In-depth understanding of transport behavior of sulfided nano zerovalent iron/reduced graphene oxide@guar gum slurry: Stability and mobility.

Nanoscale zero-valent iron (NZVI), which has the advantages of small particle size, large specific surface area, and high reactivity, is often injected into contaminated aquifers in the form of slurry. However, the prone to passivation and agglomeration as well as poor stability and mobility of NZVI limit the further application of this technology in fields. Therefore, sulfided NZVI loaded on reduced graphene oxide (S-NZVI/rGO) and guar gum (GG) with shear-thinning properties as stabilizers were used to synthesize S-NZVI/rGO@GG slurries. SEM, TEM, and FT-IR confirmed that the dispersion and anti-passivation of NZVI were optimized in the coupled system. The stability and mobility of the slurry were improved by increasing the GG concentration, enhancing the pH, and decreasing the ionic strength and the presence of Ca2+ ions, respectively. A modified advection-dispersion equation (ADE) was used to simulate the transport experiments considering the strain and physicochemical deposition/release. Meanwhile, colloidal filtration theory (CFT) demonstrated that Brownian motion plays a dominant role in the migration of S-NZVI/rGO@GG slurry, and the maximum migration distance can be increased by appropriately increasing the injection rate. Extended-Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory showed that the excellent stability and migration of S-NZVI/rGO@GG slurry mainly came from the GG spatial forces. This study has important implications for the field injection of S-NZVI/rGO@GG slurry. According to the injection parameters, the injection range of S-NZVI/rGO@GG slurry is effectively controlled, which lays the foundation for the promotion of application in actual fields.

Structural Basis of HIV-1 gp41 N-trimer for Designing Bifunctional Peptide-based Fusion Inhibitors.

BACKGROUND: Pathogenic viruses that cause large-scale global or regional outbreaks almost always contain class I fusion proteins. Although the viruses differ in morphology, they all require fusion protein-mediated virus-host cell membranes during the early stages of host cell invasion. METHOD: The CHR region and NHR region of fusion proteins can form the 6-HB structure to drive the fusion pore formation between viruses and host cells through metastable interactions. Here, we obtained bifunctional N-peptides with inhibitory activities against two viruses, HIV-1 and MERS-CoV, based on the sequences in the HIV-1 NHR region by constructing N-trimer conformation interacting with the CHR region. RESULT: This study demonstrates that N-peptides with the coiled triple helix structure obtained from the NHR region in 6-HB are able to target the CHR region and exhibit inhibitory activity against a variety of viruses. CONCLUSION: Moreover, this strategy can be used to investigate antivirals against unknown viruses for future outbreaks.

Research Strategy for Short-Peptide Fusion Inhibitors Based on 6-HB Core Structure against HIV-1: A Review.

Acquired Immune Deficiency Syndrome (AIDS) is a devastating infectious disease caused by the Human Immunodeficiency Virus type 1 (HIV-1). Enfuvirtide(T20) is the first HIV-1 fusion inhibitor for marketing, which plays an important role in AIDS treatment. However, in the clinical application process, T20 has several drawbacks, such as a high level of development of drug resistance, a short half-life in vivo, and rapid renal clearance, which severely limits the clinical application. Therefore, the development of novel fusion inhibitors to address T20 shortcomings has long been the research hotspot. Short peptides have a long half-life through modification and a high barrier to drug resistance, which is expected to solve the current fusion inhibitors dilemma. In this paper, we summarized six emerging R&D strategies for short peptide-based fusion inhibitors against HIV-1. We hope that this review will provide fresh insights into the development of novel fusion inhibitors, as well as ideas for other viral fusion inhibitor discoveries based on the common membrane fusion 6-HB core structure.

Fragment-based Drug Discovery Strategy and its Application to the Design of SARS-CoV-2 Main Protease Inhibitor.

Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) emerged at the end of 2019, causing a highly infectious and pathogenic disease known as 2019 coronavirus disease. This disease poses a serious threat to human health and public safety. The SARS-CoV-2 main protease (Mpro) is a highly sought-after target for developing drugs against COVID-19 due to its exceptional specificity. Its crystal structure has been extensively documented. Numerous strategies have been employed in the investigation of Mpro inhibitors. This paper is primarily concerned with Fragment-based Drug Discovery (FBDD), which has emerged as an effective approach to drug design in recent times. Here, we summarize the research on the approach of FBDD and its application in developing inhibitors for SARS-CoV-2 Mpro.

Optimizing drug combination and mechanism analysis based on risk pathway crosstalk in pan cancer.

Combination therapy can greatly improve the efficacy of cancer treatment, so identifying the most effective drug combination and interaction can accelerate the development of combination therapy. Here we developed a computational network biological approach to identify the effective drug which inhibition risk pathway crosstalk of cancer, and then filtrated and optimized the drug combination for cancer treatment. We integrated high-throughput data concerning pan-cancer and drugs to construct miRNA-mediated crosstalk networks among cancer pathways and further construct networks for therapeutic drug. Screening by drug combination method, we obtained 687 optimized drug combinations of 83 first-line anticancer drugs in pan-cancer. Next, we analyzed drug combination mechanism, and confirmed that the targets of cancer-specific crosstalk network in drug combination were closely related to cancer prognosis by survival analysis. Finally, we save all the results to a webpage for query ( http://bio-bigdata.hrbmu.edu.cn/oDrugCP/ ). In conclusion, our study provided an effective method for screening precise drug combinations for various cancer treatments, which may have important scientific significance and clinical application value for tumor treatment.

Synthesis, anti-inflammatory activity, and conformational relationship studies of chromone derivatives incorporating amide groups.

Inflammation is the initial biological reaction of the immune system to various stimuli such as infection, injury, or irritation. Extensive research has demonstrated that a growing array of diseases are triggered by inflammatory mechanisms. Currently, anti-inflammatory drugs are widely utilized in clinical practice due to their therapeutic advantages; however, the potential side effects cannot be ignored by us. In our work, a series of amide compounds with chromones as the parent nucleus were designed and synthesized using the principle of colligated drug design. The results of the biological evaluation indicated that four compounds exhibited lower EC50 values compared to the positive drug ibuprofen. Notably, compound 5-9 showed optimal inhibitory activity (EC50 = 5.33 ± 0.57 µM) against the production of nitric oxide (NO) induced by lipopolysaccharide (LPS) in RAW264.7 cells. Structure-activity relationships (SAR) showed that the presence of electron-withdrawing groups at positions 5 and 8, or electron-donating groups at positions 6 and 7 of the parent nucleus of the chromones can enhance the anti-inflammatory activity of the chromones. The molecular docking studies predicted the mode of interaction between the compounds and protein. Additionally, these studies have demonstrated that the amide bond is the key radical to the anti-inflammatory effect. Based on the summary of the aforementioned studies, it can be inferred that compound 5-9 exhibit potential as an anti-inflammatory drug that deserves further investigation.

Structure and Function of the SARS-CoV-2 6-HB Fusion Core and Peptide-Based Fusion Inhibitors: A Review.

SARS-CoV-2 has swept the world in recent years, triggering a global COVID-19 with a tremendous impact on human health and public safety. Similar to other coronaviruses, the six-helix bundle(6-HB) is not only a core structure driving the fusion of the SARS-CoV-2 envelope with the host cell membrane, but also the target of fusion inhibitors. The sequences from the HR1 or HR2 regions composing 6-HB are thus the original primary structures for the development of peptide-based fusion inhibitors. This review summarized the structure-activity relationship of the SARS-CoV-2 6- HB, analyzed the design methods and functional characteristics of peptide-based fusion inhibitors that contain different regions of HRs, and provided an outlook on the cutting- edge approaches for optimal modification of lead compounds (pan-coronavirization, chemical modification, superhelical construction, etc). We hope that this review will provide researchers with a comprehensive understanding of the state-of-art research progress on both 6-HB and peptide-based fusion inhibitors of SARS-CoV-2, and provide some new insights for the development of antiviral drugs.

