A dual-target SPR screening system for simultaneous ligand discovery of SARS-CoV-2 spike protein and its receptor ACE2 from Chinese herbs.

Traditional Chinese Medicine (TCM) is a supremely valuable resource for the development of drug discovery. Few methods are capable of hunting for potential molecule ligands from TCM towards more than one single protein target. In this study, a novel dual-target surface plasmon resonance (SPR) biosensor was developed to perform targeted compound screening of two key proteins involved in the cellular invasion process of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): the spike (S) protein receptor binding domain (RBD) and the angiotensin-converting enzyme 2 (ACE2). The screening and identification of active compounds from six Chinese herbs were conducted taking into consideration the multi-component and multi-target nature of Traditional Chinese Medicine (TCM). Puerarin from Radix Puerariae Lobatae was discovered to exhibit specific binding affinity to both S protein RBD and ACE2. The results highlight the efficiency of the dual-target SPR system in drug screening and provide a novel approach for exploring the targeted mechanisms of active components from Chinese herbs for disease treatment.

Hepatic and portal vein segmentation with dual-stream deep neural network.

BACKGROUND: Liver lesions mainly occur inside the liver parenchyma, which are difficult to locate and have complicated relationships with essential vessels. Thus, preoperative planning is crucial for the resection of liver lesions. Accurate segmentation of the hepatic and portal veins (PVs) on computed tomography (CT) images is of great importance for preoperative planning. However, manually labeling the mask of vessels is laborious and time-consuming, and the labeling results of different clinicians are prone to inconsistencies. Hence, developing an automatic segmentation algorithm for hepatic and PVs on CT images has attracted the attention of researchers. Unfortunately, existing deep learning based automatic segmentation methods are prone to misclassifying peripheral vessels into wrong categories. PURPOSE: This study aims to provide a fully automatic and robust semantic segmentation algorithm for hepatic and PVs, guiding subsequent preoperative planning. In addition, to address the deficiency of the public dataset for hepatic and PV segmentation, we revise the annotations of the Medical Segmentation Decathlon (MSD) hepatic vessel segmentation dataset and add the masks of the hepatic veins (HVs) and PVs. METHODS: We proposed a structure with a dual-stream encoder combining convolution and Transformer block, named Dual-stream Hepatic Portal Vein segmentation Network, to extract local features and long-distance spatial information, thereby extracting anatomical information of hepatic and portal vein, avoiding misdivisions of adjacent peripheral vessels. Besides, a multi-scale feature fusion block based on dilated convolution is proposed to extract multi-scale features on expanded perception fields for local features, and a multi-level fusing attention module is introduced for efficient context information extraction. Paired t-test is conducted to evaluate the significant difference in dice between the proposed methods and the comparing methods. RESULTS: Two datasets are constructed from the original MSD dataset. For each dataset, 50 cases are randomly selected for model evaluation in the scheme of 5-fold cross-validation. The results show that our method outperforms the state-of-the-art Convolutional Neural Network-based and transformer-based methods. Specifically, for the first dataset, our model reaches 0.815, 0.830, and 0.807 at overall dice, precision, and sensitivity. The dice of the hepatic and PVs are 0.835 and 0.796, which also exceed the numeric result of the comparing methods. Almost all the p-values of paired t-tests on the proposed approach and comparing approaches are smaller than 0.05. On the second dataset, the proposed algorithm achieves 0.749, 0.762, 0.726, 0.835, and 0.796 for overall dice, precision, sensitivity, dice for HV, and dice for PV, among which the first four numeric results exceed comparing methods. CONCLUSIONS: The proposed method is effective in solving the problem of misclassifying interlaced peripheral veins for the HV and PV segmentation task and outperforming the comparing methods on the relabeled dataset.

High-throughput BCRP inhibitors screening system based on styrene maleic acid polymer membrane protein stabilization strategy and surface plasmon resonance biosensor.

