Theoretical prediction on the insertion reactions of stannylenoid H2SnLiF with CH3X and SiH3X (X = F, Cl, Br).

Density functional theory was used to study the insertion reaction of stannylenoid H2SnLiF with CH3X, SiH3X (X = F, Cl, Br). Comparing the reaction barrier of H2SnLiF with CH3X, SiH3X, it can be found that the order of the difficulty of insertion reaction is F > Cl > Br. The insertion reaction potential barrier of SiH3X is lower than that of CH3X, which means that SiH3X is easier to react. According to the calculation results, the reaction law in THF solvent is consistent with that in vacuum, while in THF solvent, the barrier is lower and therefore more prone to reactions. This work provides theoretical support for the reaction properties of stannylenoids.

Design, synthesis and insecticidal activity of novel Isoxazoline Acylhydrazone compounds.

BACKGROUND: Nowadays, the diamondback moth has ascended to become one of the most formidable pests plaguing cruciferous vegetables. Consequently, the exigency for the development of efficacious pesticide candidates for crop protection has never been more paramount. In response to this pressing need, this study presents a compendium of novel isoxazoline derivatives, incorporating acylhydrazone moieties, synthesized with the express purpose of serving as potential insecticides. RESULTS: The structures of these derivatives were confirmed using Proton nuclear magnetic resonance (1 H NMR), Carbon-13 nuclear magnetic resonance (13 C NMR), and high-resolution mass spectrometry (HR-MS). Most of these derivatives demonstrated effective insecticidal activities against Plutella xylostella. Notably, compound E3 exhibited exceptional insecticidal activity against Plutella xylostella (LC50 = 0.19 mg L-1 ), surpassing the effectiveness of ethiprole (LC50 = 3.28 mg L-1 ), and comparable to that of fluxametamide (LC50 = 0.22 mg L-1 ). Interestingly, compound E3 also displayed potent insecticidal activity against Pyrausta nubilalis (LC50 = 0.182 mg L-1 ) and Chilo suppressalis (LC50 = 0.64 mg L-1 ), and the LC50 values of fluxametamide were 0.23 mg L-1 (P. nubilalis) and 2.26 mg L-1 (C. suppressalis), respectively. The molecular docking results revealed that the compound E3 can form a hydrogen bond and two Pi-Pi bonds with the active sites of GABA receptors. In addition, the DFT calculations were also performed to study the relationship between insecticidal activities. The structure-activity relationships suggested that the identity of the R substituent was crucial for their pesticidal activities. CONCLUSION: The results of the present study suggest that isoxazoline acylhydrazone derivatives could be promising candidates against P. xylostella and other Lepidopteran pests. © 2023 Society of Chemical Industry.

Function analysis of fish PACT gene in response to virus infection.

PACT (interferon-inducible double-stranded RNA-dependent protein kinase activator A) is a cellular protein which can activate PKR in dsRNA-independent manner. However, the role of PACT in fish virus infection remains largely unknown. In this study, a PACT homologue from grouper (Epinephelus coioides)(EcPACT) was cloned and characterized. The open reading frame of EcPACT has a full length of 924 bp and encodes a protein of 307 amino acids with a predicted molecular weight of 33.29 kDa. Similar to mammals, EcPACT contains three dsRBD domains. EcPACT shares 99.67 % homology with E. lanceolatus. Real-time fluorescence quantitative PCR results showed that EcPACT mRNA was widely expressed in all tissues and abundantly expressed in brain, blood, head kidney and kidney. In addition, SGIV and RGNNV infection significantly upregulated the transcript levels of EcPACT. Subcellular localization analysis showed that EcPACT was mainly distributed in the nucleus. Overexpression of EcPACT inhibited the replication of SGIV and RGNNV in vitro and positively regulated the expression of interferon (IFN) and pro-inflammatory factors. The results provide a better understanding of the relationship between PACT and viral infection in fish.

Design, Synthesis, and Antifungal Activity of Novel 2-Ar-1,2,3-Triazole Derivatives.