QingXiaoWuWei decoction alleviates methicillin-resistant Staphylococcus aureus-induced pneumonia in mice by regulating metabolic remodeling and macrophage gene expression network via the microbiota-short-chain fatty acids axis.

IMPORTANCE: Methicillin-resistant Staphylococcus aureus (MRSA) colonizes the upper respiratory airways and is resistant to antibiotics. MRSA is a frequently acquired infection in hospital and community settings, including cases of MRSA-induced pneumonia. Multidrug-resistant Staphylococcus aureus and the limited efficacy of antibiotics necessitate alternative strategies for preventing or treating the infection. QingXiaoWuWei decoction (QXWWD) protects against both gut microbiota dysbiosis and MRSA-induced pneumonia. Furthermore, the QXWWD-regulated metabolic remodeling and macrophage gene expression network contribute to its protective effects through the microbiota-short-chain fatty acid axis. The results of this study suggest that QXWWD and its pharmacodynamic compounds might have the potential to prevent and treat pulmonary infections, especially those caused by multidrug-resistant organisms. Our study provides a theoretical basis for the future treatment of pulmonary infectious diseases by manipulating gut microbiota and their metabolites via traditional Chinese medicine.

Multiscale integrative analyses unveil immune-related diagnostic signature for the progression of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease prevalent worldwide, with an increasing incidence associated with obesity, diabetes, and metabolic syndrome. The progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) poses a pressing health concern, highlighting the significance of accurately identifying MASLD and its progression to MASH as a primary challenge in the field. In this study, a systematic integration of 66 immune cell types was conducted. Comprehensive analyses were performed on bulk, single-cell RNA-Seq, and clinical data to investigate the immune cell types implicated in MASLD progression thoroughly. Multiple approaches, including immune infiltration, gene expression trend analysis, weighted gene coexpression network analysis, and 4 machine learning algorithms, were used to examine the dynamic changes in genes and immune cells during MASLD progression. C-X-C motif chemokine receptor 4 and dedicator of cytokinesis 8 have been identified as potential diagnostic biomarkers for MASLD progression. Furthermore, cell communication analysis at the single-cell level revealed that the involvement of C-X-C motif chemokine receptor 4 and dedicator of cytokinesis 8 in MASLD progression is mediated through their influence on T cells. Overall, our study identified vital immune cells and a 2-gene diagnostic signature for the progression of MASLD, providing a new perspective on the diagnosis and immune-related molecular mechanisms of MASLD. These findings have important implications for developing innovative diagnostic tools and therapies for MASLD.

Small molecule inhibitors against the bacterial pathogen Brucella.

Brucellosis remains one of the major zoonotic diseases worldwide. As a causative agent of brucellosis, it has many ways to evade recognition by the immune system, allowing it to replicate and multiply in the host, causing significant harm to both humans and animals. The pathogenic mechanism of Brucella has not been elucidated, making the identification of drug targets from the pathogenic mechanism a challenge. Metalloenzymatic targets and some protein targets unique to Brucella are exploitable in the development of inhibitors against this disease. The development of specific small molecule inhibitors is urgently needed for brucellosis treatment due to the antibiotic resistance of Brucella. This review summarizes the research on small molecule inhibitors of Brucella, which could be instructive for subsequent studies.

Highly Stable, Mechanically Enhanced, and Easy-to-Collect Sodium Alginate/NZVI-rGO Gel Beads for Efficient Removal of Cr(VI).

