Barcoded HIV-1 reveals viral persistence driven by clonal proliferation and distinct epigenetic patterns.

The HIV reservoir consists of infected cells in which the HIV-1 genome persists as provirus despite effective antiretroviral therapy (ART). Studies exploring HIV cure therapies often measure intact proviral DNA levels, time to rebound after ART interruption, or ex vivo stimulation assays of latently infected cells. This study utilizes barcoded HIV to analyze the reservoir in humanized mice.

An endoplasmic reticulum and lipid droplets dual-localized strategy to develop small molecular photosensitizers that induce ferroptosis during photodynamic therapy.

Organelle-localized photosensitizers have been well-developed to enhance the photodynamic therapy (PDT) efficacy through triggering given cell death. The endoplasmic reticulum (ER) and lipid droplets (LDs) are two key organelles mutually regulating ferroptosis. Thus, in this study, small molecular photosensitizer CAR PSs were developed through fragment integration strategy and the heavy-atom modification.

Interferon-ε loss is elusive 9p21 link to immune-cold tumors, resistant to immune-checkpoint therapy and endogenous CXCL9/10 induction.

Introduction: Copy-number (CN) loss of chromosome 9p, or parts thereof, impair immune response and confer ICT resistance by direct elimination of immune-regulatory genes on this arm, notably IFNγ genes at 9p24.1, and type-I interferon (IFN-I) genes at 9p21.3.

Hyper-Interferon Sensitive Influenza Induces Adaptive Immune Responses and Overcomes Resistance to Anti-PD-1 in Murine Non-Small Cell Lung Cancer.

Despite recent advances in immunotherapy with immune checkpoint inhibitors, many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment and augment antitumor T-cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, hyper-IFN-sensitive (HIS) virus, by conducting a genome-wide functional screening and introducing eight IFN-sensitive mutations in the influenza genome to enhance host IFN response.

Design and synthesis of 7-membered lactam fused hydroxypyridinones as potent metal binding pharmacophores (MBPs) for inhibiting influenza virus PA endonuclease.

Since influenza virus RNA polymerase subunit PA is a dinuclear Mn dependent endonuclease, metal-binding pharmacophores (MBPs) with Mn coordination has been elucidated as a promising strategy to develop PA inhibitors for influenza treatment. However, few attentions have been paid to the relationship between the optimal arrangement of the donor atoms in MBPs and anti-influenza A virus (IAV) efficacy. Given that, the privileged hydroxypyridinones fusing a seven-membered lactam ring with diverse side chains, chiral centers or cyclic systems were designed and synthesized.

Deep mutational scanning of influenza A virus neuraminidase facilitates the identification of drug resistance mutations .

NA is a crucial surface antigen and drug target of influenza A virus. A comprehensive understanding of NA's mutational effect and drug resistance profiles is essential for comprehending the evolutionary constraints and making informed choices regarding drug selection to combat resistance in clinical settings. In the current study, we established an efficient deep mutational screening system in mouse lung tissues and systematically evaluated the fitness effect and drug resistance to three neuraminidase inhibitors of NA single-nucleotide mutations.

CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity.

Background: Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation.

Structural characterization of an isocytosine-specific deaminase VCZ reveals its application potential in the anti-cancer therapy.

Non-natural nucleobase isocytosine (IC) is the isomer of cytosine; its chemical derivate 5-fluoroisocytosine (5-FIC) together with the isocytosine-specific deaminase (ICD) VCZ was suggested to be potential practical enzyme/prodrug pair for cancer therapy through gene-directed enzyme-prodrug therapy (GDEPT) method. In this study, we have determined the crystal structures of apo-VCZ and its complex with 5-FU. We identified the critical residues for substrate binding and catalytic reaction.

Martynoside rescues 5-fluorouracil-impaired ribosome biogenesis by stabilizing RPL27A.

Martynoside (MAR), a bioactive component in several well-known tonic traditional Chinese herbs, exhibits pro-hematopoietic activity during 5-fluorouracil (5-FU) treatment. However, the molecular target and the mechanism of MAR are poorly understood. Here, by adopting the mRNA display with a library of even-distribution (md-LED) method, we systematically examined MAR-protein interactions in vitro and identified the ribosomal protein L27a (RPL27A) as a key cellular target of MAR.

Synthesis and structure-activity optimization of 7-azaindoles containing aza-β-amino acids targeting the influenza PB2 subunit.

The PB2 subunit of influenza virus polymerase has been demonstrated as a promising drug target for anti-influenza therapy. In this work, 7-azaindoles containing aza-β- or β -amino acids were synthesized possessing a good binding affinity of PB2. The aza-β-amino acid moieties with diverse size, shape, steric hindrance and configuration were investigated.

Approaches for discovery of small-molecular antivirals targeting to influenza A virus PB2 subunit.

Influenza is an acute respiratory infectious disease caused by influenza virus, leading to huge morbidity and mortality in humans worldwide. Despite the availability of antivirals in the clinic, the emergence of resistant strains calls for antivirals with novel mechanisms of action. The PB2 subunit of the influenza A virus polymerase is a promising target because of its vital role in the 'cap-snatching' mechanism.

