Analysis of Acupoint Selection Rules for Guasha Treatment of Primary Headaches Based on Data Mining.

Objective: We aimed to understand the commonly used acupoints and the acupoint combination rules in Guasha therapy for primary headaches using data mining technology, providing a reference for the clinical application of Guasha therapy for primary headaches. Methods: Literature related to Guasha therapy for primary headaches in PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and Chinese Biomedical Literature Database were searched, up until May 12, 2023. A database of acupoints for Guasha therapy for primary headaches was established in Excel. The frequency of the acupoints used for Guasha in therapy of primary headaches were calculated by SPSS 25.0. The association rules between the acupoints were further described using SPSS Modeler 18.0. Results: A total of 67 papers were included, involving 51 acupoints for Guasha against primary headaches. The most commonly used acupoints were Fengchi, Baihui, Taiyang, Shuaigu, Tianzhu, and Hegu. The common acupoint combinations for Guasha therapy for primary headaches were Fengchi-Taiyang, Fengchi-Baihui, Fengchi-Taiyang-Baihui, Fengchi-Tianzhu-Baihui, and Fengchi-Shuaigu-Taiyang-Baihui. Conclusion: Data mining can effectively analyze the commonly used acupoints and the acupoint combination rules in Guasha therapy for primary headaches, providing a reliable basis for clinical acupoint selection.

Supramolecular copolymerization of hydrophobic and hydrophilic monomers in liquid crystalline media.

In the case of covalent polymers, immiscible polymers can be integrated by covalently linking them together, but such a strategy is not possible in supramolecular polymers. Here we report the supramolecular copolymerization of two porphyrin-based monomers, C10P2H and TEGPCu with side chains bearing cyanobiphenyl (CB) groups at the ends of hydrophobic alkyl or hydrophilic tetraethylene glycol chains, respectively. These monomers undergo self-sorting supramolecular polymerization in highly diluted solutions ([monomer] = 3.4 × 10-9 mol% (2.0 × 10-8 mol L-1)) in nonpolar media due to the incompatibility of the side chains. Surprisingly, these monomers undergo supramolecular copolymerization under high concentration conditions ([monomer] = 7.7 mol%) in the medium of 4-cyano-4'-pentyloxybiphenyl (5OCB) to form a columnar liquid crystalline phase under thermodynamic conditions, where the individual columns are composed of supramolecular block copolymers. The combination of CB ends of both monomers and the 5OCB medium is essential for the two monomers to form an integrated structure in a condensed system without phase separation.

Post-sepsis psychiatric disorder: Pathophysiology, prevention, and treatment.

Post-sepsis psychiatric disorder, encompassing anxiety, depression, post-traumatic stress disorder and delirium, is a highly prevalent complication secondary to sepsis, resulting in a marked increase in long-term mortality among affected patients. Regrettably, psychiatric impairment associated with sepsis is frequently disregarded by clinicians. This review aims to summarize recent advancements in the understanding of the pathophysiology, prevention, and treatment of post-sepsis mental disorder, including coronavirus disease 2019-related psychiatric impairment. The pathophysiology of post-sepsis psychiatric disorder is complex and is known to involve blood-brain barrier disruption, overactivation of the hypothalamic-pituitary-adrenal axis, neuroinflammation, oxidative stress, neurotransmitter dysfunction, programmed cell death, and impaired neuroplasticity. No unified diagnostic criteria for this disorder are currently available; however, screening scales are often applied in its assessment. Modifiable risk factors for psychiatric impairment post-sepsis include the number of experienced traumatic memories, the length of ICU stay, level of albumin, the use of vasopressors or inotropes, daily activity function after sepsis, and the cumulative dose of dobutamine. To contribute to the prevention of post-sepsis psychiatric disorder, it may be beneficial to implement targeted interventions for these modifiable risk factors. Specific therapies for this condition remain scarce. Nevertheless, non-pharmacological approaches, such as comprehensive nursing care, may provide a promising avenue for treating psychiatric disorder following sepsis. In addition, although several therapeutic drugs have shown preliminary efficacy in animal models, further confirmation of their potential is required through follow-up clinical studies.

Optimization and validation of a suprasystolic brachial cuff-based method for noninvasively estimating central aortic blood pressure.