Nanoscale zero-valent iron (NZVI) is a material that is extensively applied for water pollution treatment, but its poor dispersibility, easy oxidation, and inconvenient collection limit its application. To overcome these drawbacks and limit secondary contamination of nanomaterials, we confine NZVI supported by reduced graphene oxide (rGO) in the scaffold of sodium alginate (SA) gel beads (SA/NZVI-rGO). Scanning electron microscopy showed that the NZVI was uniformly dispersed in the gel beads. Fourier transform infrared spectroscopy demonstrated that the hydrogen bonding and conjugation between SA and rGO allowed the NZVI-rGO to be successfully embedded in SA. Furthermore, the mechanical strength, swelling resistance, and Cr(VI) removal capacity of SA/NZVI-rGO were enhanced by optimizing the ratio of NZVI and rGO. Interestingly, cation exchange may drive Cr(VI) removal above 82% over a wide pH range. In the complex environment of actual Cr(VI) wastewater, Cr(VI) removal efficiency still reached 70.25%. Pseudo-first-order kinetics and Langmuir adsorption isotherm are preferred to explain the removal process. The mechanism of Cr(VI) removal by SA/NZVI-rGO is dominated by reduction and adsorption. The sustainable removal of Cr(VI) by packed columns could be well fitted by the Thomas, Adams-Bohart, and Yoon-Nelson models, and importantly, the gel beads maintained integrity during the prolonged removal. These results will contribute significant insights into the practical application of SA/NZVI-rGO beads for the Cr(VI) removal in aqueous environments.

Emerging insights into ethnic-specific TP53 germline variants.

The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge because they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations on the basis of our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations and their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools, are now rapidly improving our understanding of the cancer susceptibility spectrum, leading toward more accurate and personalized cancer risk assessments.

VISTA as a ligand downregulates LPS-mediated inflammation in macrophages and neutrophils.

VISTA has been proposed to function both as a ligand and a receptor to dampen immune responses, although the role of VISTA as a ligand on myeloid cells has been largely ignored. We observed that a VISTA receptor is rapidly expressed on the surface of macrophages and neutrophils upon exposure to lipopolysaccharides (LPS). Importantly, treating LPS-stimulated macrophages and neutrophils ex vivo with a high-avidity agonist of the VISTA receptor (VISTA.COMP) results in the downregulation of pro-inflammatory cytokines and the increased expression of immunoregulatory genes. Finally, the in vivo administration of VISTA.COMP attenuated the rise in circulating TNFα, IL-6, and IL-12p40 in LPS-treated mice.

Establishment of fingerprint and mechanism of anti-myocardial ischemic effect of Syringa pinnatifolia.

This study established the fingerprint of Syringa pinnatifolia Hemsl. (SP), analyzed the SP ingredients absorbed into the rats blood, and evaluated its anti-myocardial ischemic effect to provide a scientific basis for the follow-up development and research of SP and lay a foundation for its clinical application using ultra-performance liquid chromatography-Q Exactive-mass spectrometry and GC-MS. Myocardial infarction was induced in rat by ligating the left anterior descending branch of the rat coronary artery, and SP alcohol extract was administered to evaluate its anti-myocardial ischemic effect. We analyzed the SP ingredients absorbed into the rats blood, screened the active compounds, established a database of SP anti-myocardial ischemic targets, and explored the possible mechanism of SP in treating myocardial infarction using bioinformatics. The rats were examined using echocardiography, serum biomarkers were determined, and pathological changes were observed by histopathological examination. TUNEL staining was performed to detect the apoptotic level of cells, and Western blot and quantitative real-time polymerase chain reaction were performed to detect the expression levels of Bcl-2, Bax, and Caspase-3 in heart tissues. In the fingerprint of SP, 24 common peaks were established, and the similarity evaluation results of 10 batches of SP were all >0.9. Ultra-performance liquid chromatography-Q Exactive-mass spectrometry and GC-MS detected 17 active ingredients in the drug-containing serum, including terpenoids, flavonoids, phenols, phenylpropanoids, and phenolic acids, the most abundant of which was resveratrol. Enrichment analysis of SP targets against myocardial ischemia revealed that key candidate targets of SP were significantly enriched in multiple pathways associated with apoptosis. Resveratrol was administered to the successfully modeled rats, and the results showed that the resveratrol group significantly decreased left ventricular end-diastolic diameter and left ventricular end-systolic diameter and significantly increased ejection fraction and fractional shortening in all groups compared with the model group. Resveratrol significantly decreased the levels of creatine kinase isoenzyme and lactate dehydrogenase in serum compared to the model group (P < 0.001). Hematoxylin-eosin staining of rat myocardial tissue showed that all lesions were reduced under microscopic observation in the resveratrol group compared with the model group. Real-time polymerase chain reaction and Western blot results showed that the resveratrol group downregulated the expression of the proapoptotic factor Bax, upregulated the expression of the antiapoptotic factor Bcl-2, and decreased the expression of Caspase-3. The established fingerprints are accurate, reliable, and reproducible and can be used as an effective method for quality control of the herbs. The anti-myocardial ischemia effect of SP is that resveratrol improves cardiac function and inhibits cardiomyocyte apoptosis to protect cardiomyocytes. The present study provides ample evidence for the clinical use of SP, suggesting that this drug has great potential in the treatment of ischemic heart disease.