Latency reversal plus natural killer cells diminish HIV reservoir in vivo.

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1.

Influence Mechanism on Supplier Emission Reduction Based on a Two-Level Supply Chain.

The purpose of this paper is to investigate environmental performance of a supply chain which consists of an upstream supplier and a downstream firm. A mathematical model considering both downstream firm's monitoring and governmental intervention is developed. Afterwards, a numerical example is presented to show the equilibriums of these models and the optimal choices of firms and government.

On-demand nanozyme signal enhancement at the push of a button for the improved detection of SARS-CoV-2 nucleocapsid protein in serum.

We developed an innovative 3D printed casing that incorporates a lateral-flow immunoassay, dehydrated signal enhancement reagents, and a sealed buffer chamber. With only the push of a button for signal enhancement, our device detected the SARS-CoV-2 N-protein in 40 min at concentrations as low as 0.1 ng mL in undiluted serum.

Riok3 inhibits the antiviral immune response by facilitating TRIM40-mediated RIG-I and MDA5 degradation.

The type I interferon (IFN) pathway is a key component of innate immune response upon invasion of foreign pathogens. It is also under precise control to prevent excessive upregulation and undesired inflammation cascade. In the present study, we report that Riok3, an atypical kinase, negatively regulates retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) sensing-induced type I IFN signaling.

Quantifying the Evolutionary Constraints and Potential of Hepatitis C Virus NS5A Protein.

RNA viruses, such as hepatitis C virus (HCV), influenza virus, and SARS-CoV-2, are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes, especially under different selection conditions.

Ex vivo and in vivo chemoprotective activity and potential mechanism of Martynoside against 5-fluorouracil-induced bone marrow cytotoxicity.

Martynoside (MAR) is a bioactive glycoside of Rehmannia glutinosa, a traditional Chinese herb frequently prescribed for treating chemotherapy-induced pancytopenia. Despite its clinical usage in China for thousands of years, the mechanism of MAR's hematopoietic activity and its impact on chemotherapy-induced antitumor activity are still unclear. Here, we showed that MAR protected ex vivo bone marrow cells from 5-fluorouracil (5-FU)-induced cell death and inflammation response by down-regulating the TNF signaling pathway, in which II1b was the most regulatory gene.

Tracking HIV Rebound following Latency Reversal Using Barcoded HIV.

HIV latency prevents cure of infection with antiretroviral therapy (ART) alone. One strategy for eliminating latently infected cells involves the induction of viral protein expression via latency-reversing agents (LRAs), allowing killing of host cells by viral cytopathic effects or immune effector mechanisms. Here, we combine a barcoded HIV approach and a humanized mouse model to study the effects of a designed, synthetic protein kinase C modulating LRA on HIV rebound.

Emerging roles of N6-methyladenosine (mA) modification in breast cancer.

N6-Methyladenosine (mA) is the most abundant, dynamic, and reversible epigenetic RNA modification that is found in coding and non-coding RNAs. Emerging studies have shown that mA and its regulators affect multiple steps in RNA metabolism and play broad roles in various cancers. Worldwide, breast cancer is the most prevalent cancer in female.

Predominance of positive epistasis among drug resistance-associated mutations in HIV-1 protease.

Drug-resistant mutations often have deleterious impacts on replication fitness, posing a fitness cost that can only be overcome by compensatory mutations. However, the role of fitness cost in the evolution of drug resistance has often been overlooked in clinical studies or in vitro selection experiments, as these observations only capture the outcome of drug selection. In this study, we systematically profile the fitness landscape of resistance-associated sites in HIV-1 protease using deep mutational scanning.

Clofazimine is a broad-spectrum coronavirus inhibitor that antagonizes SARS-CoV-2 replication in primary human cell culture and hamsters.

COVID-19 pandemic is the third zoonotic coronavirus (CoV) outbreak of the century after severe acute respiratory syndrome (SARS) in 2003 and Middle East respiratory syndrome (MERS) since 2012. Treatment options for CoVs are largely lacking. Here, we show that clofazimine, an anti-leprosy drug with a favorable safety and pharmacokinetics profile, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 replication in multiple systems, including the human embryonic stem cell-derived cardiomyocytes and lung cultures.

Immunotherapy for EBV-Associated Nasopharyngeal Carcinoma.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies in southern China and Southeast Asia. Unfortunately, 70% of NPC patients have locally advanced disease at the first diagnosis. Radiotherapy alone and concurrent chemoradiotherapy are important treatment approaches for NPC, but they have a limited effect on patients with locally advanced or distantly metastatic disease.

High-Throughput Fitness Profiling of Zika Virus E Protein Reveals Different Roles for Glycosylation during Infection of Mammalian and Mosquito Cells.

Zika virus (ZIKV) infection causes Guillain-Barré syndrome and severe birth defects. ZIKV envelope (E) protein is the major viral protein involved in cell receptor binding and entry and is therefore considered one of the major determinants in ZIKV pathogenesis. Here we report a gene-wide mapping of functional residues of ZIKV E protein using a mutant library, with changes covering every nucleotide position.