Triazoles are crucial molecular frameworks in the development of fungicidal compounds. Although there has been extensive research on triazole derivatives for fungicide discovery, the investigation of 2-Ar-substituted-1,2,3-triazoles remains in progress. This study reports the synthesis and evaluation of the fungicidal activity of 27 distinct 2-Ar-substituted-1,2,3-triazole derivatives. These derivatives were synthesized from anilines through a three-step process, with the key step being the Cu(II)-catalyzed annulation reaction of readily accessible alkyl 3-aminoacrylates with aryldiazonium salts. All derivatives were novel, and their structures were characterized using 1H NMR, 13C NMR, and high-resolution mass spectrometry. Their antifungal activity was tested against five phytopathogenic fungi. Twelve of the target compounds exhibited better performance than the positive control hymexazol in the fungal test. Notably, compound 6d demonstrated the most potent inhibition against Botryosphaeria dothidea with an EC50 value of 0.90 mg/L. The structure-activity relationships are also discussed in this paper. Preliminary studies on the antifungal mechanism of compound 6d revealed that it inhibits ergosterol synthesis and alters the morphology and ultrastructure of the B. dothidea mycelium. These results suggest that the designed 2-Ar-substituted-1,2,3-triazole-containing hydrazone derivatives warrant further investigation as potential lead compounds for novel antifungal agents.

Antiviral role of grouper FoxO1 against RGNNV and SGIV infection.

As a key regulator of the innate immune system, FoxO1 has a variety of activities in biological organisms. In the present study, grouper FoxO1 (EcFoxO1) was cloned and the antiviral activity in red grouper neuron necrosis virus (RGNNV) and Singapore grouper iridescent virus (SGIV) was examined. The open reading frame (ORF) of EcFoxO1 contains 2,034 base pairs that encode a protein of 677 amino acids with a predicted molecular weight of 73.21 kDa. EcFoxO1 was shown to be broadly distributed in healthy grouper tissues, and was up-regulated in vitro in response to stimulation by RGNNV and SGIV. EcFoxO1 has a whole-cell distribution in grouper spleen (GS) cells. EcFoxO1 decreased the replication of RGNNV and SGIV, and activated interferon (IFN) 3, IFN-stimulated response element (ISRE), and nuclear factor-κB (NF-κB) promoter activities. EcFoxO1 could interact with EcIRF3. Together, the results demonstrated that EcFoxO1 might be an important regulator of grouper innate immune response against RGNNV and SGIV infection.

Rapid detection of micronutrient components in infant formula milk powder using near-infrared spectroscopy.

In order to achieve rapid detection of galactooligosaccharides (GOS), fructooligosaccharides (FOS), calcium (Ca), and vitamin C (Vc), four micronutrient components in infant formula milk powder, this study employed four methods, namely Standard Normal Variate (SNV), Multiplicative Scatter Correction (MSC), Normalization (Nor), and Savitzky-Golay Smoothing (SG), to preprocess the acquired original spectra of the milk powder. Then, the Competitive Adaptive Reweighted Sampling (CARS) algorithm and Random Frog (RF) algorithm were used to extract representative characteristic wavelengths. Furthermore, Partial Least Squares Regression (PLSR) and Support Vector Regression (SVR) models were established to predict the contents of GOS, FOS, Ca, and Vc in infant formula milk powder. The results indicated that after SNV preprocessing, the original spectra of GOS and FOS could effectively extract feature wavelengths using the CARS algorithm, leading to favorable predictive results through the CARS-SVR model. Similarly, after MSC preprocessing, the original spectra of Ca and Vc could efficiently extract feature wavelengths using the CARS algorithm, resulting in optimal predictive outcomes via the CARS-SVR model. This study provides insights for the realization of online nutritional component detection and optimization control in the production process of infant formula.

Grouper Atg14 promotes Singapore grouper iridovirus (SGIV) replication by inhibiting the host innate immune response.

As one of the important members of the autophagy-related protein family, Atg14 plays a key role in the formation and maturation of autophagosomes. However, little is known about the potential roles of fish Atg14 and its roles in virus infection. In the present study, the homolog of Atg14 (EcAtg14) from the orange-spotted grouper (Epinephelus coioides) was cloned and characterized. The open reading frame (ORF) of EcAtg14 consists of 1530 nucleotides, encoding 509 amino acids, with a predicted molecular weight of 56.9 kDa. EcAtg14 was distributed in all tested tissues, with higher expression in liver, blood and spleen. The expression of EcAtg14 was increased in grouper spleen (GS) cells after Singapore grouper iridovirus (SGIV) infection. EcAtg14 was distributed in the cytoplasm of GS cells. Overexpression of EcAtg14 promoted SGIV replication in GS cells and inhibited IFN3, ISRE and NF-κB promoter activities. Co-immunoprecipitation results showed that there was an interaction between EcAtg14 and EcBeclin. EcAtg14 also promoted the synthesis of LC3-II in GS cells. These findings provide a basis for understanding the innate immune mechanism of grouper against viral infection.

