First Discovery of Novel Cytosine Derivatives Containing a Sulfonamide Moiety as Potential Antiviral Agents

A series of cytosine derivatives containing a sulfonamide moiety were designed and synthesized, and their antiviral activities against pepper mild mottle virus (PMMoV) were systematically evaluated. Then, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed to study the structure-activity relationship according to the pEC50 of the compounds’ protective activities. Next, compound A32 with preferable antiviral activity on PMMoV was obtained based on the CoMSIA and CoMFA models, with an EC50 of 19.5 μg/mL, which was superior to the template molecule A25 (21.3 μg/mL) and ningnanmycin (214.0 μg/mL). In addition, further studies showed that the antiviral activity of compound A32 against PMMoV was in accord with the up-regulation of proteins expressed in the defense response and carbon fixation in photosynthetic organisms. These results indicated that cytosine derivatives containing a sulfonamide moiety could be used as novel potential antiviral agents for further research and development

Novel Cinnamic Acid Derivatives Containing the 1,3,4-Oxadiazole Moiety: Design, Synthesis, Antibacterial Activities, and Mechanisms

There is a lack of effective antibacterial agents against rice bacterial leaf streak and leaf blight. Cinnamic acid derivatives containing the 1,3,4-oxadiazole moiety were synthesized, and their antibacterial activities against Xanthomonas oryzae pv. oryzicola (Xoc) and X. oryzae pv. oryzae (Xoo) were evaluated. Based on the three-dimensional quantitative structure–activity relationship (3D-QSAR) model, compound 31 with better antibacterial activity against Xoc was designed and synthesized, and the 50% effective concentration (EC50) value was 0.2 mg/L. The curative and protective activities of compound 31 against rice bacterial leaf streak at 100 mg/L were 39.5 and 35.4%, respectively, which were higher than those of thiodiazole copper (28.4 and 20.7%, respectively). The antibacterial activity of compound 31 against rice bacterial leaf streak is closely associated with the activity of related defensive enzymes and the increase in glutathione metabolism

Novel Cinnamic Acid Derivatives Containing the 1,3,4-Oxadiazole Moiety: Design, Synthesis, Antibacterial Activities, and Mechanisms

There is a lack of effective antibacterial agents against rice bacterial leaf streak and leaf blight. Cinnamic acid derivatives containing the 1,3,4-oxadiazole moiety were synthesized, and their antibacterial activities against Xanthomonas oryzae pv. oryzicola (Xoc) and X. oryzae pv. oryzae (Xoo) were evaluated. Based on the three-dimensional quantitative structure–activity relationship (3D-QSAR) model, compound 31 with better antibacterial activity against Xoc was designed and synthesized, and the 50% effective concentration (EC50) value was 0.2 mg/L. The curative and protective activities of compound 31 against rice bacterial leaf streak at 100 mg/L were 39.5 and 35.4%, respectively, which were higher than those of thiodiazole copper (28.4 and 20.7%, respectively). The antibacterial activity of compound 31 against rice bacterial leaf streak is closely associated with the activity of related defensive enzymes and the increase in glutathione metabolism

First Discovery of Novel Cytosine Derivatives Containing a Sulfonamide Moiety as Potential Antiviral Agents

A series of cytosine derivatives containing a sulfonamide moiety were designed and synthesized, and their antiviral activities against pepper mild mottle virus (PMMoV) were systematically evaluated. Then, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed to study the structure-activity relationship according to the pEC50 of the compounds’ protective activities. Next, compound A32 with preferable antiviral activity on PMMoV was obtained based on the CoMSIA and CoMFA models, with an EC50 of 19.5 μg/mL, which was superior to the template molecule A25 (21.3 μg/mL) and ningnanmycin (214.0 μg/mL). In addition, further studies showed that the antiviral activity of compound A32 against PMMoV was in accord with the up-regulation of proteins expressed in the defense response and carbon fixation in photosynthetic organisms. These results indicated that cytosine derivatives containing a sulfonamide moiety could be used as novel potential antiviral agents for further research and development

Covalent Organic Framework Nanocages with Enhanced Carrier Utilization and Cavitation Effect for Cancer Sonodynamic Therapy

Ultrasound (US)-triggered sonodynamic therapy (SDT) is an emerging method for treating cancer due to its non-invasive nature and high-depth tissue penetration ability. However, current sonosensitizers commonly have unsatisfactory quantum yields of free radicals. In this work, we have developed unique organic semiconductor π-conjugated covalent organic framework nanocages (COFNs) as highly efficient sonosensitizers to boost free radical (1O2 and •OH) production and cancer therapy. With the hollow and porous structure and band transport behavior, COFNs displayed remarkably improved SDT performance through enhanced electron utilization and cavitation effect, with a 1.8-fold increase in US pressure and a 64.8% increase in 1O2 production relative to the core–shell-structured COF under US irradiation. The in vitro and in vivo experimental results verified the elevated SDT performance, showing a high tumor suppression of 91.4% against refractory breast cancer in mice. This work provides a promising strategy to develop high-performance sonosensitizers for cancer therapy

