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Background: Yinqiaosan decoction (YQSD), a traditional Chinese medicinal recipe, has been employed to treat influenza in China for approximately 300 years. Objective: Our study aimed to explore the mechanisms of YQSD against influenza via in vivo and in vitro experimental studies. Study design: and methods UHPLC-Q-TOF-MS/MS was utilized to examine the substances of the YQSD. The chemical components of YQSD detected by UHPLC-Q-TOF-MS/MS were used for network pharmacology analysis. The antiviral effect of YQSD in vivo was investigated. The potential mechanisms of YQSD in combating influenza, which were predicted from network pharmacology analysis, were validated in vitro. Results: By use of UHPLC-Q-TOF-MS/MS, 97 compounds were identified from YQSD. Network pharmacology analysis revealed that the therapeutic effect of YQSD against influenza may be associated with the regulation of T cell receptors (TCR) and Phosphoinositide 3-Kinase (PI3K)- protein kinase B (Akt) signaling pathways. Treatment with YQSD significantly prolonged the mean survival time of the mice and reduced lung injury due to the influenza A virus in vivo. It was discovered that YQSD efficiently inhibited the expression of inflammation-related cytokines. Moreover, YQSD has been found to significantly reduce the expression levels of cluster of differentiation 3 (CD3), monocyte chemoattractant protein-1 (MCP-1), and H1N1 virus nucleoprotein (NP), and prevent the decrease of epithelial cadherin (E-cadherin) protein. In addition, YQSD can inhibit the phosphorylation of the zeta chain of T cell receptor-associated protein kinase 70 (ZAP70) and PI3K proteins in vitro. Conclusion: The capacity of YQSD to suppress viral multiplication and inflammatory response by modulating T cell immunity may explain its effect against influenza viral pneumonia, which may involve the regulation of TCR and PI3K signaling pathways.

Abstract P2X receptors are ATP-activated cation channels, and the P2X4 subtype plays important roles in the immune system and the central nervous system, particularly in neuropathic pain. Therefore, P2X4 receptors are of increasing interest as potential drug targets. Here, we report the cryo-EM structures of the zebrafish P2X4 receptor in complex with two P2X4 subtype-specific antagonists, BX430 and BAY-1797. Both antagonists bind to the same allosteric site located at the subunit interface at the top of the extracellular domain. Structure-based mutational analysis by electrophysiology identified the important residues for the allosteric inhibition of both zebrafish and human P2X4 receptors. Structural comparison revealed the ligand-dependent structural rearrangement of the binding pocket to stabilize the binding of allosteric modulators, which in turn would prevent the structural changes of the extracellular domain associated with channel activation. Furthermore, comparison with the previously reported P2X structures of other subtypes provided mechanistic insights into subtype-specific allosteric inhibition.

When using runoff infiltration devices to remove nitrogen and phosphorus pollutants from urban runoff, the quality of the effluent is affected by the length of dry spells between rain events. This study presents a novel analysis of how these dry periods impact the device’s effectiveness in removing pollutants and the resulting biological succession within the filter. Our analysis examines nitrogen and phosphorus removal in a rainwater filtration context, providing new insights into how dry period duration influences infiltration system performance. The results indicate that biological processes have a significant impact on reducing total nitrogen (TN) and total phosphorus (TP) contents under different drying periods. A 3-day drying period is most effective for reducing TN through biological processes, while a 7-day period is best for TP reduction. This suggests that moderately extending the drying period improves TP removal efficiency but does not enhance TN removal. The dominant bacterial phylum responsible for denitrification and phosphorus removal is Proteobacteria, with Pseudomonas and Acinetobacter as the leading genera. As the drying period lengthens, the dominant genera shift from Pseudomonas to Massilia. At a 3-day drying period, denitrification primarily occurs through Pseudomonas on the surfaces of maifanite and zeolite. At a 7-day dry-out period, Acinetobacter is mainly responsible for phosphate removal on maifanite surfaces. However, after a 14-day dry-out period, both biomass and bioactivity of Pseudomonas and Acinetobacter decrease, leading to reduced efficiency in removing nitrogen and phosphorus pollutants from runoff infiltration devices. These results aid in developing runoff infiltration devices for specific scenarios and offer crucial guidance for regulating runoff pollution control technologies.