Assessing the effect of powder characteristics of infant milk on the compressibility of milk powder compression molding.

Infant formula is an important food for those infants who are deprived of breast milk. However, infant formula powder is prone to fly apart, moisture absorption, sticky spoon, and inaccurate measurement. Block infant formula can solve these problems well. In this study, the characteristics (including particle structure morphology, moisture content, particle size, etc.) of infant formula powder were investigated on the compressive strength and solubility of block infant formula after compression molding with infant formula powder as the object. The results showed that the compressive strength and solubility of the block infant formula made from milk powder with a moisture content of 4.75%, particle size larger than 80 mesh, and morphology of compact grape structure appendages were the best. Therefore, milk powder with this characteristic is the most suitable for the preparation of block infant formula. This study provides referenceable experimental data and theoretical basis for the preparation and application of block infant formula.

Singapore grouper iridovirus VP122 targets grouper STING to evade the interferon immune response.

Singapore grouper iridovirus (SGIV) is a highly pathogenic Iridoviridae that causes hemorrhage and spleen enlargement in grouper. Despite previous genome annotation efforts, many open reading frames (ORFs) in SGIV remain uncharacterized, with largely unknown functions. In this study, we identified the protein encoded by SGIV ORF122, now referred to as VP122. Notably, overexpression of VP122 promoted SGIV replication. Moreover, VP122 exhibited antagonistic effects on the natural antiviral immune response through the cGAS-STING signaling pathway. It specifically inhibited the cGAS-STING-triggered transcription of various immune-related genes, including IFN1, IFN2, ISG15, ISG56, PKR, and TNF-α in GS cells. Additionally, VP122 significantly inhibited the activation of the ISRE promoter mediated by EccGAS and EcSTING but had no effect on EccGAS or EcSTING alone. Immunoprecipitation and Western blotting experiments revealed that VP122 specifically interacts with EcSTING but not EccGAS. Notably, this interaction between VP122 and EcSTING was independent of any specific domain of EcSTING. Furthermore, VP122 inhibited the self-interaction of EcSTING. Interestingly, VP122 did not affect the recruitment of EcTBK1 and EcIRF3 to the EcSTING complex. Collectively, our results demonstrate that SGIV VP122 targets EcSTING to evade the type I interferon immune response, revealing a crucial role for VP122 in modulating the host-virus interaction.

New Insights into Phospholipid Profile Alteration of Bigeye Tuna (Thunnus obesus) during Daily Cooking Processes Using Rapid Evaporative Ionization Mass Spectrometry.

Bigeye tuna (BET, Thunnus obesus) is one of the most nutritious and luxurious cosmopolitan fish. The cooked BET products are capturing the interests of consumers by enhancing flavor and ensuring microbiological safety; however, the lipidomic fingerprints during daily cooking processes have not been investigated. In this work, lipid phenotypic data variation in BET during air-frying, roasting, and boiling was studied comprehensively using iKnife rapid evaporative ionization mass spectrometry (REIMS). The outstanding lipid ions mainly including fatty acids (FAs) and phospholipids (PLs) were identified structurally. It was demonstrated that the rates of heat transfer and lipid oxidation in air-fried BET were slower than those in roasted and boiled BET by elucidating the lipid oxidation and PL hydrolysis mechanism. Furthermore, multivariate REIMS data analysis (e.g., discriminant analysis, support vector machine, neutral network, and machine learning models) was used to characterize the lipid profile change in different cooked BET samples, among which FAC22:6, PL18:3/22:6, PL18:1/22:6, and others were the salient contributing features for determining the cooked BET samples. These results may provide a potential strategy for a healthy diet by controlling and improving functional food quality in daily cooking.

Prevention of dextran sulfate sodium (DSS)-induced ulcerative colitis in mice by a synbiotic approach using probiotic and lactulose.

