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Daqingshan is located in the northwestern North China Craton where late Neoarchaean supracrustal rocks occur widely, but where magmatic zircon ages have rarely been reported for plutonic rocks. In this study, we report SIMS U–Pb zircon ages and Hf isotope, whole-rock element and Nd isotope compositions for 12 magmatic samples, including TTG, quartz monzonitic and monzogranitic gneisses, and meta-gabbroic and dioritic rocks. They have magmatic zircon ages of 2530–2469 Ma; some samples have ages of Nd(t) and in situ magmatic zircon ϵHf(t) values of +1.2 to +2.4 and −1.1 to +6.2, respectively. Quartz monzonite and monzogranite gneisses and gabbroic to dioritic rocks have similar Nd–Hf isotope compositions to the TTG gneisses. The absence of zircon >2.6 Ga in the early Precambrian rocks suggests that the Sanggan Group may have formed in an oceanic environment, whereas the TTG rocks formed as a result of partial melting of the basaltic rocks of the Sanggan Group under relatively low-pressure conditions. Combined with previous studies, the main conclusions are that in the Daqingshan area, late Neoarchaean magmatism was widespread, the late Mesoarchaean – early Neoarchaean was an important period of juvenile continental crustal growth, and the late Neoarchaean supracrustal and plutonic rocks most likely formed in an arc environment. These are common signatures for Neoarchaean crustal evolution throughout much of the North China Craton, and also globally.

Motivation Cell-type annotation plays a crucial role in single-cell RNA-seq (scRNA-seq) data analysis. As more and more well-annotated scRNA-seq reference data are publicly available, automatical label transference algorithms are gaining popularity over manual marker gene-based annotation methods. However, most existing methods fail to unify cell-type annotation with dimensionality reduction and are unable to generate deep latent representation from the perspective of data generation. Results In this article, we propose scSemiGAN, a single-cell semi-supervised cell-type annotation and dimensionality reduction framework based on a generative adversarial network, to overcome these challenges, modeling scRNA-seq data from the aspect of data generation. Our proposed scSemiGAN is capable of performing deep latent representation learning and cell-type label prediction simultaneously. Through extensive comparison with four state-of-the-art annotation methods on diverse simulated and real scRNA-seq datasets, scSemiGAN achieves competitive or superior performance in multiple downstream tasks including cell-type annotation, latent representation visualization, confounding factor removal and enrichment analysis. Availability and implementation The code and data of scSemiGAN are available on GitHub: https://github.com/rafa-nadal/scSemiGAN. Supplementary information Supplementary data are available at Bioinformatics online.

A novel theranostic co-prodrug

MotivationSingle-cell RNA-sequencing (scRNA-seq) is widely used to reveal cellular heterogeneity, complex disease mechanisms and cell differentiation processes. Due to high sparsity and complex gene expression patterns, scRNA-seq data present a large number of dropout events, affecting downstream tasks such as cell clustering and pseudo-time analysis. Restoring the expression levels of genes is essential for reducing technical noise and facilitating downstream analysis. However, existing scRNA-seq data imputation methods ignore the topological structure information of scRNA-seq data and cannot comprehensively utilize the relationships between cells.ResultsHere, we propose a single-cell Graph Contrastive Learning method for scRNA-seq data imputation, named scGCL, which integrates graph contrastive learning and Zero-inflated Negative Binomial (ZINB) distribution to estimate dropout values. scGCL summarizes global and local semantic information through contrastive learning and selects positive samples to enhance the representation of target nodes. To capture the global probability distribution, scGCL introduces an autoencoder based on the ZINB distribution, which reconstructs the scRNA-seq data based on the prior distribution. Through extensive experiments, we verify that scGCL outperforms existing state-of-the-art imputation methods in clustering performance and gene imputation on 14 scRNA-seq datasets. Further, we find that scGCL can enhance the expression patterns of specific genes in Alzheimer’s disease datasets.Availability and implementationThe code and data of scGCL are available on Github: https://github.com/zehaoxiong123/scGCL.Supplementary informationSupplementary data are available at Bioinformatics online.

Hepatocellular carcinoma is one of the malignancies worldwide with a high mortality rate and an increasing incidence. Molecular Targeted agents are its common first-line treatment. Organoid technology, as a cutting-edge technology, is gradually being applied in the development of therapeutic oncology. Organoid models can be used to perform sensitivity screening of targeted drugs to facilitate the development of innovative therapeutic agents for the treatment of hepatocellular carcinoma. The purpose of this review is to provide an overview of the opportunities and challenges of hepatocellular carcinoma organoids in targeted drug sensitivity testing as well as a future outlook.