An atlas of immune cell exhaustion in HIV-infected individuals revealed by single-cell transcriptomics

Chronic infection with human immunodeficiency virus (HIV) can cause progressive loss of immune cell function, or exhaustion, which impairs control of virus replication. However, little is known about the development and maintenance, as well as heterogeneity of immune cell exhaustion. Here, we investigated the effects of HIV infection on immune cell exhaustion at the transcriptomic level by analyzing single-cell RNA sequencing of peripheral blood mononuclear cells from four healthy subjects (37,847 cells) and six HIV-infected donors (28,610 cells). We identified nine immune cell clusters and eight T cell subclusters, and three of these (exhausted CD4+ and CD8+ T cells and interferon-responsive CD8+ T cells) were detected only in samples from HIV-infected donors. An inhibitory receptor KLRG1 was identified in a HIV-1 specific exhausted CD8+ T cell population expressing KLRG1, TIGIT, and T-betdimEomeshi markers. Ex-vivo antibody blockade of KLRG1 restored the function of HIV-specific exhausted CD8+ T cells demonstrating the contribution of KLRG1+ population to T cell exhaustion and providing an immunotherapy target to treat HIV chronic infection. These data provide a comprehensive analysis of gene signatures associated with immune cell exhaustion during HIV infection, which could be useful in understanding exhaustion mechanisms and developing new cure therapies.</p

Synthesis, Antiviral Activity, and Mechanisms of Purine Nucleoside Derivatives Containing a Sulfonamide Moiety

Novel purine nucleoside derivatives containing a sulfonamide moiety were prepared, as well as their antiviral activities against potato virus Y (PVY), cucumber mosaic virus (CMV), and tobacco mosaic virus (TMV) were evaluated. The antiviral mechanisms of the compounds were investigated. Results showed that most of the compounds had good antiviral activities. Compound 5 at 500 μg/mL exhibited excellent curative and protective activities of 52.5% and 60.0% and of 52.0% and 60.2% for PVY and CMV, respectively, which are higher than those of ningnanmycin (48.1%, 49.6%; 45.3%, 47.7%), ribavirin (38.3%, 48.2%; 40.8%, 45.5%), and chitosan oligosaccharide (32.5%, 33.8%; 35.1%, 34.6%). Moreover, compound 5 displayed good inactivating activity against TMV, with an EC50 value of 48.8 μg/mL, which is better than that of ningnanmycin (84.7 μg/mL), ribavirin (150.4 μg/mL), and chitosan oligosaccharide (521.3 μg/mL). The excellent antiviral activity of compound 5 is related to its immune induction effect which can regulate the physiological and biochemical processes in plants, including defense-related enzyme activities, defense-related genes, and photosynthesis-related proteins. These results indicate that purine nucleoside derivatives containing a sulfonamide moiety are worthy of further research and development as new antiviral agents

Piezotronic Effect-Augmented Cu_2–<i>x</i>O–BaTiO₃ Sonosensitizers for Multifunctional Cancer Dynamic Therapy

Ultrasound (US)-triggered sonodynamic therapy (SDT) based on semiconductor nanomaterials has attracted considerable attention for cancer therapy. However, most inorganic sonosensitizers suffer from low efficiency due to the rapid recombination of electron–hole pairs. Herein, the Cu2–xO–BaTiO3 piezoelectric heterostructure was fabricated as a sonosensitizer and chemodynamic agent, simultaneously, for improving reactive oxygen species (ROS) generation and cancer therapeutic outcome. Under US irradiation, the Cu2–xO–BaTiO3 heterojunction with a piezotronic effect exhibits high-performance singlet oxygen (1O2) and hydroxyl radical (•OH) generation to enhance SDT. Moreover, it possesses Fenton-like reaction activity to convert endogenous H2O2 into •OH for chemodynamic therapy (CDT). The integration of SDT and CDT substantially boosts ROS generation and cellular mitochondria damage, and the in vitro and in vivo results demonstrate high cytotoxicity and tumor inhibition on murine refractory breast cancer. This work realizes improvement in cancer therapy using piezoelectric heterostructures with piezotronic effects

Machine Learning Approaches-Driven for Mortality Prediction for Patients Undergoing Craniotomy in ICU

We aimed to predict the mortality of patients with craniotomy in ICU by using predictive models to extract the high-risk factors leading to the death of patients from a retrospective a study. Five machine-learning (ML) algorithms were applied for training on mortality predictive models with the data from a surgical intensive care unit (ICU) database of the Fujian Provincial Hospital in China. The accuracy, precision, recall, f1 score and the area under the receiver operator characteristic curve (AUC) were used to evaluate the performance of different models, and the calibration of the model was evaluated by brier score. We demonstrated that eXtreme Gradient Boosting (XGBoost) was more suitable for the task, demonstrating a AUC of 0.84. We analyzed the feature importance with the Local Interpretable Model-agnostic Explanations (LIME) analysis and further identified the high-risk factors of mortality in ICU through this study. This study established the mortality predictive model of patients who had undergone craniotomy in ICU. Identification of the factors that had great influence on mortality has the potential to provide auxiliary decision support for clinical medical staff on their practices.</p