In this research, the synbiotic effects of the probiotic Lactiplantibacillus plantarum YW11 and lactulose on intestinal morphology, colon function, and immune activity were evaluated in a mouse model of UC induced by dextran sulfate sodium (DSS). The results revealed that L. plantarum YW11 in combination with lactulose decreased the severity of colitis in mice and improved the structure of the damaged colon, as assessed using colon length and disease condition. Moreover, colonic levels of pro-inflammatory cytokines (IL-1ß, IL-6, IL-12, TNF-α, and IFN-γ) were significantly lower and anti-inflammatory factors (IL-10) were significantly higher following the synbiotic supplementation. The synbiotic also exerted antioxidant effects by up-regulating SOD and CAT levels and down-regulating MDA levels in colon tissue. It could also reduce the relative expression of iNOS mRNA and increase the relative expression of nNOS and eNOS mRNA. Western blot confirmed the increased expression of c-Kit, IκBα, and SCF and significantly reduced expression of the NF-κB protein. Therefore, the combination of L. plantarum YW11 and lactulose exerted therapeutic effects mainly through the NF-κB anti-inflammatory pathway, which represented a novel synbiotic approach in the prevention of colonic inflammation.

Insight into the addition reactions of stannylenoid H2SnLiF with ethylene.

CONTEXT: Tetrylenoids, R2EXM (E = Si, Ge, and Sn; X = electronegative group; M = alkali metal), have electrophilic and nucleophilic properties just like carbenoid. As the products of carbenoid compounds with olefins, the cyclopropane fraction has been found to be biologically active in many natural and artificial compounds. Can carbenoid analogues of stannylenoid facilitate similar cyclopropanation reactions? METHODS: Addition reaction of the stannylenoid compound H2SnLiF with ethylene was investigated using density function theory (DFT) at the M062X/def2-TZVP level. The single-point energy calculations were performed on the basis of QCISD/def2-TZVP level. RESULTS: Two possible pathways were found for the addition reaction of H2SnLiF (R1) with ethylene (R2). The most favorable path is the two successive reactions of H2SnLiF and ethylene through the ternary ring product c-H2Sn(CH2)2 (P1) and then the formation of the five-membered ring product (P2). Solvation-related studies have shown that addition reactions are more likely to occur in the presence of THF solvents. This work provides theoretical support for the reactions of stannylenoid with olefins.

Isolation, Characterization, and Transcriptome Analysis of an ISKNV-Like Virus from Largemouth Bass.

Largemouth bass (Micropterus salmoides) is an important commercial fish farmed in China. Challenges related to diseases caused by pathogens, such as iridovirus, have become increasingly serious. In 2017, we detected iridovirus-infected diseased largemouth bass in Zunyi, Guizhou Province. The isolated virus was identified as an infectious spleen and kidney necrosis virus (ISKNV)-like virus (ISKNV-ZY). ISKNV-ZY induces a cytopathic effect after infecting mandarin fish brain (MFB) cells. Abundant hexagonal virus particles were observed in the cytoplasm of ISKNV-ZY-infected MFB cells, using electron microscopy. The whole genome of ISKNV-ZY contained 112,248 bp and 122 open reading frames. Phylogenetic tree analysis showed that ISKNV-ZY was most closely related to BCIV, indicating that it is an ISKNV-like megalocytivirus. ISKNV-ZY-infected largemouth bass started to die on day six and reached a death peak on days 7-8. Cumulative mortality reached 100% on day 10. Using RNA sequencing-based transcriptome analysis after ISKNV-ZY infection, 6254 differentially expressed unigenes (DEGs) were identified, of which 3518 were upregulated and 2673 downregulated. The DEGs were associated with endocytosis, thermogenesis, oxidative phosphorylation, the JAK-STAT signaling pathway, the MAPK signaling pathway, etc. These results contribute to understanding the molecular regulation mechanism of ISKNV infection and provide a basis for ISKNV prevention.