Multidrug resistance (MDR) is a dominant challenge in cancer chemotherapy failure. The over-expression of breast cancer resistance protein (BCRP) in tumorous cells, along with its extensive substrate profile, is a leading cause of tumor MDR. Herein, on the basis of styrene maleic acid (SMA) polymer membrane protein stabilization strategy and surface plasmon resonance (SPR) biosensor, a novel high-throughput screening (HTS) system for BCRP inhibitors has been established. Firstly, LLC-PK1 and LLC-PK1/BCRP cell membranes were co-incubated with SMA polymers to construct SMA lipid particles (SMALPs). PK1-SMALPs were thus immobilized in channel 1 of the L1 chip as the reference channel, and BCRP-SMALPs were immobilized in channel 2 as the detection channel to establish the BCRP-SMALPs-SPR screening system. The methodological investigation demonstrated that the screening system was highly specific and stable. Three active compounds were screened out from 26 natural products and their affinity constants with BCRP were determined. The KD of xanthotoxin, bergapten, and naringenin were 5.14 µM, 4.57 µM, and 3.72 µM, respectively. The in vitro cell verification experiments demonstrated that xanthotoxin, bergapten, and naringenin all significantly increased the sensitivity of LLC-PK1/BCRP cells to mitoxantrone with possessing reversal BCRP-mediated MDR activity. Collectively, the developed BCRP-SMALPs-SPR screening system in this study has the advantages of rapidity, efficiency, and specificity, providing a novel strategy for the in-depth screening of BCRP inhibitors with less side effects and higher efficacy.

Biodegradable and flame-retardant cellulose-based wearable triboelectric nanogenerator for mechanical energy harvesting in firefighting clothing.

Integrating flexible triboelectric nanogenerators (TENGs) into firefighting clothing offers exciting opportunities for wearable portable electronics in personal protective technology. However, it is still a grand challenge to produce eco-friendly TENGs from biodegradable and low-cost natural polymers for mechanical-energy harvesting and self-powered sensing. Herein, conductive polypyrrole (PPy) and natural chitosan (CS)/phytic acid (PA) tribonegative materials were employed onto the Lycra fabric (LC) in turn to assemble the biodegradable and flame-retardant single-electrode mode LC/PPy/CS/PA TENG (abbreviated as LPCP-TENG). The resultant LPCP-TENG exhibits truly wearable breathability (1378.6 mm/s), elasticity (breaking elongation 291 %), and shape adaptivity performance that can produce an open circuit voltage of 0.3 V with 2 N contact pressure at a working frequency of 5 Hz with a limiting oxygen index of 35.2 %. Furthermore, facile monitoring for human motion of firefighters on fireground is verified by LPCP-TENG when used as self-powered flexible tactile sensor. In addition, degradation experiments have shown that waste LPCP-TENG can be fully degraded in soil within 120 days. This work broadens the applicational range of wearable TENG to reduce the environmental effects of abandoned TENG, exhibiting prosperous applications prospects in the field of wearable power source and self-powered motion detection sensor for personal protection application on fireground.

Tumor-Associated Monocytes Reprogram CD8+ T Cells into Central Memory-Like Cells with Potent Antitumor Effects.

CD8+ T cells are critical for host antitumor responses, whereas persistent antigenic stimulation and excessive inflammatory signals lead to T cell dysfunction or exhaustion. Increasing early memory T cells can improve T cell persistence and empower T cell-mediated tumor eradication, especially for adoptive cancer immunotherapy. Here, it is reported that tumor-associated monocytes (TAMos) are highly correlated with the accumulation of CD8+ memory T cells in human cancers. Further analysis identifies that TAMos selectively reprogram CD8+ T cells into T central memory-like (TCM-like) cells with enhanced recall responses. L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting TCM-like cell generation. Moreover, the modified T cells by TAMo exposure and L-NMMA treatment exhibit long-term persistence and elicit superior antitumor effects in vivo. Mechanistically, the transmembrane protein CD300LG is involved in TAMo-mediated TCM-like cell polarization in a cell-cell contact-dependent manner. Thus, the terminally differentiated TAMo subset (CD300LGhighACElow) mainly contributes to TCM-like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.

New Mode of Asymmetric Induction for Enantioselective Radical N-Heterobicyclization via Kinetically Stable Chiral Radical Center.