Supracrustal rocks and garnet granite within the high-grade metamorphic complex in Daqingshan, at the northern margin of the Palaeoproterozoic Khondalite Belt, North China Craton (NCC), preserve various mineral assemblages that record three distinct stages of their metamorphic evolution. The mineral assemblages representative of prograde metamorphism (M1) comprise plagioclase (Pl) + quartz (Q) ± biotite (Bio) inclusions preserved in garnet porphyroblasts in gneiss and granite members. The metamorphic peak mineral assemblages (M2) are represented by garnet (Gt) + Pl + Bio + Q + sillimanite (Sil) + K-feldspar (Kfs) in each rock’s matrix. Retrograde mineral assemblages (M3) that formed during post-peak, near-isothermal decompression (ITD) occur between relict garnet porphyroblasts and matrix minerals. These M3 assemblages consist of Bio + cordierite (Crd) + Pl + Gt + Q + Sil + Kfs. Phase equilibria modelling shows that the supracrustal rocks record clockwise pressure–temperature (P–T) trajectories from 650 to 750 °C/5.3–8.9 kbar (M1) up to 800–830 °C/9.8–11.2 kbar (M2), to 760–830 °C/4.8–6.2 kbar (M3). Geochemical similarities between the Daqingshan supracrustal rocks (i.e. garnet-biotite gneisses) and garnet granites, such as relative enrichment in K, Rb, and Ba, and depletion in Th, U, Ta, Nb, P, and Ti, imply a petrological affinity. Sensitive high-resolution ion microprobe analysis (SHRIMP) U–Pb dating of zircons reveals that the protolith of the Daqingshan supracrustal rocks formed at ~2.5 Ga and subsequently metamorphosed at ~2.45–2.37 Ga. Anatexis likely occurred at ~2.43–2.40 Ga during the retrograde near-ITD stage. Combined with previous studies, the timing of metamorphism and anatexis in the Daqingshan area may be connected with the regional mafic magmatism.

Hypocalcemia is a disease that adversely affects the production and reproduction of dairy cows. A portable device for rapid bovine blood calcium sensing has been growing in demand. Herein, we report a smartphone-based ratiometric fluorescence probe (SRFP) platform as a new way to detect and quantify calcium ions (Ca2+) in blood serum. Specifically, we employed a cost-effective and portable smartphone-based platform coupled with customized software that evaluates the response of Ca2+ ions to ratiometric fluorescence probe in bovine serum. The platform consists of a three-dimensional (3D) printed housing and low-cost optical components that excite fluorescent probe and selectively transmit fluorescence emissions to smartphones. The customized software is equipped with a calibration model to quantify the acquired fluorescence images and quantify the concentration of Ca2+ ions. The ratio of the green channel to the red channel bears a highly reproducible relationship with Ca2+ ions concentration from 10 μM to 40 μM in bovine serum. Our detection system has a limit of detection (LOD) of 1.8 μM in bovine serum samples and the recoveries of real samples ranged from 92.8% to 110.1%, with relative standard deviation (RSD) ranging from 1.72% to 4.89%. The low-cost SRFP platform has the potential to enable campesino to rapidly detect Ca2+ ions content in bovine serum on-demand in any environmental setting.

With the development of linnovative regulations on drug clinical trials in mainland China, the quantity and quality of drug clinical trials have gradually improved over the past decade. Based on the information of the clinical trials from the online drug clinical trial registration platform of National Medical Products Administration, we reviewed the data of drug clinical trials in mainland China from 2009 to 2020. A total of 8,593 clinical trials have been conducted during this period. The annual number of clinical trials has been increasing gradually, and peaked in 2017. There were 2,127, 1,051, 1,551, and 156 phases I, II, III, and IV clinical trials respectively. In addition, there were 3,441 bioequivalence studies. Trials for anti-tumor drugs ranked the highest (19.45%), followed by trials of drugs for infections and infestations (12.96%) and those for cardiovascular diseases (9.00%). Meanwhile the number of the clinical trial sites also increased annually. However, there were only 116 and 130 clinical trials of drugs for children and rare diseases respectively. The geographical distribution of the sites was uneven. This mapping review provides an overall look of clinical trials in China, which may be useful for domestic and international sponsors.