Clinical studies have extensively demonstrated that central aortic blood pressure (CABP) has greater clinical significance in comparison with peripheral blood pressure. Despite the existence of various techniques for noninvasively measuring CABP, the clinical applications of most techniques are hampered by the unsatisfactory accuracy or large variability in measurement errors. In this study, we proposed a new method for noninvasively estimating CABP with improved accuracy and reduced uncertain errors. The main idea was to optimize the estimation of the pulse wave transit time from the aorta to the occluded lumen of the brachial artery under a suprasystolic cuff by identifying and utilizing the characteristic information of the cuff oscillation wave, thereby improving the accuracy and stability of the CABP estimation algorithms under various physiological conditions. The method was firstly developed and verified based on large-scale virtual subject data (n = 800) generated by a computational model of the cardiovascular system coupled to a brachial cuff, and then validated with small-scale in vivo data (n = 34). The estimation errors for the aortic systolic pressure were -0.05 ± 0.63 mmHg in the test group of the virtual subjects and -1.09 ± 3.70 mmHg in the test group of the patients, both demonstrating a good performance. In particular, the estimation errors were found to be insensitive to variations in hemodynamic conditions and cardiovascular properties, manifesting the high robustness of the method. The method may have promising clinical applicability, although further validation studies with larger-scale clinical data remain necessary.

Antimicrobial Protein LECT2-b Helps Maintain Gut Microbiota Homeostasis via Selectively Targeting Certain Pathogenic Bacteria.

Antimicrobial peptides/proteins (AMPs) constitute a critical component of gut immunity in animals, protecting the gut from pathogenic bacteria. However, the interactions between AMPs and gut microbiota remain elusive. In this study, we show that leukocyte-derived chemotaxin-2 (LECT2)-b, a recently discovered AMP, helps maintain gut homeostasis in grass carp (Ctenopharyngodon idella), one of the major farmed fish species globally, by directly regulating the gut microbiota. Knockdown of LECT2-b resulted in dysregulation of the gut microbiota. Specifically, LECT2-b deficiency led to the dominance of Proteobacteria, consisting of proinflammatory bacterial species, over Firmicutes, which includes anti-inflammatory bacteria. In addition, the opportunistic pathogenic bacteria genus Aeromonas became the dominant genus replacing the probiotic bacteria Lactobacillus and Bacillus. Further analysis revealed that this effect was due to the direct and selective inhibition of certain pathogenic bacterial species by LECT2-b. Moreover, LECT2-b knockdown promoted biofilm formation by gut microbiota, resulting in tissue damage and inflammation. Importantly, LECT2-b treatment alleviated the negative effects induced by LECT2-b knockdown. These findings highlight the crucial role of LECT2-b in maintaining the gut microbiota homeostasis and mucosal health. Overall, our study provides important data for understanding the roles of AMPs in the regulation of gut homeostasis in animals.

Oxygen affinity and light intensity induced robust phosphorus removal and fragile ammonia removal in a non-aerated bacteria-algae system.

Non-aerated bacteria-algae system gaining O2 through photosynthesis presents an alternative for costly mechanical aeration. This study investigated oxygen supply and performance of nutrients removal at low and high light intensity (LL and HL). The results showed that P removal was high and robust (LL 97 ± 1.8 %, HL 95 % ± 2.9 %), while NH4+-N removal fluctuated dramatically (LL 66 ± 14.7 %, HL 84 ± 8.6 %). Oxygen generated at illumination of 200 µmol m-2 s-1, 6 h was sufficient to sustain aerobic phase for 2.25 g/L MLSS. However, O2 produced by algae was preferentially captured in the order of heterotrophic bacteria (HB), ammonia oxidizing bacteria (AOB), nitrite oxidizing bacteria (NOB). Oxygen affinity coupled with light intensity led to NOB suppression with stable nitrite accumulation ratio of 57 %. Free nitrous acid (FNA) and light stimulated the abundance of denitrifying polyphosphate accumulating organism (DPAO) of Flavobacterium, but with declined P-accumulating metabolism (PAM) of P release, P/C, K/P and Mg/P ratios. Flavobacterium and cyanobacteria Leptolyngbya, along with biologically induced CaP in extracellular polymeric substances was the key to robust P removal. AOB of Ellin6067 and DPAO of Flavobacteria offer a promising scenario for partial nitrification-denitrifying phosphorus removal.

Discovery, Crystallographic Studies, and Mechanistic Investigations of Novel Phenylalanine Derivatives Bearing a Quinazolin-4-one Scaffold as Potent HIV Capsid Modulators.

Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives 12a2 and 21a2 showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of 12a2 and 21a2 in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably, 12a2 and 21a2 significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of 12a2 in human liver microsomes compared to controls. Overall, 12a2 and 21a2 highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.

Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability.

Interfering with the assembly of hepatitis B virus (HBV) capsid is a promising approach for treating chronic hepatitis B (CHB). In order to enhance the metabolic stability and reduce the strong hERG inhibitory effect of HBV capsid assembly modulator (CAM) GLS4, we rationally designed a series of carboxyl-containing heteroaryldihydropyrimidine (HAP) derivatives based on structural biology information combined with medicinal chemistry strategies. The results from biological evaluation demonstrated that compound 6a-25 (EC50 = 0.020 µM) exhibited greater potency than the positive drug lamivudine (EC50 = 0.09 µM), and was comparable to the lead compound GLS4 (EC50 = 0.007 µM). Furthermore, it was observed that 6a-25 reduced levels of core protein (Cp) and capsid in cells. Preliminary assessment of drug-likeness revealed that 6a-25 exhibited superior water solubility (pH 2.0: 374.81 µg mL-1; pH 7.0: 6.85 µg mL-1; pH 7.4: 25.48 µg mL-1), liver microsomal metabolic stability (t1/2 = 108.2 min), and lower hERG toxicity (10 µM inhibition rate was 72.66%) compared to the lead compound GLS4. Overall, compound 6a-25 holds promise for further investigation.

A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation.

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

Bibliometric analysis and visualization of research trends on HIV-1 capsid inhibitors (2000-2022).

Background: Acquired immunodeficiency syndrome (AIDS) has seriously endangered human life and health, the main pathogenic agent is human immunodeficiency virus type 1 (HIV-1). The combination antiretroviral therapy (cART) has shown serious drug resistance and side effects, and the discovery of HIV-1 capsid inhibitors is an effective way to solve the problem. Recent studies have shown significant progress in the research of HIV-1 capsid inhibitors. However, there is still a lack of comprehensive overview of bibliometric analysis in this field. This study aimed to provide the research trends and hotspots of HIV-1 capsid inhibitors. Method: Publications related to HIV-1 capsid inhibitors from 2000 to 2022 were searched on the Web of Science Core Collection (WoSCC) database and screened according to inclusion criteria. VOSviewer was conducted to evaluate the results. Results: 96 publications from 25 countries were finally included, and the number of annual publications related to HIV-1 capsid inhibitors showed an increasing trend. The United States was the most productive country with the most publication number, H-index, and total citation number, as well as the widest international cooperation. The most popular journal in this field was Journal of Virology. Drexel University was the most productive institution, and Simon Cocklin participated in the most publications. Keywords co-occurrence analysis exhibited that studying the molecular mechanism of capsid protein, discovering drug candidates, and improving antiretroviral therapy are the main and hot topics in this field. Conclusion: This is the first bibliometric study in the field of HIV-1 capsid inhibitors, which comprehensively analyzed the research trends and hotspots in this direction. This work is expected to provide the scientific community with new insights to promote the research of HIV-1 capsid inhibitors.

An Atlas of Grass Carp IgM+ B Cells in Homeostasis and Bacterial Infection Helps to Reveal the Unique Heterogeneity of B Cells in Early Vertebrates.

Teleost B cells are primitive lymphocytes with both innate and adaptive immune functions. However, the heterogeneity and differentiation trajectory of teleost B cells remain largely unknown. In this study, the landscape of grass carp IgM+ (gcIgM+) B cells was revealed by single-cell RNA sequencing. The results showed that gcIgM+ B cells mainly comprise six populations: (im)mature B cells, innate B cells, proliferating B cells, plasma cells, CD22+ cells, and CD34+ cells, among which innate B cells and proliferating B cells were uncommon B cell subsets with, to our knowledge, new characteristics. Remarkably, three functional IgMs were discovered in grass carp, and a significant percentage of gcIgM+ B cells, especially plasma cells, expressed multiple Igµ genes (Igµ1, Igµ2, and/or Igµ3). More importantly, through single-cell sorting combined with Sanger sequencing, we found that distinct VHDJH recombination patterns of Igµ genes were present in single IgM+ B cells, indicating that individual teleost B cells might produce multiple Abs by coexpressing rearranged IgM subclass genes. Moreover, the percentage of IgM1highIgM2highIgM3high plasma cells increased significantly after bacterial infection, suggesting that individual plasma cells might tend to produce multiple IgMs to resist the infection in teleost fish. In summary, to our knowledge, this study not only helps to uncover the unique heterogeneity of B cells in early vertebrates but also provided significant new evidence supporting the recently proposed "one cell-multiple Abs" paradigm, challenging the classical rule of "one cell-one Ab."