Abstract Depression is highly prevalent and easily relapses. Psychological interventions are effective for the prevention of depression relapse. This systematic review and network meta-analysis aimed to compare the efficacy at the same follow-up time points of psychological interventions in depression. We searched PubMed, Embase, and PsycINFO via OVID, and the Cochrane Library published up to December 12, 2021, and PubMed up to July 1, 2022. The primary outcome was depression relapse, considering the same time points that were extracted on survival curves or relapse curves. The study protocol was registered with PROSPERO, CRD42022343327. A total of 2,871 patients were included from 25 RCTs. Mindfulness-based cognitive therapy (MBCT) was significantly better than placebo at the 3 months, the 6 months, and the 9 months at follow-up. Cognitive behavioral therapy (CBT) was significantly better than treatment as usual at the 3 months, the 9 months, the 12 months, and the 15 months at follow-up. CBT was significantly better than placebo at the 21 months and the 24 months at follow-up. Behavioral activation therapy was significantly better than placebo at the 21 months and the 24 months at follow-up. Interpersonal psychotherapy was significantly better than placebo at the 24-month follow-up. All psychological interventions included in the study were significantly better than supportive counseling most of the time. The results were robust in various sensitivity and subgroup analyses. In conclusion, MBCT had a continuous effect in preventing relapse of depression. CBT had the longest but not continuous effect in preventing relapse of depression. The effects of behavioral activation therapy and interpersonal therapy for the prevention of depression appeared late. All psychological interventions included in the study were more effective than supportive counseling. More evidence is needed from large comparative trials that provide long-term follow-up data.

Abstract The nervous system plays an irreplaceable role in maintaining homeostasis and coordinating with the external environment. However, the incidence of neurological diseases is high and increasing year by year. Long drug development cycles, low efficacy, improper models and other bottlenecks restrict the prevention and treatment of diseases. Organ‐on‐chips (OOCs), as in vitro constructed organ microsystems, have made remarkable progress in recent years. The blood–brain barrier chip, neurovascular unit chip, nerve signal transduction chip, and other chips related to brain function have been widely studied. However, in vitro modeling of complex biological systems remains a major challenge for OOCs. The future development goal of OOC is to realize automatic culture, organ function simulation, and real‐time monitoring of physiological and biochemical indicators. In this paper, a strategy for optimizing the structure and functional interface of cell‐derived modules is presented, and a specific model of the automated integration system is proposed. It aims to build standardized and commercial chips related to brain functions and systems by integrating multidisciplinary strengths. In addition, it will drive the progress of life science research, disease modeling, and drug research and promote the development of related industries.

The use of space environment to carry out life science research is of great significance. However, there are limitations in complex manipulation, research models based on mammalian and 2-dimensional cell culture experiments, etc. Microfluidic chips possess the characteristics of integrating the relevant functions of traditional laboratories into micron-scale chips, with low energy consumption, high throughput, and automation. The application of microfluidic chips can overcome the challenges of space environments, the scarce experimental resources, and the unmanned operation problems to some extent. Moreover, microfluidic chips can realize long-term experimental operation and remote data recording and transmission. To carry out related research with microfluidic chips, the actuation and control of microfluidics are very important. In this paper, the microfluidic actuated and controlled technologies in microfluidic chips are reviewed, and then the application of microfluidic chips and microfluidic actuated and controlled systems in space life science is also briefly described.