Enantioselective radical N-heterobicyclization of N-allylsulfamoyl azides have been developed via metalloradical catalysis (MRC). The Co(II)-based catalytic system can homolytically activate the organic azides with varied electronic and steric properties for asymmetric radical N-heterobicyclization under mild conditions without the need of oxidants, allowing for stereoselective construction of chiral [3.1.0]-bicyclic sulfamoyl aziridines in excellent yields with high diastereoselectivities and enantioselectivities. The key to achieving the enantioselective radical process relies on catalyst development through ligand design. We demonstrate that the use of new-generation D2-symmetric chiral bridged amidoporphyrin ligand HuPhyrin with judicious variation of the alkyl bridge length can dictate both reactivity and selectivity of Co(II)-based MRC. We present both experimental and computational studies that shed light on the working details of the unprecedented mode of asymmetric induction consisting of enantioface-selective radical addition and stereospecific radical substitution. We showcase the synthetic applications of the resulting enantioenriched bicyclic aziridines through a number of stereospecific transformations.

Allulose mitigates chronic enteritis by reducing mitochondria dysfunction via regulating cathepsin B production.

Metabolic changes have been linked to the development of inflammatory bowel disease (IBD), which includes colitis. Allulose, an endogenous bioactive monosaccharide, is vital to the synthesis of numerous compounds and metabolic processes within living organisms. Nevertheless, the precise biochemical mechanism by which allulose inhibits colitis remains unknown. Allulose is an essential and intrinsic protector of the intestinal mucosal barrier, as it maintains the integrity of tight junctions in the intestines, according to the current research. It is also important to know that there is a link between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), chemically-induced colitis in rodents, and lower levels of allulose in the blood. Mice with colitis, either caused by dextran sodium sulphate (DSS) or naturally occurring colitis in IL-10-/- mice, had less damage to their intestinal mucosa after being given allulose. Giving allulose to a colitis model starts a chain of reactions because it stops cathepsin B from ejecting and helps lysosomes stick together. This system effectively stops the activity of myosin light chain kinase (MLCK) when intestinal epithelial damage happens. This stops the breakdown of tight junction integrity and the start of mitochondrial dysfunction. To summarise, the study's findings have presented data that supports the advantageous impact of allulose in reducing the advancement of colitis. Its ability to stop the disruption of the intestinal barrier enables this. Therefore, allulose has potential as a medicinal supplement for treating colitis.

Multi-omics landscape to decrypt the distinct flavonoid biosynthesis of Scutellaria baicalensis across multiple tissues.

Scutellaria baicalensis Georgi, also known as huang-qin in traditional Chinese medicine, is a widely used herbal remedy due to its anticancer, antivirus, and hepatoprotective properties. The S. baicalensis genome was sequenced many years ago; by contrast, the proteome as the executer of most biological processes of S. baicalensis in the aerial parts, as well as the secondary structure of the roots (xylem, phloem, and periderm), is far less comprehensively characterized. Here we attempt to depict the molecular landscape of the non-model plant S. baicalensis through a multi-omics approach, with the goal of constructing a highly informative and valuable reference dataset. Furthermore, we provide an in-depth characterization dissection to explain the two distinct flavonoid biosynthesis pathways that exist in the aerial parts and root, at the protein and phosphorylated protein levels. Our study provides detailed spatial proteomic and phosphoproteomic information in the context of secondary structures, with implications for the molecular profiling of secondary metabolite biosynthesis in non-model medicinal plants.

Activity of thonningianin A against Candida albicans in vitro and in vivo.

Fungal infections are increasing rapidly, and antifungal agents used in clinics are limited. Therefore, novel antifungal agents with high efficiency are urgently required. In this study, we investigated the antifungal activity of thonningianin A (THA), a natural compound that is widely found in plants. We first determined the activity of THA against Candida albicans, one of the most common fungal pathogens, and found that THA showed antifungal activity against all C. albicans tested, including several fluconazole-resistant isolates. THA also inhibits the growth of non-Candida albicans species. In addition, THA displayed antibiofilm activity and could not only inhibit biofilm formation but also destroy mature biofilms. The in vivo antifungal efficacy of THA was confirmed in a Galleria mellonella infection model. Further studies revealed that THA could enhance intracellular reactive oxygen species (ROS) production and regulate the transcription of several redox-related genes. Specifically, caspase activity and expression of CaMCA1, a caspase-encoding gene in C. albicans, were remarkably increased upon THA treatment. Consistent with this, in the presence of THA, the Camca1 null mutant displayed higher survival rates and reduced caspase activity compared to the wild-type or CaMCA1-reintroduced strains, indicating an important role of CaMCA1 in the antifungal activity of THA. Taken together, our results indicate that THA possesses excellent antifungal activity and may be a promising novel antifungal candidate. KEY POINTS: • THA exhibits activity against Candida species, including fluconazole-resistant isolates • THA inhibits biofilm formation and destroys mature biofilm • Elevated ROS production and CaMCA1-mediated caspase activity are involved in the antifungal mechanisms of THA.