Traditional Chinese medicine decoctions and Chinese patent medicines for the treatment of depression: Efficacies and mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is a major mental disorder and it is currently recognized as the second-leading cause of disability worldwide. However, the therapeutic effect of antidepressants remains unsatisfactory. Traditional Chinese medicine (TCM) has been widely used for centuries, including commonly-used complementary and alternative medical therapies for depression. Recent clinical trials have been carried out to assess the efficacy and safety of TCM, and to explore the mechanisms of action in relation to the treatment of depression. AIM OF THE STUDY: To summarize frequently used TCM decoctions and Chinese patent medicines (CPM) for treating depression, review their clinical therapeutic effects in treating depressive disorders, consider their possible mechanisms, and characterize the relationships between their efficacy and mechanisms. MATERIALS AND METHODS: We performed a computerized literature search using the electronic databases such as PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases, with the keywords "depression", "traditional Chinese medicine decoction", "Chinese patent medicine", "application", "mechanism", and their combinations, from January 1, 2000 to August 8, 2022 (inclusive). RESULTS: A total of 51 papers were identified. We reviewed studies on six each TCM decoctions and CPMs, which demonstrated their significant clinical efficacy for treating depression and examined their mechanisms of action. The anti-depressive effects were related to: 1) increased monoamine neurotransmitter levels, 2) inhibiting hyperactivity of the hypothalamic-pituitary-adrenal axis, 3) regulating hippocampal neurons and neurotrophic factors, 4) regulating immune cytokines, 5) counteracting excitatory amino acid toxicity, and 6) regulating microbe-gut-brain axis function. CONCLUSION: TCM plays an increasingly important role in the management of depression by enhancing the therapeutic effects and alleviating the side effects of antidepressant chemicals.

Catalytic Cyanation of C-N Bonds with CO2/NH3.

Cyanation of benzylic C-N bonds is useful in the preparation of important α-aryl nitriles. The first general catalytic cyanation of α-(hetero)aryl amines, analogous to the Sandmeyer reaction of anilines, was developed using reductive cyanation with CO2/NH3. A broad array of α-aryl nitriles was obtained in high yields and regioselectivity by C-N cleavage of intermediates as ammonium salts. Good tolerance of functional groups such as ethers, CF3, F, Cl, esters, indoles, and benzothiophenes was achieved. Using 13CO2, a 13C-labeled tryptamine homologue (five steps, 31% yield) and Cysmethynil (six steps, 37% yield) were synthesized. Both electronic and steric effects of ligands influence the reactivity of alkyl nickel species with electrophilic silyl isocyanates and thus determine the reactivity and selectivity of the cyanation reaction. This work contributes to the understanding of the controllable activation of CO2/NH3 and provides the promising potential of the amine cyanation reaction in the synthesis of bio-relevant molecules.

Rethinking the Importance of Quantization Bias, Toward Full Low-Bit Training.

Quantization is a promising technique to reduce the computation and storage costs of DNNs. Low-bit ( ≤ 8 bits) precision training remains an open problem due to the difficulty of gradient quantization. In this paper, we find two long-standing misunderstandings of the bias of gradient quantization noise. First, the large bias of gradient quantization noise, instead of the variance, is the key factor of training accuracy loss. Second, the widely used stochastic rounding cannot solve the training crash problem caused by the gradient quantization bias in practice. Moreover, we find that the asymmetric distribution of gradients causes a large bias of gradient quantization noise. Based on our findings, we propose a novel adaptive piecewise quantization method to effectively limit the bias of gradient quantization noise. Accordingly, we propose a new data format, Piecewise Fixed Point (PWF), to present data after quantization. We apply our method to different applications including image classification, machine translation, optical character recognition, and text classification. We achieve approximately 1.9 âˆ¼ 3.5× speedup compared with full precision training with an accuracy loss of less than 0.5%. To the best of our knowledge, this is the first work to quantize gradients of all layers to 8 bits in both large-scale CNN and RNN training with negligible accuracy loss.

CH4 activation by PtX+ (X = F, Cl, Br, I).

Reactions of PtX+ (X = F, Cl, Br, I) with methane have been investigated at the density functional theory (DFT) level. These reactions take place more easily along the low-spin potential energy surface. For HX (X = F, Cl, Br, I) elimination, the formal oxidation state of the metal ion appears to be conserved, and the importance of this reaction channel decreases in going as the sequence: X = F, Cl, Br, I. A reversed trend is observed in the loss of H2 for X = F, Cl, Br, while it is not favorable for PtI+ in the loss of either HI or H2. For HX eliminations, the transfer form of H is from proton to atom, last to hydride, and the mechanisms are from PCET to HAT, last to HT for the sequence of X = F, Cl, Br, I. One reason is mainly due to the electronegativity of halogens. Otherwise, the mechanisms of HX eliminations also can be explained by the analysis of Frontier Molecular Orbitals. While for the loss of H2, the transfer of H is in the form of hydride for all the X ligands. Noncovalent interactions analysis also can be explained the reaction mechanisms.