A Bioinformatics Study of Immune Infiltration-Associated Genes in Sciatica.

Sciatica has been widely studied, but the association of sciatica with immune infiltration has not been studied. We aimed to screen key genes and to further investigate the impact of immune infiltration in patients with sciatica. The bioinformatics analyzes were performed based on the GSE150408 dataset. Subsequently, we used CIBERSORT to study the immune infiltration in the disease group. Results showed that 13 genes were with differentially expressions in the sciatica group compared to healthy participants, including 8 up-regulated and 5 down-regulated genes. Through the LASSO model and SVM-RFE analysis, a total of 6 genes have intersections, namely SLED1, CHRNB3, BEGAIN, SPTBN2, HRASLS2, and OSR2. The ROC curve area also confirmed the reliability of this method. CIBERPORT analysis showed that T cell gamma delta infiltration decreased and neutrophil infiltration increased in the disease group. Then the association of these six key genes with immune infiltration was further verified. We found six overlapping genes and found that they were closely associated with the total immune infiltration in the sciatic nerve disease group. These findings may provide new ideas for the diagnosis and therapeutics of patients with sciatica.

Photoelectrochemical detection of microRNAs based on target-triggered self-assembly of energy band position-matched CdS QDs and C3N4 nanosheets.

An ultrasensitive photochemical biosensor based on the target miRNA-triggered catalytic hairpin assembly (CHA) reaction between Au nanoparticles (AuNPs)/C3N4 nanosheets and CdS quantum dots (QDs) was developed for the determination of miRNAs. Firstly, AuNPs/C3N4 nanosheets were immobilized onto a working glassy carbon electrode. Then, the hairpin probe 1 (H1) was loaded through Au-S bonding. Afterward, the unbound sites were blocked with 6-mercaptohexanol to avoid nonspecific adsorption. In the presence of the target miRNA, the CHA reaction between the H1 and hairpin probe 2-CdS QDs (H2-CdS QDs) could be triggered. As a result, the AuNPs/C3N4 nanosheet and CdS QDs were linked by the double helix structure H1-H2. Unlike the other CHA reactions, H2 used in this work is longer than H1 so that the AuNPs/C3N4 nanosheets could touch the CdS QDs. Given the matched energy band positions between the C3N4 nanosheet and CdS QDs, a strong photocurrent could be obtained after the CHA reaction was triggered by the target miRNA. In addition, p-type C3N4 nanosheets and n-type CdS QDs presented reduction photocurrents and oxidation photocurrents, respectively. Therefore, the photocurrents were vectors in this design that can eliminate the interference of nonspecific adsorption and avoid the generation of false-positive signals. Under the optimal conditions, the limit of detection was 92 aM. The constructed photoelectrochemical biosensor showed good reproducibility and selectivity in the analysis of serum samples, which indicates its great prospects in disease diagnostics and bioanalysis.

Agonistic nanobodies and antibodies to human VISTA.