Threshold values of brachial cuff-measured arterial stiffness indices determined by comparisons with the brachial-ankle pulse wave velocity: a cross-sectional study in the Chinese population.

Background: Arterial Velocity-pulse Index (AVI) and Arterial Pressure-volume Index (API), measured by a brachial cuff, have been demonstrated to be indicative of arterial stiffness and correlated with the risk of cardiovascular events. However, the threshold values of AVI and API for screening increased arterial stiffness in the general population are yet to be established. Methods: The study involved 860 subjects who underwent general physical examinations (M/F = 422/438, age 53.4 ± 12.7 years) and were considered to represent the general population in China. In addition to the measurements of AVI, API and brachial-ankle pulse wave velocity (baPWV), demographic information, arterial blood pressures, and data from blood and urine tests were collected. The threshold values of AVI and API were determined by receiver operating characteristic (ROC) analyses and covariate-adjusted ROC (AROC) analyses against baPWV, whose threshold for diagnosing high arterial stiffness was set at 18 m/s. Additional statistical analyses were performed to examine the correlations among AVI, API and baPWV and their correlations with other bio-indices. Results: The area under the curve (AUC) values in ROC analysis for the diagnosis with AVI/API were 0.745/0.819, 0.788/0.837, and 0.772/0.825 (95% CI) in males, females, and all subjects, respectively. Setting the threshold values of AVI and API to 21 and 27 resulted in optimal diagnosis performance in the total cohort, whereas the threshold values should be increased to 24 and 29, respectively, in order to improve the accuracy of diagnosis in the female group. The AROC analyses revealed that the threshold values of AVI and API increased markedly with age and pulse pressure (PP), respectively. Conclusions: With appropriate threshold values, AVI and API can be used to perform preliminary screening for individuals with increased arterial stiffness in the general population. On the other hand, the results of the AROC analyses imply that using threshold values adjusted for confounding factors may facilitate the refinement of diagnosis. Given the fact that the study is a cross-sectional one carried out in a single center, future multi-center or follow-up studies are required to further confirm the findings or examine the value of the threshold values for predicting cardiovascular events.

Design, synthesis, and mechanistic study of 2-piperazineone-bearing peptidomimetics as novel HIV capsid modulators.

HIV-1 capsid (CA) is an attractive target for its indispensable roles in the viral life cycle. We report the design, synthesis, and mechanistic study of a novel series of 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking the structure of host factors binding to CA. F-Id-3o was the most potent compound from the synthesized series, with an anti-HIV-1 EC50 value of 6.0 µM. However, this series of compounds showed a preference for HIV-2 inhibitory activity, in which Id-3o revealed an EC50 value of 2.5 µM (anti-HIV-2 potency), an improvement over PF74. Interestingly, F-Id-3o did bind HIV-1 CA monomers and hexamers with comparable affinity, unlike PF74, consequently showing antiviral activity in the early and late stages of the HIV-1 lifecycle. Molecular dynamics simulations shed light on F-Id-3o and Id-3o binding modes within the HIV-1/2 CA protein and provide a possible explanation for the increased anti-HIV-2 potency. Metabolic stability assays in human plasma and human liver microsomes indicated that although F-Id-3o has enhanced metabolic stability over PF74, further optimization is necessary. Moreover, we utilized computational prediction of drug-like properties and metabolic stability of F-Id-3o and PF74, which correlated well with experimentally derived metabolic stability, providing an efficient computational pipeline for future preselection based on metabolic stability prediction. Overall, the 2-piperazineone-bearing peptidomimetics are a promising new chemotype in the CA modulators class with considerable optimization potential.

Improved stability and activity of laccase through de novo and post-synthesis immobilization on a hierarchically porous metal-organic framework (ZIF-8).

Porous materials such as metal-organic frameworks (MOFs) are considered to be suitable materials for immobilizing enzymes to improve their stability. However, conventional MOFs reduce the enzymes' catalytic activity due to difficulties with mass transfer and diffusing reactants after their micropores are occupied by enzyme molecules. To address these issues, a novel hierarchically structured zeolitic imidazolate framework-8 (HZIF-8) was prepared to study the effects of different laccase immobilization approaches such as the post-synthesis (LAC@HZIF-8-P) and de novo (LAC@HZIF-8-D) immobilization of catalytic activities for removing 2,4-dichlorophenol (2,4-DCP). The results showed higher catalytic activity for the laccase-immobilized LAC@HZIF-8 prepared using different methods than for the LAC@MZIF-8 sample, with 80% of 2,4-DCP removed under optimal conditions. These results could be attributable to the multistage structure of HZIF-8. The LAC@HZIF-8-D sample was stable and superior to LAC@HZIF-8-P, maintaining a 2,4-DCP removal efficiency of 80% after three recycles and demonstrating superior laccase thermostability and storage stability. Moreover, after loading with copper nanoparticles, the LAC@HZIF-8-D approach exhibited a 2,4-DCP removal efficiency of 95%, a promising finding for its potential use in environmental purification.