CO2 -Promoted Direct Acylation of Amines and Phenols by the Activation of Inert Thioacid Salts.

Herein a carbon dioxide-promoted synthetic approach for the direct amidation between unactivated thioacid salts and amines under mild conditions was developed for a wide range of substrates. The method afforded amides in good to excellent yields under transition-metal-free and activation-reagent-free conditions, in sharp contrast to early methodologies on amide synthesis based on transition-metal catalysis. The method offered a greener and transition metal-free protocol applicable to pharmaceuticals preparations. Phenolic compounds were also found to be suitable acylation substrates with potassium thiosulfide KHS as the only byproduct. Moreover, this approach was applied to amide synthesis of valuable bio-active molecules such as moclobemide, melatonin, and a fungicide. Insights into the reaction mechanism involving carbon dioxide were provided through NMR spectroscopy and computational calculations. A plausible mechanism was proposed that involves weak interactions between carbon dioxide and potassium thioacetate in a dynamic equilibrium state formation of a six-membered ring.

DNA Nanodevices: From Mechanical Motions to Biomedical Applications.

Inspired by molecular machines in nature, artificial nanodevices have been designed to realize various biomedical functions. Self-assembled deoxyribonucleic acid (DNA) nanostructures that feature designed geometries, excellent spatial accuracy, nanoscale addressability, and marked biocompatibility provide an attractive candidate for constructing dynamic nanodevices with biomarker- targeting and stimuli-responsiveness for biomedical applications. Here, a summary of typical construction strategies of DNA nanodevices and their operating mechanisms are presented. We also introduced recent advances in employing DNA nanodevices as platforms for biosensing and intelligent drug delivery. Finally, the broad prospects and main challenges of the DNA nanodevices in biomedical applications are also discussed.

Interaction Between Chinese Medicine and Warfarin: Clinical and Research Update.

Background: Warfarin is a commonly used oral anticoagulant. It has a narrow therapeutic window and wide variation in individualized dosing, and is used clinically for the treatment of thromboembolic diseases. Due to the widespread use of traditional Chinese medicine (TCM) in China and the complex composition and diverse mechanisms of action of TCM, the combination of TCM and warfarin in patients has led to fluctuations in the international normalized ratio of warfarin or bleeding. To ensure rational clinical use, we summarize the TCMs with which warfarin interacts and the possible mechanisms, with a view to providing a clinical reference. Aim of the study: To summarize the mechanisms by which Chinese herbal medicines affect the enhancement or weakening of the anticoagulant effect of warfarin, to provide theoretical references for clinicians and pharmacists to use warfarin safely and rationally, and to avoid the adverse effects associated with the combination of Chinese herbal medicines and warfarin. Methods: A computerized literature search of electronic databases, including PubMed, MEDLINE, Cochrane Library, Web of Science (WOS), China National Knowledge Infrastructure (CNKI) and WANFANG Data was performed. Key words used in the literature search were "warfarin", "Chinese medicine", "traditional Chinese medicine", "Chinese patent medicine" etc. and their combinations in a time limit from January 1, 1990 to May 1, 2021. A total of 64 articles were obtained following the selection process, including clinical reports, pharmacological experiments and in vitro experiments which were reviewed to determine the mechanism of the anticoagulant effect of herbal medicine on warfarin. Results: The mechanisms affecting the anticoagulant effect of warfarin are complex, and herbal medicines may enhance and diminish the anticoagulant effect of warfarin through a variety of mechanisms; thus, clinical use needs to be cautious. Some herbal medicines have shown inconsistent results in both in vivo and ex vivo experiments, pharmacology and clinical studies, and should be the focus of future research. Conclusion: With the widespread use of TCM, the combination of warfarin and TCM is more common. This article will promote clinicians' knowledge and understanding of the TCMs which interact with warfarin, in order to avoid the occurrence of adverse clinical treatment processes, and improve the efficacy and safety.