Chimeric antigen receptor T cell (CAR-T cell) therapy has shown impressive success in the treatment of hematological malignancies, but the systemic toxicity and complex manufacturing process of current autologous CAR-T cell therapy hinder its broader applications. Universal CAR-T cells have been developed to simplify the production process through isolation and editing of allogeneic T cells from healthy persons, but the allogeneic CAR-T cells have recently encountered safety concerns, and clinical trials have been halted by the FDA. Thus, there is an urgent need to seek new ways to overcome the barriers of current CAR-T cell therapy. In-vivo CAR-T cells induced by nanocarriers loaded with CAR-genes and gene-editing tools have shown efficiency for regressing leukemia and reducing systemic toxicity in a mouse model. The in-situ programming of autologous T-cells avoids the safety concerns of allogeneic T cells, and the manufacture of nanocarriers can be easily standardized. Therefore, the in-vivo induced CAR-T cells can potentially overcome the abovementioned limitations of current CAR-T cell therapy. Here, we provide a review on CAR structures, gene-editing tools, and gene delivery techniques applied in immunotherapy to help design and develop new in-vivo induced CAR-T cells.

This study seeks to provide a basic approach to fulfill the spatial visualization of geopolitical environmental factors required for the navigation of vessels in the Arctic. Multi-dimensional geopolitical environmental factors of the Arctic Passage are analyzed and classified into geopolitics, geoeconomics, geo-military, geoculture, and laws and regulations related to geography. Their characteristics are extracted to form an attribute information table matching spatial layers. Based on the information category and basic characteristics, the spatial match method is applied and connected with the spatial layers to examine the spatial point, polyline, and polygon. According to the qualitative description, the study extracted the quantitative indicators for the following spatial-temporal pattern analysis. The standard deviational ellipse is used to analyze the spatial-temporal patterns and trends of the geopolitical environmental indicators of the Arctic Passage in the Arctic and Northeast Asia. The expansion and contraction of geoinformation coexist in the countries surrounding the Arctic Passage. The spatial-temporal changes indicate that the Arctic channel has a great economic impact on the Nordic countries and Northeast Asia, especially the coastal areas of China and Japan. The characteristic extraction and spatial match of the geopolitical environment provide integrated Arctic geoinformation inquiry and services for the diplomatic, administrative, and legal preparations required for Arctic navigation. Therefore, the geospatial analysis conducted provides scientific support and a basis for the geographical distribution and developing trends of visualization and spatial-temporal pattern in Arctic navigation. The results of this research will help decision-makers to make a comprehensive judgment on governance related to the sustainable development of the Arctic Passage.

Identifying the cellular origins and mapping the dendritic and axonal arbors of neurons have been century old quests to understand the heterogeneity among these brain cells. Current Brainbow based transgenic animals take the advantage of multispectral labeling to differentiate neighboring cells or lineages, however, their applications are limited by the color capacity. To improve the analysis throughput, we designed Bitbow, a digital format of Brainbow which exponentially expands the color palette to provide tens of thousands of spectrally resolved unique labels. We generated transgenic Bitbow Drosophila lines, established statistical tools, and streamlined sample preparation, image processing, and data analysis pipelines to conveniently mapping neural lineages, studying neuronal morphology and revealing neural network patterns with unprecedented speed, scale, and resolution.

At present, deep learning has achieved excellent achievements in image processing and computer vision and is widely used in the field of watermarking. Attention mechanism, as the research hot spot of deep learning, has not yet been applied in the field of watermarking. In this paper, we propose a deep learning and attention network for robust image watermarking (DARI-Mark). The framework includes four parts: an attention network, a watermark embedding network, a watermark extraction network, and an attack layer. The attention network used in this paper is the channel and spatial attention network, which calculates attention weights along two dimensions, channel and spatial, respectively, assigns different weights to pixels in different channels at different positions and is applied in the watermark embedding and watermark extraction stages. Through end-to-end training, the attention network can locate nonsignificant areas that are insensitive to the human eye and assign greater weights during watermark embedding, and the watermark embedding network selects this region to embed the watermark and improve the imperceptibility. In watermark extraction, by setting the loss function, larger weights can be assigned to watermark-containing features and small weights to noisy signals, so that the watermark extraction network focuses on features about the watermark and suppresses noisy signals in the attacked image to improve robustness. To avoid the phenomenon of gradient disappearance or explosion when the network is deep, both the embedding network and the extraction network have added residual modules. Experiments show that DARI-Mark can embed the watermark without affecting human subjective perception and that it has good robustness. Compared with other state-of-the-art watermarking methods, the proposed framework is more robust to JPEG compression, sharpening, cropping, and noise attacks.