The V-domain Ig Suppressor of T-cell Activation (VISTA) is an immune checkpoint regulator that suppresses immune responses and is readily expressed on human and murine myeloid cells and T cells. This immunosuppressive pathway can be activated using VISTA agonists. Here, we report the development of murine anti-human VISTA (anti-hVISTA) monoclonal antibodies (mAbs), anti-hVISTA nanobodies (Nbs), and cross-reactive rat anti-murine/human VISTA (anti-hmVISTA) mAbs. All mAbs and Nbs generated bound to VISTA (human and/or murine) with dissociation constants in the sub-nanomolar or low nanomolar range. Competition analysis revealed that the selected Nbs bound the same or a nearby epitope(s) as the human VISTA-specific mAbs. However, the cross-reactive mAbs only partially competed with Nbs for binding to hVISTA. All mAbs and one Nb (hVISTANb7) were able to strongly detect VISTA expression on primary human monocytes. Importantly, the murine anti-hVISTA mAbs 7E12 and 7G5 displayed strong agonistic activity in human peripheral blood mononuclear cell cultures, while Nb7 and rat anti-hmVISTA mAbs 3C3, 7C6, 7C7, and 7G1 also behaved as hVISTA agonists, albeit to a lesser extent. Cross-reactive mAbs 7C7 and 7G1 further displayed agonistic potential in murine splenocyte assays. Importantly, mAb 7G1 significantly reduced inflammation associated with the murine model of imiquimod-induced psoriasis. These agonistic VISTA mAbs may represent therapeutic leads to treat inflammatory disorders.

One-Step Synthesis of Water-Soluble Silver Sulfide Quantum Dots and Their Application to Bioimaging.

This work reports a simple water-phase microwave method for the synthesis of water-soluble red emission Ag2S quantum dots at low temperatures without the need for an anaerobic process. It is worth noting that the prepared water-soluble Ag2S quantum dots enjoy positive water dispersion stability. 3-(4,5)-Dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) results showed that the prepared Ag2S quantum dots had promising biocompatibility and low cytotoxicity. In addition, we further applied the low-toxicity near-infrared Ag2S quantum dots for cell imaging, demonstrating a promising biological probe for cell imaging.

Metabolic and Process Engineering of Clostridium beijerinckii for Butyl Acetate Production in One Step.

n-Butyl acetate is an important food additive commonly produced via concentrated sulfuric acid catalysis or immobilized lipase catalysis of butanol and acetic acid. Compared with chemical methods, an enzymatic approach is more environmentally friendly; however, it incurs a higher cost due to lipase production. In vivo biosynthesis via metabolic engineering offers an alternative to produce n-butyl acetate. This alternative combines substrate production (butanol and acetyl-coenzyme A (acetyl-CoA)), alcohol acyltransferase expression, and esterification reaction in one reactor. The alcohol acyltransferase gene ATF1 from Saccharomyces cerevisiae was introduced into Clostridium beijerinckii NCIMB 8052, enabling it to directly produce n-butyl acetate from glucose without lipase addition. Extractants were compared and adapted to realize glucose fermentation with in situ n-butyl acetate extraction. Finally, 5.57 g/L of butyl acetate was produced from 38.2 g/L of glucose within 48 h, which is 665-fold higher than that reported previously. This demonstrated the potential of such a metabolic approach to produce n-butyl acetate from biomass.

Drug treatment of ankylosing spondylitis and related complications: an overlook review.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by back pain and progressive spinal stiffness. The prevalence of AS is 30 per 10,000 people. The patients often have complications or co-existing diseases, which may affect the choice of drugs and the treatment effects. However, the pathogenesis of AS is still controversial. Inflammation takes a key role in the occurrence and development of AS. Therefore, antiinflammation is crucial in the management of AS. The goals and principles of AS management is to achieve remission, control disease activity and improve the quality of the life of patients. What is more, drug therapy is still a primary part of AS management. Due to the heterogeneity of AS patients, the effect of conventional treatment is limited. There is evidence that multidisciplinary therapy (MDT) is of great value in drug selection and reasonable combination. To conclude and reach a better understanding, we took a brief overlook of the drug treatment of AS and its related complications.