Arabinose confers protection against intestinal injury by improving integrity of intestinal mucosal barrier.

There is a growing amount of research that highlights the significant involvement of metabolic imbalance and the inflammatory response in the advancement of colitis. Arabinose is a naturally occurring bioactive monosaccharide that plays a crucial role in the metabolic processes and synthesis of many compounds in living organisms. However, the more detailed molecular mechanism by which the administration of arabinose alleviates the progression of colitis and its associated carcinogenesis is still not fully understood. In the present study, arabinose is recognized as a significant and inherent protector of the intestinal mucosal barrier through its role in preserving the integrity of tight junctions within the intestines. Also, it is important to note that there is a positive correlation between the severity of inflammatory bowel disease (IBD) and colorectal cancer (CRC), as well as chemically-induced colitis in mice, and lower levels of arabinose in the bloodstream. In two mouse models of colitis, caused by dextran sodium sulfate (DSS) or by spontaneous colitis in IL-10-/- mice, damage to the intestinal mucosa was reduced by giving the mice arabinose. When arabinose is administrated to model with colitis, it sets off a chain of events that help keep the lysosomes together and stop cathepsin B from being released. During the progression of intestinal epithelial injury, this process blocks myosin light chain kinase (MLCK) from damaging tight junctions and causing mitochondrial dysfunction. In summary, the results of the study have provided evidence supporting the beneficial effects of arabinose in mitigating the progression of colitis. This is achieved through its ability to avoid dysregulation of the intestinal barrier. Consequently, arabinose may hold promise as a therapeutic supplementation for the management of colitis.

Synthesis of 3-aminotetrahydro-1H-carbazols by visible-light photocatalyzed cycloaddition of cyclopropylanilines with 2-alkenylarylisocyanides.

A visible-light-induced cycloaddition between 2-alkenylarylisocyanides and cyclopropylanilines is reported. This cascade radical reaction constructs two new C-C bonds and two rings to afford 3-aminotetrahydro-1H-carbazols with high atom and step economy. The mechanism is rationalized as involving sequential distonic radical cation formation/isocyanide insertion/5-exo-trig cyclization/intramolecular iminium ion addition/tautomerization.

Preparation and performance of anti-icing and deicing PF-POS@SiO2/CB photothermal superhydrophobic coatings for electrical insulators.

Insulator string icing can cause flashovers or even blackouts in transmission systems and the existing mature deicing methods are usually costly or time consuming. So, in this research PF-POS@SiO2/CB superhydrophobic coatings (SiO2/CB-0, SiO2/CB-10, SiO2/CB-20, SiO2/CB-30, SiO2/CB-40 and SiO2/CB-50) with photothermal deicing and passive anti-icing properties were designed and prepared on the surface of two types of insulator materials (glass and ceramic) by using a simple spraying method. Then, the wettability properties, photothermal properties, and anti-icing/deicing properties of the coatings with the addition of different amounts of SiO2/CB were evaluated. PF-POS@SiO2/CB coatings with no less than 30 wt% of CB (carbon black) content simultaneously exhibit excellent passive anti-icing and deicing performance. For SiO2/CB-30, the water contact angle is as high as 164.9° and the rolling angle is as low as 3° because the combination of silica and carbon black nanoparticles gives the coating a micro/nanostructure and the low surface energy of 1H,1H,2H,2H-perfluorodecyltriethoxysilane leads to superhydrophobic properties, and the equilibrium temperature of the coating is up to 71.1 °C at 1 solar irradiation because of the photothermal effect of carbon black. The results of the analysis of anti-icing/deicing properties of the coatings to evaluate their potential for engineering applications demonstrate that it takes longer time for ice to form on the coated surface than on a substrate without coating, and the ice completely melts under sunlight after 10 min and falls off automatically by its weight for the addition of 30 wt% carbon black and above, showing excellent deicing performance. Both types of substrates show excellent adhesion with the superhydrophobic coating, which can be classified as class 1 based on the paint and varnish-cross-section test method, and the ceramic material exhibits better adhesion than the glass.