Avian reoviruses (ARV) are a group of poultry pathogens that cause runting and stunting syndrome (RSS), a condition otherwise known as “frozen chicken”, which are characterized by dramatically delayed growth in broilers. It has been known that p17, a nonstructural protein encoded by ARV, prohibits cellular proliferation by halting the cell cycle at the G2/M phase, the result of which is directly associated with the typical clinical sign of RSS. Nevertheless, the mechanism by which p17 modulates cell-cycle progression remains largely unknown. Here, we screened the interactome of ectopically expressed p17 through a yeast two-hybrid assay and identified Bub3, a cellular mitotic checkpoint protein, as a binding partner of p17. The infection of the Vero cells by ARV downregulated the Bub3 expression, while the knockdown of Bub3 alleviated the p17-modulated cell-cycle arrest during ARV infection. Remarkably, the suppression of Bub3 by RNAi in the Vero cells significantly reduced the viral mRNA and protein abundance, which eventually led to diminished virus replication. Altogether, our findings reveal that ARV p17 impedes host cell proliferation through a Bub3-dependent cell-cycle arrest, which eventually contributes to efficient virus replication. These results also unveil a hitherto unknown therapeutic target for RSS.

Summary: The CorC/CNNM family of Na+-dependent Mg2+ transporters is ubiquitously conserved from bacteria to humans. CorC, the bacterial CorC/CNNM family of proteins, is involved in resistance to antibiotic exposure and in the survival of pathogenic microorganisms in their host environment. The CorC/CNNM family proteins possess a cytoplasmic region containing the regulatory ATP-binding site. CorC and CNNM have attracted interest as therapeutic targets, whereas inhibitors targeting the ATP-binding site have not been identified. Here, we performed a virtual screening of CorC by targeting its ATP-binding site, identified a compound named IGN95a with inhibitory effects on ATP binding and Mg2+ export, and determined the cytoplasmic domain structure in complex with IGN95a. Furthermore, a chemical cross-linking experiment indicated that with ATP bound to the cytoplasmic domain, the conformational equilibrium of CorC was shifted more toward the inward-facing state of the transmembrane domain. In contrast, IGN95a did not induce such a shift.

Finding neural features of suicide attempts (SA) in major depressive disorder (MDD) may be helpful in preventing suicidal behavior. The ventral and medial prefrontal cortex (PFC), as well as the amygdala form a circuit implicated in emotion regulation and the pathogenesis of MDD. The aim of this study was to identify whether patients with MDD who had a history of SA show structural and functional connectivity abnormalities in the amygdala and PFC relative to MDD patients without a history of SA. We measured gray matter volume in the amygdala and PFC and amygdala-PFC functional connectivity using structural and functional magnetic resonance imaging (MRI) in 158 participants [38 MDD patients with a history of SA, 60 MDD patients without a history of SA, and 60 healthy control (HC)]. MDD patients with a history of SA had decreased gray matter volume in the right and left amygdala (F = 30.270, P = 0.000), ventral/medial/dorsal PFC (F = 15.349, P = 0.000), and diminished functional connectivity between the bilateral amygdala and ventral and medial PFC regions (F = 22.467, P = 0.000), compared with individuals who had MDD without a history of SA, and the HC group. These findings provide evidence that the amygdala and PFC may be closely related to the pathogenesis of suicidal behavior in MDD and implicate the amygdala-ventral/medial PFC circuit as a potential target for suicide intervention.

Melanoidin is one of the most important ingredients in black garlic due to the high nutritional values and biological functions. High hydrostatic pressures from 200 to 500 MPa were employed to extract the melanoidins from black garlic for improving the extraction efficiency and enhancing the activities. The results indicated that total phenolics, flavonoids, and sugar yields were all increased when pressure was applied and the antioxidant and overall reducing power was maximized. The bioactive properties of protein tyrosine phosphatase 1B, angiotensin-converting enzyme, and trypsin inhibitory activities were also enhanced compared with the control. Moreover, FT-IR spectroscopy indicated high pressure altered the melanoidin structures to different degrees. It was found that an application of 300 MPa for 5 min was the optimal treatment protocol under all operating conditions.

