Early family socioeconomic status and asthma-related outcomes in school-aged children: Results from seven birth cohort studies.

OBJECTIVE: To examine the associations between maternal education and household income during early childhood with asthma-related outcomes in children aged 9-12 years in the UK, the Netherlands, Sweden, Australia, the USA and Canada. METHODS: Data on 31 210 children were obtained from 7 prospective birth cohort studies across six countries. Asthma-related outcomes included ever asthma, wheezing/asthma attacks and medication control for asthma. Relative social inequalities were estimated using pooled risk ratios (RRs) adjusted for potential confounders (child age, sex, mother ethnic background and maternal age) for maternal education and household income. The Slope Index of Inequality (SII) was calculated for each cohort to evaluate absolute social inequalities. RESULTS: Ever asthma prevalence ranged from 8.3% (Netherlands) to 29.1% (Australia). Wheezing/asthma attacks prevalence ranged from 3.9% (Quebec) to 16.8% (USA). Pooled RRs for low (vs high) maternal education and low (vs high) household income were: ever asthma (education 1.24, 95% CI 1.13 to 1.37; income 1.28, 95% CI 1.15 to 1.43), wheezing/asthma attacks (education 1.14, 95% CI 0.97 to 1.35; income 1.22, 95% CI 1.03 to 1.44) and asthma with medication control (education 1.16, 95% CI 0.97 to 1.40; income 1.25, 95% CI 1.01 to 1.55). SIIs supported the lower risk for children with more highly educated mothers and those from higher-income households in most cohorts, with few exceptions. CONCLUSIONS: Social inequalities by household income on the risk of ever asthma, wheezing/asthma attacks, and medication control for asthma were evident; the associations were attenuated for maternal education. These findings support the need for prevention policies to address the relatively high risks of respiratory morbidity in children in families with low socioeconomic status.

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Understanding the Effects of Ligand Configuration on Protoporphyrinogen IX Oxidase with Rationally Designed 3-(N-Phenyluracil)but-2-enoates.

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is a promising target for green herbicide discovery. However, the ligand configuration effects on PPO activity were still poorly understood. Herein, we designed 3-(N-phenyluracil)but-2-enoates using our previously developed active fragments exchange and link (AFEL) approach and synthesized a series of novel compounds with nanomolar ranges of Nicotiana tabacum PPO (NtPPO) inhibitory potency and promising herbicidal potency. Our systematic structure-activity relationship investigations showed that the E isomers of 3-(N-phenyluracil)but-2-enoates displayed improved bioactivity than their corresponding Z isomers. Using molecular simulation studies, we found that the E isomers showed a relatively lower entropy change and could sample more stable binding conformation to the receptor than the Z isomers. Our density functional theory (DFT) calculations showed that the E isomers showed higher chemical reactivity and lower electronic chemical potential than their corresponding Z isomers. Compound E-Ic emerged as the optimal compound with a Ki value of 3.0 nM against NtPPO, exhibiting a broader spectrum of weed control than saflufenacil at 37.5-75 g ai/ha and also safe to maize at 75 g ai/ha, which could be considered as a promising lead herbicide for further development.

Dual-Responsive Supramolecular Polymeric Nanomedicine for Self-Cascade Amplified Cancer Immunotherapy.

Insufficient tumor immunogenicity and immune escape from tumors remain common problems in all tumor immunotherapies. Recent studies have shown that pyroptosis, a form of programmed cell death that is accompanied by immune checkpoint inhibitors, can induce effective immunogenic cell death and long-term immune activation. Therapeutic strategies to jointly induce pyroptosis and reverse immunosuppressive tumor microenvironments are promising for cancer immunotherapy. In this regard, a dual-responsive supramolecular polymeric nanomedicine (NCSNPs) to self-cascade amplify the benefits of cancer immunotherapy is designed. The NCSNPs are formulated by ß-cyclodextrin coupling nitric oxide (NO) donor, a pyroptosis activator, and NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor, and self-assembled through host-guest molecular recognition and hydrophobic interaction to obtain nanoparticles. NCSNPs possess excellent tumor accumulation and bioavailability attributed to ingenious supramolecular engineering. The study not only confirms the occurrence of NO-triggered pyroptosis in tumors for the first time but also reverses the immunosuppressive microenvironment in tumor sites via an IDO inhibitor by enhancing the infiltration of cytotoxic T lymphocytes, to achieve remarkable inhibition of tumor proliferation. Thus, this study provides a novel strategy for cancer immunotherapy.

