. The results showed a high concentration of BPF could significantly reduce the survival rate of RAW264.7 macrophages. Although the medium concentration (20–50 μM) of BPF seemed to have no impact on the cell activity of macrophages, it caused the occurrence of apoptosis. The results of differential transcription showed that compared with the control group, 121 genes were upregulated and 82 genes were downregulated in the BPF group. The significantly changed gene functions were mainly concentrated in cell cycle, phagosome, lysosome, and antigen processing and presentation. These findings provide valuable information for correctly understanding the immunotoxicity risk of BPF and may help to improve the hazard identification of bisphenol compounds.

Obesity is one of the risk factors of metabolic diseases. Decreased sensitivity to insulin or impairment of the insulin signaling pathway may affect the metabolism of adipose tissue. Bisphenol F (BPF) has been widely used in various products as a substitute for bisphenol A (BPA). BPA has been defined as “obesogen”. However, knowledge about the correlation between BPF and obesity is very limited. This study was aimed to explore the effects of BPF on glucose metabolism and insulin sensitivity in mammalian tissues, using a mouse 3T3-L1 adipocyte line as the model. Differentiated 3T3-L1 adipocytes were treated with BPF at various concentrations for 24 h or 48 h, followed by the measurement of cell viability, lipid accumulation, expression levels of adipocytokines, glucose consumption, and impairment of the insulin signaling pathway. The results indicated that BPF had no effect on the size of 3T3-L1 adipocytes, but the expression of leptin, adiponectin and apelin was decreased, while that of chemerin and resistin was increased after 48 h of BPF treatment. Moreover, BPF inhibited the glucose consumption, the expression of GLUT4, and its translocation to the plasma membranes in 3T3-L1 adipocytes. Western blot analysis indicated that the activation of IRS-1/PI3K/AKT signaling pathway was inhibited by BPF, which resulted in reduced GLUT4 translocation. In conclusion, our data suggest that exposure of adipocytes to BPF may alter the expression of calorie metabolism-related adipokines and suppress insulin-stimulated glucose metabolism by impairing the insulin signaling (IRS-1/PI3K/AKT) pathway.

Mesenchymal stem cells (MSCs) have emerged as putative therapeutic tools due to their intrinsic tumor tropism, and anti-tumor and immunoregulatory properties. The limited passage and self-differentiation abilities of MSCs in vitro hinder preclinical studies on them. In this study, we focused on the safety of immortalized mesenchymal stem cells (im-MSCs) and, for the first time, studied the feasibility of im-MSCs as candidates for the treatment of glioma. The im-MSCs were constructed by lentiviral transfection of genes. The proliferative capacity of im-MSCs and the proliferative phenotype of MSCs and MSCs co-cultured with glioma cells (U87) were measured using CCK-8 or EdU assays. After long-term culture, karyotyping of im-MSCs was conducted. The tumorigenicity of engineered MSCs was evaluated using soft agar cloning assays. Next, the engineered cells were injected into the brain of female BALB/c nude mice. Finally, the cell membranes of im-MSCs were labeled with DiO or DiR to detect their ability to be taken up by glioma cells and target in situ gliomas using the IVIS system. Engineered cells retained the immunophenotype of MSC; im-MSCs maintained the ability to differentiate into mesenchymal lineages in vitro; and im-MSCs showed stronger proliferative capacity than unengineered MSCs but without colony formation in soft agar, no tumorigenicity in the brain, and normal chromosomes. MSCs or im-MSCs co-cultured with U87 cells showed enhanced proliferation ability, but did not show malignant characteristics in vitro. Immortalized cells continued to express homing molecules. The cell membranes of im-MSCs were taken up by glioma cells and targeted in situ gliomas in vivo, suggesting that im-MSCs and their plasma membranes can be used as natural drug carriers for targeting gliomas, and providing a safe, adequate, quality-controlled, and continuous source for the treatment of gliomas based on whole-cell or cell membrane carriers.

Image-guided and robotic bronchoscopy is currently under intense research and development for a broad range of clinical applications, especially for minimally invasive biopsy and surgery of peripheral pulmonary nodules or lesions that are frequently discovered by CT or MRI scans. Optical imaging and spectroscopic modalities at the near-infrared (NIR) window hold great promise for bronchoscopic navigation and guidance because of their high detection sensitivity and molecular/cellular specificity. However, light scattering and background interference are two major factors limiting the depth of tissue penetration of photons, and diseased lesions such as small tumors buried under the tissue surface often cannot be detected. Here we report the use of a miniaturized Raman device that is inserted into one of the bronchoscope channels for sensitive detection of “phantom” tumors using fresh pig lung tissues and surface-enhanced Raman scattering (SERS) nanoparticle tags. The ex vivo results demonstrate not only the feasibility of using Raman spectroscopy for endoscopic guidance, but also show that ultrabright SERS nanoparticles allow detection through a bronchial wall of 0.85 mm in thickness and a 5 mm-thick layer of lung tissue (approaching the fourth-generation airway). This work highlights the prospects and potential of Raman-guided bronchoscopy for minimally invasive imaging and detection of lung lesions.

Background: Glioma is the most common malignant tumor of the central nervous system, and often displays invasive growth. Recently, circular RNA (circRNA), which is a novel non-coding type of RNA, has been shown to play a vital role in glioma tumorigenesis. However, the functions and mechanism of lipocalin-2 (Lcn2)-derived circular RNA (hsa_circ_0088732) in glioma progression remain unclear.Methods: We evaluated hsa_circ_0088732 expression by fluorescence in situ hybridization (FISH), Sanger sequencing, and PCR assays. Cell apoptosis was evaluated by flow cytometry and Hoechst 33258 staining. Transwell migration and invasion assays were performed to measure cell metastasis and viability. In addition, the target miRNA of hsa_circ_0088732 and the target gene of miR-661 were predicted by a bioinformatics analysis, and the interactions were verified by dual-luciferase reporter assays. RAB3D expression was analyzed by an immunochemistry assay, and E-cadherin, N-cadherin, and vimentin protein expression were examined by western blot assays. A mouse xenograft model was developed and used to analyze the effects of hsa_circ_0088732 on glioma growth in vivo.Results: We verified that hsa_circ_0088732 is circular and highly expressed in glioma tissues. Knockdown of hsa_circ_0088732 induced glioma cell apoptosis and inhibited glioma cell migration, invasion, and epithelial-mesenchymal transition (EMT). We found that hsa_circ_0088732 negatively regulated miR-661 by targeting miR-661, and RAB3D was a target gene of miR-661. In addition, inhibition of miR-661 promoted glioma cell metastasis and suppressed cell apoptosis. Knockdown of RAB3D induced cell apoptosis and suppressed cell metastasis. Moreover, hsa_circ_0088732 accelerated glioma progression through its effects on the miR-661/RAB3D axis. Finally, results from a mouse xenograft model confirmed that knockdown of hsa_circ_0088732 induced miR-661 expression, resulting in suppression of RAB3D expression and inhibition of tumor growth in vivo.Conclusion: We demonstrated that hsa_circ_0088732 facilitated glioma progression by sponging miR-661 to increase RAB3D expression. This study provides a theoretical basis for understanding the development and occurrence of glioma, as well as for the development of targeted drugs.