Expression of chloride channel 1 (CLCN1/ClC-1) in skeletal muscle is driven by alternative splicing, a process regulated in part by RNA-binding protein families MBNL and CELF. Aberrant splicing of CLCN1 produces many mRNAs, which were translated into inactive proteins, resulting in myotonia in myotonic dystrophy (DM), a genetic disorder caused by the expansion of a CTG or CCTG repeat. This increase in abnormal splicing variants containing exons 6B, 7A or the insertion of a TAG stop codon just before exon 7 leads to a decrease in expression of the normal splice pattern. The majority of studies examining splicing in CLCN1 have been performed using mouse Clcn1, as have investigations into the activation and suppression of normal splicing variant expression by MBNL1-3 and CELF3–6, respectively. In contrast, examinations of human CLCN1 have been less common due to the greater complexity of splicing patterns. Here, we constructed a minigene containing CLCN1 exons 5–7 and established a novel assay system to quantify the expression of the normal splicing variant of CLCN1 using real-time RT-PCR. Antisense oligonucleotides could promote normal CLCN1 alternative splicing but the effective sequence was different from that of Clcn1. This result differs from previous reports using Clcn1, highlighting the effect of differences in splicing patterns between mice and humans.

To improve the antioxidant activity (AA), digestibility, and quality of fiber-rich dumpling wrappers, potato, okara, and konjac flours were added to wheat flour. The contents of these additional ingredients in the dumpling wrapper were optimized using the response surface methodology and the synthetic evaluation method. The dietary fiber content (DFC) and AA of blend flours and the optimized cooking time (OCT), cooking loss (CL), hardness, chewiness, firmness, color, and sensory evaluation (SE) of dumpling wrappers were evaluated as response quality parameters. The optimized flour was identified containing 17.5 g of potato flour, 8.5 g of okara flour, and 1.2 g of konjac flour per 100 g of blend flour, which resulted in a higher synthetic evaluation index value (0.71 compared with 0.68 for wheat flour). The qualities of the optimized flour dumpling wrappers were compared with those of wheat flour dumpling wrappers to verify the practicality of the optimized flour. The results showed that the optimized flour showed better comprehensive qualities, especially regarding DFC (9.59%, fourfold higher than that of wheat flour) and AA. Furthermore, the predicted glycemic index (GI) of the optimized flour (74.93%) was lower than that of the wheat flour (81.47%). Overall, the addition of potato, okara, and konjac flours can significantly (P

The Shuiyindong Gold Mine hosts one of the largest and highest-grade, strata-bound Carlin-type gold deposits discovered to date in Southwestern China. The outcrop stratigraphy and drill core data of the deposit reveal Middle–Upper Permian and Lower Triassic formations. The ore is mainly hosted in Upper Permian bioclastic limestone near the axis of an anticline. The gold is mainly hosted in arsenian pyrite and arsenopyrite, mainly existing in the form of crystal lattice gold, submicroscopic particles and nanoparticles. Fluorite commonly occurs at the vicinity of an unconformity between the Middle–Upper Permian formations, which is proposed to be the structural conduit that fed the ore fluids. Calcite commonly fills fractures at the periphery of decarbonated rocks, which contain high grade orebodies. This study aimed to verify the occurrence of two distinct hydrothermal events at the Shuiyindong, based on Sm–Nd isotope dating of the fluorite and calcite. For this purpose, rare-earth element (REE) concentrations, Sm/Nd isotope ratios, and Sm–Nd isochron ages of the fluorite and calcite were determined. The fluorite and calcite contain relatively high total concentrations of REE (12.3–25.6 μg/g and 5.71–31.7 μg/g, respectively), exhibit variable Sm/Nd ratios (0.52–1.03 and 0.57–1.71, respectively), and yield Sm–Nd isochron ages of 200.1 ± 8.6 Ma and 150.2 ± 2.2 Ma, with slightly different initial ε Nd ( t ) values of −4.4 and −1.1, respectively. These two groups of Sm–Nd isochron ages suggest two episodes of hydrothermal events at the Shuiyindong gold deposit. The age of the calcite probably represents the late stage of the gold mineralization period. The initial ε Nd ( t ) values of the fluorite and calcite indicate that the Nd was probably derived from mixtures of basaltic volcanic tuff and bioclastic limestone from the Permian formations.