Heavy metal contamination in soil has become a serious environmental problem in China, and chromium is one of the major threats to human health. In order to better understand the transfer pattern of heavy metal hexavalent chromium from polluted sites into surface water, the influencing factors that affect solute transfer from soil into the surface runoff with linear and nonlinear adsorption equations based on a two-layer incomplete mixing model were analyzed in this study. The Quasi-Newton method was used to optimize model parameters by fitting with the experimental laboratory data of chromium (Cr(VI)) in surface runoff. The local sensitivity analysis and the Morris global sensitivity analysis approaches were used to assess the parameter importance of rainfall intensity p, the thickness of the mixing layer hmix, incomplete mixing parameter α and γ, the soil adsorption parameters, and the initial soil water content θ0. The study results showed that the optimized nonlinear models were better consistent with the experimental results than the linear adsorption equation model. The results of global sensitivity indicated that rainfall intensity p was the main factor influencing Cr(VI) transport from the soil into surface runoff. The hmix and the α in the two-layer model were vital parameters that influenced such transport processes. Moreover, the soil adsorption properties and the θ0 had the lowest effects on runoff Cr(VI) loss. The results indicate that for controlling pollution migration in surface runoff, it is essential to focus on the analysis of precipitation conditions and soil properties that control the thickness of the mixing layer and the degree of mixing.

Facile, efficient, and inexpensive biosensing systems are in high demand for biomedical test. In recent years, numerous smartphone-based biosensing systems have been developed to match demand for biomedical test in source-limited environment. However, application of these smartphone-based biosensing systems was limited because of performance gap between the smartphone-based systems and commercial plate readers. In this study, we have developed a smart tablet-phone-based colorimetric plate reader (STPCPR) with intelligent and dynamic light modulation for broad-range colorimetric assays. The STPCPR allows controllable modulation of exciting light in three different color channels that is lack in conventional smartphone-based system. Using optimized exciting modulation, the STPCPR shows higher sensitivities, lower detection limits, and broader detection ranges in test of pigments, proteins, and cells when compared to conventional plate readers and smartphone-based system. Therefore, the developed STPCPR can serve as an ideal next-generation smartphone-based biosensing system for point-of-care colorimetric test in diverse biomedical applications in source-limited environment.

In this study, we tested uniaxial compression deformation and uniaxial compression creep on red sandstone specimens with fine- and medium-sized particles; microstructure development and acoustic emission (AE) were recorded. The creep deformation characteristics and AE parameters of these two kinds of sandstone specimens were then compared and analysed. Results show that the microstructure of fine-grained sandstone is the granular sand-like structure, and the medium-grained sandstone has a grain-like microstructure. The particle size obviously influences uniaxial compressive mechanism; the medium-grained sandstone has a higher creep deformation than the fine-grained sandstone, while the AE amplitude, AE event rate and AE ring-down count rate of the medium- and fine-grained sandstone specimens have similar trend during the creep stage. The failure of both medium- and fine-grained sandstone mainly occurs in the transient and accelerated creep stages during the creep process. By combining the variation of AE parameters and AE-r value (the ratio of the accumulative hits and the cumulative energy) in the various creep stages, we found the creep damage to sandstone could be predicted to a certain extent.

In this study, two novel resonance light scattering (RLS) methods were developed for the determination of benzalkonium chloride. These methods were based on the formation of inorganic anionic-surfactant aggregates in a Clark-Lubs medium, which increases the resonance light scattering intensity of the reaction system and were also predominantly divided into sodium tungstate-benzalkonium chloride (method A) or phosphomolybdate-benzalkonium chloride (method B). The detection is performed both at 285 nm. Under the established conditions, the limits of quantification ranged from 0.10 mg L–1 to 1.00 mg L–1 with the R values of 0.9994 and from 0.20 mg · L–1 to 3.20 mg · L–1 with the R values of 0.9991, with good precision and accuracy both for method A and method B. The limits of detection were 0.029 mg · L–1 for method A and 0.013 mg · L–1 for method B. These two methods were successfully applied for the assay of benzalkonium chloride for the first time. All validation parameters were in agreement with the International Conference on Harmonization of Requirements for Registration Pharmaceuticals for Human Use (ICH) guidelines. Compared to the classical spectrophotometric method, these two methods take advantages of rapidity, high efficiency and good selectivity.