Combination of canagliflozin and puerarin alleviates the lipotoxicity to diabetic kidney in mice.

Diabetic kidney disease is one of the most serious complications of diabetes. Although diabetic kidney disease can be effectively controlled through strict blood glucose management and corresponding symptomatic treatment, these therapies cannot reduce its incidence in diabetic patients. The sodium-glucose cotransporter 2 (SGLT2) inhibitors and the traditional Chinese herb "Gegen" have been widely used in diabetes-related therapy. However, it remains unclear whether the combined use of these two kinds of medicines contributes to an increased curative effect on diabetic kidney disease. In this study, we examined this issue by evaluating the efficacy of the combination of puerarin, an active ingredient of Gegen, and canagliflozin, an SGLT2 inhibitor for a 12-week intervention using a mouse model of diabetes. The results indicated that the combination of puerarin and canagliflozin was superior to canagliflozin alone in improving the metabolic and renal function parameters of diabetic mice. Our findings suggested that the renoprotective effect of combined puerarin and canagliflozin in diabetic mice was achieved by reducing renal lipid accumulation. This study provides a new strategy for the clinical prevention and treatment of diabetic kidney disease. The puerarin and SGLT2 inhibitor combination therapy at the initial stage of diabetes may effectively delay the occurrence of diabetic kidney injury, and significantly alleviate the burden of renal lipotoxicity.

Computer-aided drug design in seeking viral capsid modulators.

Approved or licensed antiviral drugs have limited applications because of their drug resistance and severe adverse effects. By contrast, by stabilizing or destroying the viral capsid, compounds known as capsid modulators prevent viral replication by acting on new targets and, therefore, overcoming the problem of clinical drug resistance. For example, computer-aided drug design (CADD) methods, using strategies based on structures of biological targets (structure-based drug design; SBDD), such as docking, molecular dynamics (MD) simulations, and virtual screening (VS), have provided opportunities for fast and effective development of viral capsid modulators. In this review, we summarize the application of CADD in the discovery, optimization, and mechanism prediction of capsid-targeting small molecules, providing new insights into antiviral drug discovery modalities.

Comparative study on antibacterial characteristics of the multiple liver expressed antimicrobial peptides (LEAPs) in teleost fish.

Antimicrobial peptides are important components of the host innate immune system, forming the first line of defense against infectious microorganisms. Among them, liver-expressed antimicrobial peptides (LEAPs) are a family of antimicrobial peptides that widely exist in vertebrates. LEAPs include two types, named LEAP-1 and LEAP-2, and many teleost fish have two or more LEAP-2s. In this study, LEAP-2C from rainbow trout and grass carp were discovered, both of which are composed of 3 exons and 2 introns. The antibacterial functions of the multiple LEAPs were systematically compared in rainbow trout and grass carp. The gene expression pattern revealed that rainbow trout and grass carp LEAP-1, LEAP-2A, LEAP-2B and/or LEAP-2C were differentially expressed in various tissues/organs, mainly in liver. After bacterial infection, the expression levels of LEAP-1, LEAP-2A, LEAP-2B and/or LEAP-2C in the liver and gut of rainbow trout and grass carp increased to varying degrees. Moreover, the antibacterial assay and bacterial membrane permeability assay showed that rainbow trout and grass carp LEAP-1, LEAP-2A, LEAP-2B and LEAP-2C all have antibacterial activities against a variety of Gram-positive and Gram-negative bacteria with varying levels through membrane rupture. Furthermore, cell transfection assay showed that only rainbow trout LEAP-1, but not LEAP-2, can lead to the internalization of ferroportin, the only iron exporter on cell surface, indicating that only LEAP-1 possess iron metabolism regulation activity in teleost fish. Taken together, this study systematically compared the antibacterial function of LEAPs in teleost fish and the results suggest that multiple LEAPs can enhance the immunity of teleost fish through different expression patterns and different antibacterial activities to various bacteria.