Reversed phase liquid chromatography with mass spectrometry (RPLC-MS) peptide mapping is routinely used for interrogating molecular and structural attributes such as amino acid composition, sequence variants, and post-translational modifications (PTMs) in antibody-derived therapeutics. RPLC has some limitations that often impact the analysis of certain peptides including large hydrophobic peptides, hydrophilic di-/tripeptides and glycopeptides. Capillary zone electrophoresis with mass spectrometry (CZE-MS) has great potential for peptide mapping due to high efficiency and outstanding sensitivity. In this report we demonstrate the utility of CZE-MS as an orthogonal and complementary technique to RPLC-MS for peptide mapping analyses of antibody--drug conjugates (ADCs) and their parent antibodies. This work is based on high-resolution CZE-MS separation recently developed in our group, where a mixed aqueous--organic solvent system containing N,N-dimethylacetamide (DMA) or N,N-dimethylformamide (DMF) was used to improve the separation selectivity. The results described here show several advantages of CZE-MS for the analysis of small hydrophilic di-/tripeptides, large hydrophobic peptides, glycopeptides, and hydrophobic drug-linked peptides. [ABSTRACT FROM AUTHOR]

Peptide mapping with mass spectrometry (MS) detection is a powerful technique routinely used for interrogating physicochemical properties of proteins. Peptide mapping benefits from an efficient front-end separation to increase selectivity and reduce complexity prior to MS detection. The most commonly used method for peptide mapping is based on reverse phase liquid chromatography with mass spectrometry. Capillary zone electrophoresis with mass spectrometry (CZE-MS) is an orthogonal technique with growing attention for peptide mapping of biotherapeutic proteins due to its high efficiency and sensitivity. However, that growth has been slow due to poorer peptide resolution and method robustness compared to RPLC. Here we present results from optimization of CZE-MS peptide mapping separation using mixed aqueous--aprotic dipolar solvent (N,N-dimethylacetamide (DMA) and N,N-dimethylformamide (DMF), as the background electrolyte (BGE) to improve the separation performance. Addition of DMA or DMF to the BGE impacts separation selectivity through differential change in pKa of the peptides. The CZE-MS peptide mapping method with the modified BGE produced significant improvement in resolution over the conventional CZE-MS methods. The method was evaluated with both sheathless and sheathflow CE-MS ion sources. [ABSTRACT FROM AUTHOR]

Top-down proteomics offers the potential for full protein characterization, but many challenges remain for this approach, including efficient protein separations and effective fragmentation of intact proteins. Capillary zone electrophoresis (CZE) has shown great potential for separation of intact proteins, especially for differentially modified proteoforms of the same gene product. To date, however, CZE has been used only with collision-based fragmentation methods. Here we report the first implementation of electron transfer dissociation (ETD) with online CZE separations for top-down proteomics, analyzing a mixture of four standard proteins and a complex protein mixture from the Mycobacterium marinum bacterial secretome. Using a multipurpose dissociation cell on an Orbitrap Elite system, we demonstrate that CZE is fully compatible with ETD as well as higher energy collisional dissociation (HCD), and that the two complementary fragmentation methods can be used in tandem on the electrophoretic time scale for improved protein characterization. Furthermore, we show that activated ion electron transfer dissociation (AI-ETD), a recently introduced method for enhanced ETD fragmentation, provides useful performance with CZE separations to greatly increase protein characterization. When combined with HCD, AI-ETD improved the protein sequence coverage by more than 200% for proteins from both standard and complex mixtures, highlighting the benefits electron-driven dissociation methods can add to CZE separations. [ABSTRACT FROM AUTHOR]