The antibody drug conjugate drug MRG003 comprises an anti-epidermal growth factor receptor (EGFR) humanized immunoglobulin G1 monoclonal antibody that is conjugated with monomethyl auristatin E via a valine-citrulline linker. There is currently insufficient evidence of this drug's safety and efficacy.To evaluate the safety and maximum tolerated dose of MRG003 in a phase 1a study and investigate the preliminary antitumor activity in EGFR-expressing patients in a phase 1b study.This nonrandomized open-label, single-arm, phase 1, multicenter study of solid tumors was divided into 2 parts, phase 1a dose escalation and phase 1b dose expansion. Patients with advanced or metastatic solid tumors who had failed outcomes from or were not able to receive standard treatment were enrolled in phase 1a without EGFR prescreening. Phase 1b recruited EGFR-positive patients with refractory advanced squamous cell carcinomas of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), and colorectal cancer (CRC). This study was conducted at 7 Chinese centers between April 11, 2018, and March 29, 2021 (data cutoff date). Data analysis took place between April 2021 and June 2021.An intravenous dose of 0.1 to 2.5 mg/kg of MRG003 was administered every 3 weeks during phase 1a. During phase 1b, patients were administered the recommended dose identified in phase 1a.The primary end points were dose-limiting toxic effects in phase 1a and objective response rate in phase 1b. The safety, tolerability, immunogenicity, and pharmacokinetics of MRG003 were assessed. Tumor assessment was evaluated by RECIST 1.1.Twenty-two patients (mean [range] age, 54.5 [32.0-67.0] years; 9 women [41%]) were enrolled in phase 1a and 39 patients (mean [range] age, 50.4 [27.0-75.0] years; 8 women [21%]) in phase 1b. The recommended dose was identified as 2.5 mg/kg. Eighty-nine percent of adverse events (AEs) were associated with MRG003 treatment, and most AEs were grade 1 to 2. Nineteen patients (31%) reported grade 3 or greater treatment-related AEs, including hyponatremia, leukocytopenia, neutropenia, increased aspartate aminotransferase levels, and febrile neutropenia. In phase 1a, 1 patient (5%) achieved a partial response, and 5 (23%) achieved stable disease. In phase 1b, 8 patients (21%) achieved a confirmed partial response, and 12 (31%) achieved stable disease. The objective response rates for SCCHN, NPC, and CRC were 40%, 44%, and 0%, and the disease control rates were 100%, 89%, and 25%, respectively.The findings of this nonrandomized clinical trial suggest that MRG003 showed a manageable safety profile and promising antitumor activity in patients with EGFR-positive NPC and SCCHN.Clinicaltrials.gov Identifier: NCT04868344.

A high-throughput instrument to measure the full spectral properties of biochemical agents is necessary for fast screening in fields such as medical tests, environmental monitoring, and food analysis. However, this need has currently not been fully met by the commercial microplate reader (CMR). In this study, we have developed an automated high-throughput efficient microplate reader (AHTEMR) platform by combining a spectrometer and high-precision ball screw two-dimensional motion slide together, for high-throughput and full-spectrum-required biochemical assays. A two-dimensional slide working on a ball screw was driven by a stepper motor with a custom-designed master control circuit and used as a motion system of the AHTEMR platform to achieve precise positioning and fast movement of the microplate during measurements. A compact spectrometer was coupled with an in-house designed optical pathway system and used to achieve rapid capture of the full spectral properties of biochemical agents. In a performance test, the AHTEMR platform successfully measured the full spectral absorbance of bovine serum albumin (BSA) and glucose solution in multiple wells of the microplate within several minutes and presented the real-time full spectral absorbance of BSA and glucose solution. Compared with the CMR, the AHTEMR is 79 times faster in full-spectrum measurements and 2.38 times more sensitive at the optimal wavelength of 562 nm. The rapid measurement also demonstrated the great capacity of the AHTEMR platform for screening out the best colorimetric wavelengths for tests of BSA and glucose development, which will provide a promising approach to achieving high-throughput and full-spectrum-required biochemical assays.