Temperature-Arousing Self-Powered Fire Warning E-Textile Based on p-n Segment Coaxial Aerogel Fibers for Active Fire Protection in Firefighting Clothing.

Firefighting protective clothing is a crucial protective equipment for firefighters to minimize skin burn and ensure safety firefighting operation and rescue mission. A recent increasing concern is to develop self-powered fire warning materials that can be incorporated into the firefighting clothing to achieve active fire protection for firefighters before the protective clothing catches fire on fireground. However, it is still a challenge to facilely design and manufacture thermoelectric (TE) textile (TET)-based fire warning electronics with dynamic surface conformability and breathability. Here, we develop an alternate coaxial wet-spinning strategy to continuously produce alternating p/n-type TE aerogel fibers involving n-type Ti3C2Tx MXene and p-type MXene/SWCNT-COOH as core materials, and tough aramid nanofiber as protective shell, which simultaneously ensure the flexibility and high-efficiency TE power generation. With such alternating p/n-type TE fibers, TET-based self-powered fire warning sensors with high mechanical stability and wearability are successfully fabricated through stitching the alternating p-n segment TE fibers into aramid fabric. The results indicate that TET-based fire warning electronics containing 50 p-n pairs produce the open-circuit voltage of 7.5 mV with a power density of 119.79 nW cm-2 at a temperature difference of 300 °C. The output voltage signal is then calculated as corresponding surface temperature of firefighting clothing based on a linear relationship between TE voltage and temperature. The fire alarm response time and flame-retardant properties are further displayed. Such self-powered fire warning electronics are true textiles that offer breathability and compatibility with body movement, demonstrating their potential application in firefighting clothing.

Contrast-Enhanced Liver Magnetic Resonance Image Synthesis Using Gradient Regularized Multi-Modal Multi-Discrimination Sparse Attention Fusion GAN.

PURPOSES: To provide abdominal contrast-enhanced MR image synthesis, we developed an gradient regularized multi-modal multi-discrimination sparse attention fusion generative adversarial network (GRMM-GAN) to avoid repeated contrast injections to patients and facilitate adaptive monitoring. METHODS: With IRB approval, 165 abdominal MR studies from 61 liver cancer patients were retrospectively solicited from our institutional database. Each study included T2, T1 pre-contrast (T1pre), and T1 contrast-enhanced (T1ce) images. The GRMM-GAN synthesis pipeline consists of a sparse attention fusion network, an image gradient regularizer (GR), and a generative adversarial network with multi-discrimination. The studies were randomly divided into 115 for training, 20 for validation, and 30 for testing. The two pre-contrast MR modalities, T2 and T1pre images, were adopted as inputs in the training phase. The T1ce image at the portal venous phase was used as an output. The synthesized T1ce images were compared with the ground truth T1ce images. The evaluation metrics include peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and mean squared error (MSE). A Turing test and experts' contours evaluated the image synthesis quality. RESULTS: The proposed GRMM-GAN model achieved a PSNR of 28.56, an SSIM of 0.869, and an MSE of 83.27. The proposed model showed statistically significant improvements in all metrics tested with p-values < 0.05 over the state-of-the-art model comparisons. The average Turing test score was 52.33%, which is close to random guessing, supporting the model's effectiveness for clinical application. In the tumor-specific region analysis, the average tumor contrast-to-noise ratio (CNR) of the synthesized MR images was not statistically significant from the real MR images. The average DICE from real vs. synthetic images was 0.90 compared to the inter-operator DICE of 0.91. CONCLUSION: We demonstrated the function of a novel multi-modal MR image synthesis neural network GRMM-GAN for T1ce MR synthesis based on pre-contrast T1 and T2 MR images. GRMM-GAN shows promise for avoiding repeated contrast injections during radiation therapy treatment.