Preparation of the monoclonal antibody against Nile tilapia Igλ and study on the Igλ+ B cell subset in Nile tilapia.

Immunoglobulins (Igs) are important effector molecules that mediate humoral immunity. A typical Ig consists of two heavy and two light chains. In teleosts, three Ig heavy chain isotypes (Igµ, Igδ and Igτ) and three Ig light chain isotypes (Igκ, Igλ and Igσ) have been identified. Compared to the heavy chains, teleost Ig light chains have been poorly studied due to the lack of antibodies. In this study, a mouse anti-Nile tilapia Igλ monoclonal antibody (mAb) was prepared, which could specifically recognize Igλ in serum and Igλ+ B cells in tissues. Further, the composition of IgM+ and Igλ+ B cell subsets was analyzed using this antibody and a mouse anti-tilapia IgM heavy chain mAb. The ratio of IgM+Igλ+ B cells to total IgM+ B cells in head kidney and peripheral blood was about 30%, while that in spleen was about 50%; the ratio of IgM-Igλ+ B cells to total Igλ+ B cells in head kidney and peripheral blood was about 45%, while that in spleen was about 25%. The IgM-Igλ+ B cells was speculated to be IgT+ B cells. Finally, we detected an increase in the level of specific antibodies against the surface antigen-Sip of Streptococcus agalactiae in serum after S. agalactiae infection, indicating that mouse anti-tilapia Igλ mAb can be used to detect the antibody level after immunization of Nile tilapia, which lays a foundation for the evaluation of immunization effect of tilapia vaccine.

The discovery and design of novel HIV-1 capsid modulators and future perspectives.

INTRODUCTION: Although combination antiretroviral therapy (cART) has achieved significant success in treating HIV, the emergence of multidrug-resistant viruses and cumulative medication toxicity make it necessary to find new classes of antiretroviral agents with novel mechanisms of action. With high sequence conservation, the HIV-1 capsid (CA) protein has attracted attention as a prospective therapeutic target due to its crucial structural and regulatory functions in the HIV-1 replication cycle. AREA COVERED: Herein, the authors provide a cutting-edge overview of current advances in the design and discovery of CA modulators, PF74, GS-6207 and their derivativeswhich targets a therapeutically attractive NTD-CTD interprotomer pocket within the hexameric configuration of HIV-1 CA. The discovery and development of these compounds, and derivatives thereof, have provided valuable information for the design of second-generation CA-targeting antivirals. EXPERT OPINION: Despite some successes in designing and discovering HIV-1 CA modulators, more studies are required to decipher which chemical groups confer specific desirable properties. The future of CA-modulating compounds may lie in covalent inhibition and the creation of proteolysis-targeting chimeras (PROTACs). Moreover, biological interrogation of the process of CA uncoating, virus-host interactions, and studies on the lattice-binding restriction factors may improve our knowledge of HIV-1 CA and support the design of new antiviral agents.

Discovery and Mechanistic Investigation of Piperazinone Phenylalanine Derivatives with Terminal Indole or Benzene Ring as Novel HIV-1 Capsid Modulators.

HIV-1 capsid (CA) performs multiple roles in the viral life cycle and is a promising target for antiviral development. In this work, we describe the design, synthesis, assessment of antiviral activity, and mechanistic investigation of 20 piperazinone phenylalanine derivatives with a terminal indole or benzene ring. Among them, F2-7f exhibited moderate anti-HIV-1 activity with an EC50 value of 5.89 µM, which was slightly weaker than the lead compound PF74 (EC50 = 0.75 µM). Interestingly, several compounds showed a preference for HIV-2 inhibitory activity, represented by 7f with an HIV-2 EC50 value of 4.52 µM and nearly 5-fold increased potency over anti-HIV-1 (EC50 = 21.81 µM), equivalent to PF74 (EC50 = 4.16 µM). Furthermore, F2-7f preferred to bind to the CA hexamer rather than to the monomer, similar to PF74, according to surface plasmon resonance results. Molecular dynamics simulation indicated that F2-7f and PF74 bound at the same site. Additionally, we computationally analyzed the ADMET properties for 7f and F2-7f. Based on this analysis, 7f and F2-7f were predicted to have improved drug-like properties and metabolic stability over PF74, and no toxicities were predicted based on the chemotype of 7f and F2-7f. Finally, the experimental metabolic stability results of F2-7f in human liver microsomes and human plasma moderately correlated with our computational prediction. Our findings show that F2-7f is a promising small molecule targeting the HIV-1 CA protein with considerable development potential.