The study of brain science is vital to human health. The application of hyperspectral imaging in biomedical fields has grown dramatically in recent years due to their unique optical imaging method and multidimensional information acquisition. Hyperspectral imaging technology can acquire two-dimensional spatial information and one-dimensional spectral information of biological samples simultaneously, covering the ultraviolet, visible and infrared spectral ranges with high spectral resolution, which can provide diagnostic information about the physiological, morphological and biochemical components of tissues and organs. This technology also presents finer spectral features for brain imaging studies, and further provides more auxiliary information for cerebral disease research. This paper reviews the recent advance of hyperspectral imaging in cerebral diagnosis. Firstly, the experimental setup, image acquisition and pre-processing, and analysis methods of hyperspectral technology were introduced. Secondly, the latest research progress and applications of hyperspectral imaging in brain tissue metabolism, hemodynamics, and brain cancer diagnosis in recent years were summarized briefly. Finally, the limitations of the application of hyperspectral imaging in cerebral disease diagnosis field were analyzed, and the future development direction was proposed.

The natural products piperlongumine and piperine have been shown to inhibit cancer cell proliferation through elevation of reactive oxidative species (ROS) and eventually cell death, but only have modest cytotoxic potencies. A series of 14 novel phenylallylidenecyclohexenone analogues based on piperlongumine and piperine therefore were designed and synthesized, and their pharmacological properties were evaluated. Most of the compounds produced antiproliferative activities against five human cancer cells with IC50 values lower than those of piperlongumine and piperine. Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 μM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 μM). Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU. Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP), and induced autophagy in Bel-7402/5-FU cells via regulation of autophagy-related proteins LC3, p62, and beclin-1. Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways. In conclusion, 9m could be a promising candidate for the treatment of drug-resistant cancer cells and, as such, warrants further investigation.

In this study, we present detrital zircon U-Pb dating and paleontological data for the newly identified Ayadeng Formation in the northern margin of the North China Block (NCB) and Xibiehe Formation (molasse) in the Bainaimiao arc belt (BAB), which could provide strong evidence indicating the affinity of the BAB and the evolution of the southeast Central Asian orogenic belt (CAOB). Zircon U-Pb data of siltstone samples and paleontological data indicate the Ayadeng Formation dates back to the Early Ordovician. Although its location is near the NCB, its zircon age spectra and paleontology share a closer affinity with those of Tarim and NE Gondwana, as the U-Pb data suggest an age range of 490–2 192 Ma (peak age=629, 788, 965 and 1 935 Ma), and similar gastropod fossils are found in Tarim and NE Gondwana. The U-Pb ages of meta-sandstone samples in the Xuniwusu Formation indicate a shared inheritance with the Ayadeng Formation (before 440 Ma), and the U-Pb ages of sandstone samples in the Xibiehe Formation are concentrated, with age peaks centered at ca. 420 Ma. Fossil corals occur in these two formations, and their age components also indicate a collisional setting. Therefore, it is speculated that the BAB drifted away from Tarim or NE Gondwana during the Ordovician and became attached to northern NCB between 440–420 Ma as an exotic terrane. During the Early Paleozoic, there may have occurred a collision between an arc and a continental block.

The Neoarchaean crustal evolutionary processes of the North China Craton (NCC) provide a window to understanding the crust–mantle interaction in the Early Earth. The Jiefangyingzi amphibolites are ...

All-inorganic perovskite solar cells (PSCs) are attracting considerable attention due to their excellent thermal stability. However, their unsatisfactory power-conversion efficiency and moisture instability lead to challenges for practical commercialization. Here, a facile but effective strategy is demonstrated to stabilize/passivate the cubic phase of CsPbI3 by inhibiting the moisture invasion using 18-crown-6 ether (Crown). The strong interaction between Crown and surface Cs+ ion not only effectively improved the moisture tolerance, but also simultaneously reduced surface defects and related migrations, thus accordingly improving the phase and operation stability of the CsPbI3 films and devices. Based on the obtained high-quality CsPbI3–Crown films, PSCs with up to 16.9% efficiency were fabricated. The devices readily maintained ∼91% of the initial PCE for more than 1000 h (85 °C, N2) and even ∼90% for up to 2000 h (relative humidity 20%) without encapsulation. More importantly, the developed strategy has been successfully used to fabricate large-area CsPbI3 modules, showing an efficiency of up to 11.8% with the 16 cm2 total area. A stability performance that can retain ∼95% of the original value for over 500 h (operating conditions, relative humidity 60%) with encapsulation has also been achieved in the first PSC module based on the CsPbI3 system.