Development of a DNA aptamer targeting IDO1 with anti-tumor effects.

Immune checkpoint blockade has become an effective approach to reverse the immune tolerance of tumor cells. Indoleamine 2,3-dioxygenase 1 (IDO1) is frequently upregulated in many types of cancers and contributes to the establishment of an immunosuppressive cancer microenvironment, which has been thought to be a potential target for cancer therapy. However, the development of IDO1 inhibitors for clinical application is still limited. Here, we isolated a DNA aptamer with a strong affinity and inhibitory activity against IDO1, designated as IDO-APT. By conjugating with nanoparticles, in situ injection of IDO-APT to CT26 tumor-bearing mice significantly suppresses the activity of regulatory T cells and promotes the function of CD8+ T cells, leading to tumor suppression and prolonged survival. Therefore, this functional IDO1-specific aptamer with potent anti-tumor effects may serve as a potential therapeutic strategy in cancer immunotherapy. Our data provide an alternative way to target IDO1 in addition to small molecule inhibitors.

Numerical analysis of aerospace plate damage via 3D electrical impedance tomography.

The carbon fiber reinforced plastic (CFRP) is widely used in the aerospace industry due to its high strength and lightweight characteristics, making it crucial to ensure the reliability of these materials. This has led to an increasing focus on research on the health monitoring technologies of aerospace materials. Electrical impedance tomography (EIT) is a non-invasive and cost-effective technology that has the potential to realize real-time health monitoring of materials by measuring changes in electrical parameters. This paper investigates the application of EIT for direct 3D reconstruction of damage in CFRP laminates with significant conductivity anisotropy distribution. Based on the corrected sensitivity matrix formula, the direct 3D image reconstruction method combined with the fast iterative shrinkage-thresholding algorithm (FISTA) is proposed to achieve damage imaging of CFRP laminates in the inverse problem. The fast convergence of the FISTA makes it possible to solve complex inverse problems. The numerical simulation results indicate that, compared with 2D EIT, the proposed method is more capable of providing damage information, especially in the depth direction. This research plays a constructive role in realizing 3D image reconstruction of CFRP material damage and has significant implications for improving the reliability and safety of CFRP materials in aerospace applications.

Focal-Point Analysis to Achieve Accurate CCSD(T) Data Set References for Static Polarizabilities.

Static polarizability is an important ingredient for describing optical phenomena, intermolecular interactions, etc. It also offers a way to gauge the accuracy of the electronic structure methods. However, polarizability data sets that include a large variety of species with high-quality reference data are still lacking. In this work, we calibrate the reference data of two existing data sets, HR46 (Hickey and Rowley J. Phys. Chem. A 2014, 118, 3678-3687.) and T145 (Thakkar et al. Chem. Phys. Lett. 2015, 635, 257-261.), consisting of molecules with sizes up to 15 atoms. We apply the focal-point analysis (FPA) to the isotropic and anisotropic polarizability calculations, achieving the MP2 correlation contribution by the complete basis set (CBS) extrapolation of aug-cc-pCV[Q5]Z, augmented by the CCSD(T) correlation contribution from the CBS extrapolation of aug-cc-pV[XY]Z with [XY] = [Q5], [TQ], and [DT], respectively, to accommodate the computation to the system size. We conclude that our reference data are close to the CCSD(T)/aug-cc-pCV[Q5]Z quality, which are beneficial to the future assessment and benchmark studies of other electronic structure methods, in particular, density functional approximations.

Development of a modularized aptamer targeting the nuclear T-cell suppressor PAC1.

Aptamers associated with cancer targeting therapy are commonly focused on cell membrane proteins; however, the study of intracellular, particularly, nuclear proteins is limited. The nuclear phosphatase PAC1 has been reported to be a potential T cell-related immunotherapeutic target. Here, we identified an aptamer, designated as PA5, with high affinity and specificity for PAC1 through the systematic evolution of ligands by exponential enrichment (SELEX) procedure. We then developed a dual-module aptamer PAC1-AS consisting of a cell-internalizing module and a targeting module, which can recognize PAC1 in the nucleus under physiological conditions. This modularized aptamer raises the possibility of manipulating endosomes and provides insights into the exploration and development of an efficient cancer immunotherapy approach.