High-throughput cardiotoxicity assessment is important for large-scale preclinical screening in novel drug development. To improve the efficiency of drug development and avoid drug-induced cardiotoxicity, there is a huge demand to explore the automatic and intelligent drug assessment platforms for preclinical cardiotoxicity investigations. In this work, we proposed an automatic and intelligent strategy that combined automatic feature extraction and multi-labeled neural network (MLNN) to process cardiomyocytes mechanical beating signals detected by an interdigital electrode biosensor for the assessment of drug-induced cardiotoxicity. Taking advantages of artificial neural network, our work not only classified different drugs inducing different cardiotoxicities but also predicted drug concentrations representing severity of cardiotoxicity. This has not been achieved by conventional strategies like principal component analysis and visualized heatmap. MLNN analysis showed high accuracy (up to 96%) and large AUC (more than 98%) for classification of different drug-induced cardiotoxicities. There was a high correlation (over 0.90) between concentrations reported by MLNN and experimentally treated concentrations of various drugs, demonstrating great capacity of our intelligent strategy to predict the severity of drug-induced cardiotoxicity. This new intelligent bio-signal processing algorithm is a promising method for identification and classification of drug-induced cardiotoxicity in cardiological and pharmaceutical applications.

Electrophysiological recording is a widely used method to investigate cardiovascular pathology, pharmacology and developmental biology. Microelectrode arrays record the electrical potential of cells in a minimally invasive and high-throughput way. However, commonly used microelectrode arrays primarily employ planar microelectrodes and cannot work in applications that require a recording of the intracellular action potential of a single cell. In this study, we proposed a novel measuring method that is able to record the intracellular action potential of a single cardiomyocyte by using a nanowell patterned microelectrode array (NWMEA). The NWMEA consists of five nanoscale wells at the center of each circular planar microelectrode. Biphasic pulse electroporation was applied to the NWMEA to penetrate the cardiomyocyte membrane, and the intracellular action potential was continuously recorded. The intracellular potential recording of cardiomyocytes by the NWMEA measured a potential signal with a higher quality (213.76 ± 25.85%), reduced noise root-mean-square (~33%), and higher signal-to-noise ratio (254.36 ± 12.61%) when compared to those of the extracellular recording. Compared to previously reported nanopillar microelectrodes, the NWMEA could ensure single cell electroporation and acquire high-quality action potential of cardiomyocytes with reduced fabrication processes. This NWMEA-based biosensing system is a promising tool to record the intracellular action potential of a single cell to broaden the usage of microelectrode arrays in electrophysiological investigation.

Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the “double-locked” strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-β-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of β-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first “key”) and pH (second “key”), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.

A series of novel nitric oxide (NO)-releasing 5,8-quinolinedione/furoxan hybrids (8a-h and 9a-h) were designed and synthesized through coupling different alkanolamine substituted phenylsulfonyl furoxan with 5,8-quinolinedione. Most compounds displayed high cytotoxic activity against drug-sensitive/-resistant cancer cells. In particular, the ICsub50/subof 9a (0.42 µM) was about 9-fold lower than that of β-lap (3.69 µM) and 12-fold lower than that of SAHA (5.24 µM) in drug-resistant cancer cells. Also, 9a was demonstrated to selectively inhibit the growth of Bel7402/5-FU cancer cells. Mechanistic studies demonstrated that 9a could serve as an NO donor and nicotinamide quinone oxidoreductase 1 (NQO1) inhibitor (ICsub50/sub = 0.8 µM), which could induce the highest level of NO and reactive oxygen species (ROS) in Bel-7402/5-FU cancer cells. Furthermore, 9a could promote tumor cell apoptosis and autophagy via regulation of apoptosis-related protein (Bax, Bcl-2, and Caspase 3) and autophagy-associated proteins (LC3 and p62) in Bel-7402/5-FU cells. Taken together, 9a may be considered as a promising candidate for a further comprehensive study involving drug-resistant hepatocellular carcinoma.

Theranostic agents for concurrent cancer therapy and diagnosis have begun attracting attention as a promising modality. However, accurate imaging and identification remains a great challenge for theranostic agents. Here, we designed and synthesized a novel theranostic agent H6M based on the “double-locked” strategy by introducing an electron-withdrawing nitro group into 1-position of a pH-responsive 3-amino-β-carboline and further covalently linking the hydroxamic acid group, a zinc-binding group (ZBG), to the 3-position of β-carboline to obtain histone deacetylase (HDAC) inhibitory effect for combined HDAC-targeted therapy. We found that H6M can be specifically reduced under overexpressed nitroreductase (NTR) to produce H6AQ, which emits bright fluorescence at low pH. Notably, H6M demonstrated a selective fluorescence imaging via successive reactions with NTR (first “key”) and pH (second “key”), and precisely identified tumor margins with a high S/N ratio to guide tumor resection. Finally, H6M exerted robust HDAC1/cancer cell inhibitory activities compared with a known HDAC inhibitor SAHA. Therefore, the NTR/pH-activated theranostic agent provided a novel tool for precise diagnosis and efficient tumor therapy.

Preclinical investigation of drug-induced cardiotoxicity is of importance for drug development. To evaluate such cardiotoxicity, in vitro high-throughput interdigitated electrode-based recording of cardiomyocytes mechanical beating is widely used. To automatically analyze the features from the beating signals for drug-induced cardiotoxicity assessment, artificial neural network analysis is conventionally employed and signals are segmented into cycles and feature points are located in the cycles. However, signal segmentation and location of feature points for different signal shapes require design of specific algorithms. Consequently, this may lower the efficiency of research and the applications of such algorithms in signals with different morphologies are limited. Here, we present a biosensing system that employs nonlinear dynamic analysis-assisted neural network (NDANN) to avoid the signal segmentation process and directly extract features from beating signal time series. By processing beating time series with fixed time duration to avoid the signal segmentation process, this NDANN-based biosensing system can identify drug-induced cardiotoxicity with accuracy over 0.99. The individual drugs were classified with high accuracies over 0.94 and drug-induced cardiotoxicity levels were accurately predicted. We also evaluated the generalization performance of the NDANN-based biosensing system in assessing drug-induced cardiotoxicity through an independent dataset. This system achieved accuracy of 0.85-0.95 for different drug concentrations in identification of drug-induced cardiotoxicity. This result demonstrates that our NDANN-based biosensing system has the capacity of screening newly developed drugs, which is crucial in practical applications. This NDANN-based biosensing system can work as a new screening platform for drug-induced cardiotoxicity and improve the efficiency of bio-signal processing.

The natural products piperlongumine (1) and ligustrazine (2) have been reported to exert antiproliferative effects against various types of cancer cells by up-regulating the level of reactive oxidative species (ROS). However, the moderate activities of 1 and 2 limit their application. To improve their potential antitumor activity, novel piperlongumine/ligustrazine derivatives were designed and prepared, and their potential pharmacological effects were determined in vitro and in vivo. Among the derivatives obtained, 11 exerted more prominent inhibitory activities against proliferation of drug-sensitive/-resistant cancer cells with lower IC50 values than 1. Particularly, the IC50 value of 11 against drug-resistant Bel-7402/5-FU cells was 0.9 μM, which was about 9-fold better than that of 1 (IC50 value of 8.4 μM). Mechanistic studies showed that 11 demonstrated thioredoxin reductase (TrxR) inhibitory activity, increase of ROS levels, decrease of mitochondrial transmembrane potential levels, and occurrence of DNA damage and autophagy, in a dose-dependent manner, via regulation of DNA damage protein H2AX and autophagy-associated proteins LC3, beclin-1, and p62 in drug-resistant Bel-7402/5-FU cells. Finally, compound 11 at 5 mg/kg displayed potent antitumor activity in vivo with tumor suppression of 76% (w/w). Taken together, compound 11 may represent a promising candidate drug for the chemotherapy of drug-resistant hepatocellular carcinoma and warrant more intensive study.

Cardiovascular disease is the number one cause of death in humans. Therefore, cardiotoxicity is one of the most important adverse effects assessed by arrhythmia recognition in drug development. Recently, cell-based techniques developed for arrhythmia recognition primarily employ linear methods such as time-domain analysis that detect and compare individual waveforms and thus fall short in some applications that require automated and efficient arrhythmia recognition from large datasets. We carried out the first report to develop a biosensing system that integrated impedance measurement and multiparameter nonlinear dynamic algorithm (MNDA) analysis for drug-induced arrhythmia recognition and classification. The biosensing system cultured cardiomyocytes as physiologically relevant models, used interdigitated electrodes to detect the mechanical beating of the cardiomyocytes, and employed MNDA analysis to recognize drug-induced arrhythmia from the cardiomyocyte beating recording. The best performing MNDA parameter, approximate entropy, enabled the system to recognize the appearance of sertindole- and norepinephrine-induced arrhythmia in the recording. The MNDA reconstruction in phase space enabled the system to classify the different arrhythmias and quantify the severity of arrhythmia. This new biosensing system utilizing MNDA provides a promising and alternative method for drug-induced arrhythmia recognition and classification in cardiological and pharmaceutical applications.

Bruton's tyrosine kinase (BTK) regulates multiple important signaling pathways and plays a key role in the proliferation, survival, and differentiation of B-lineage cells and myeloid cells. BTK is a promising target for the treatment of hematologic malignancies. Ibrutinib, the first-generation BTK inhibitor, was approved to treat several B-cell malignancies. Despite the remarkable potency and efficacy of ibrutinib against various lymphomas and leukemias in the clinics, there are also some clinical limitations, such as off-target toxicities and primary/acquired drug resistance. As strategies to overcome these challenges, second- and third-generation BTK inhibitors, BTK-PROTACs, as well as combination therapies have been explored. In this review, we summarize clinical developments of the first-, second- and third-generation BTK inhibitors, as well as recent advances in BTK-PROTACs and ibrutinib-based combination therapies.

Chemodynamic therapy (CDT) based on intracellular Fenton reactions is attracting increasing interest in cancer treatment. A simple and novel method to regulate the tumor microenvironment for improved CDT with satisfactory effectiveness is urgently needed. Therefore, glutathione (GSH)/ROS (reactive oxygen species) dual-responsive supramolecular nanoparticles (GOx@BNPs) for chemo–chemodynamic combination therapy were constructed via host–guest complexation between water-soluble pillar[6]arene and the ferrocene-modified natural anticancer product betulinic acid (BA) prodrug, followed by encapsulation of glucose oxidase (GOx) in the nanoparticles. The novel supramolecular nanoparticles could be activated by the overexpressed GSH and ROS in the tumor microenvironment (TME), not only accelerating the dissociation of nanoparticles—and, thus, improving the BA recovery and release capability in tumors—but also showing the high-efficiency conversion of glucose into hydroxyl radicals (·OH) in succession through intracellular Fenton reactions. Investigation of antitumor activity and mechanisms revealed that the dramatic suppression of cancer cell growth induced by GOx@BNPs was derived from the elevation of ROS, decrease in ATP and mitochondrial transmembrane potential (MTP) and, finally, cell apoptosis. This work presents a novel method for the regulation of the tumor microenvironment for improved CDT, and the preparation of novel GSH/ROS dual-responsive supramolecular nanoparticles, which could exert significant cytotoxicity against cancer cells through the synergistic interaction of chemodynamic therapy, starvation therapy, and chemotherapy (CDT/ST/CT).

Fault location of the distribution network is an important direction in the construction of distribution automation. For the problem of slow convergence of intelligent optimization algorithms and easy to fall into local optimality, the multi-population particle swarm optimization algorithm is proposed. The algorithm is compared with single population particle swarm algorithm on IEEE69 node model, it is proved that the new algorithm can find fault location faster. Then the effectiveness of the algorithm in a variety of distribution network fault location scenarios is verified, including single fault location and multiple fault location, and the algorithm can also accurately locate when the input information is distorted which shows good fault tolerance.

A microfluidic array was constructed for trapping single cell and loading identical dynamic biochemical stimulation for gain a better understanding of Ca2+ signaling at single cell resolution in the present study. This microfluidic array consists of multiple radially aligned flow channels with equal intersection angles, which was designed by a combination of stagnation point flow and physical barrier. Numerical simulation results and trajectory analysis have shown the effectiveness of this single cell trapping device. Fluorescent experiment results demonstrated the effects of flow rate and frequency of dynamic stimulus on the profiles of biochemical concentration which exposed on captured cells. In this microarray, the captured single cells in each trapping channels were able to receive identical extracellular dynamic biochemical stimuli which being transmitted from the entrance in the middle of the microfluidic array. Besides, after loading dynamic Adenosine Triphosphate (ATP) stimulation on captured cells by this device, consistent average intracellular Ca2+ dynamics phase and cellular heterogeneity were observed in captured single K562 cells. Furthermore, this device is able to be used for investigating cellular respond on single cell resolution to temporally varying environments by modulating the stimulation signal in terms of concentration, pattern, and duration of exposure.