Fructose-1,6-bisphosphatase 1 dephosphorylates and inhibits TERT for tumor suppression.

Telomere dysfunction is intricately linked to the aging process and stands out as a prominent cancer hallmark. Here we demonstrate that telomerase activity is differentially regulated in cancer and normal cells depending on the expression status of fructose-1,6-bisphosphatase 1 (FBP1). In FBP1-expressing cells, FBP1 directly interacts with and dephosphorylates telomerase reverse transcriptase (TERT) at Ser227. Dephosphorylated TERT fails to translocate into the nucleus, leading to the inhibition of telomerase activity, reduction in telomere lengths, enhanced senescence and suppressed tumor cell proliferation and growth in mice. Lipid nanoparticle-mediated delivery of FBP1 mRNA inhibits liver tumor growth. Additionally, FBP1 expression levels inversely correlate with TERT pSer227 levels in renal and hepatocellular carcinoma specimens and with poor prognosis of the patients. These findings demonstrate that FBP1 governs cell immortality through its protein phosphatase activity and uncover a unique telomerase regulation in tumor cells attributed to the downregulation or deficiency of FBP1 expression.

Self-adaptive pyroptosis-responsive nanoliposomes block pyroptosis in autoimmune inflammatory diseases.

Nanoliposomes have a broad range of applications in the treatment of autoimmune inflammatory diseases because of their ability to considerably enhance drug transport. For their clinical application, nanoliposomes must be able to realize on-demand release of drugs at disease sites to maximize drug-delivery efficacy and minimize side effects. Therefore, responsive drug-release strategies for inflammation treatment have been explored; however, no specific design has been realized for a responsive drug-delivery system based on pyroptosis-related inflammation. Herein, we report a pioneering strategy for self-adaptive pyroptosis-responsive liposomes (R8-cardiolipin-containing nanoliposomes encapsulating dimethyl fumarate, RC-NL@DMF) that precisely release encapsulated anti-pyroptotic drugs into pyroptotic cells. The activated key pyroptotic protein, the N-terminal domain of gasdermin E, selectively integrates with the cardiolipin of liposomes, thus forming pores for controlled drug release, pyroptosis, and inflammation inhibition. Therefore, RC-NL@DMF exhibited effective therapeutic efficacies to alleviate autoimmune inflammatory damages in zymosan-induced arthritis mice and dextran sulfate sodium-induced inflammatory bowel disease mice. Our novel approach holds great promise for self-adaptive pyroptosis-responsive on-demand drug delivery, suppressing pyroptosis and treating autoimmune inflammatory diseases.

ATP-Responsive Manganese-Based Bacterial Materials Synergistically Activate the cGAS-STING Pathway for Tumor Immunotherapy.

Stimulating the cyclic guanosine monophophate(GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial strategy by which bacteria activate the tumor immune system. However, the limited stimulation capability poses significant challenges in advancing bacterial immunotherapy. Here, an adenosine 5'-triphosphate (ATP)-responsive manganese (Mn)-based bacterial material (E. coli@PDMC-PEG (polyethylene glycol)) is engineered successfully, which exhibits an exceptional ability to synergistically activate the cGAS-STING pathway. In the tumor microenvironment, which is characterized by elevated ATP levels, this biohybrid material degrades, resulting in the release of divalent manganese ions (Mn2+) and subsequent bacteria exposure. This combination synergistically activates the cGAS-STING pathway, as Mn2+ enhances the sensitivity of cGAS to the extracellular DNA (eDNA) secreted by the bacteria. The results of the in vivo experiments demonstrate that the biohybrid materials E. coli@PDMC-PEG and VNP20009@PDMC-PEG effectively inhibit the growth of subcutaneous melanoma in mice and in situ liver cancer in rabbits. Valuable insights for the development of bacteria-based tumor immunotherapy are provided here.

Rapid classification of coffee origin by combining mass spectrometry analysis of coffee aroma with deep learning.

Mislabeling the geographical origin of coffee is a prevalent form of fraud. In this study, a rapid, nondestructive, and high-throughput method combining mass spectrometry (MS) analysis and intelligence algorithms to classify coffee origin was developed. Specifically, volatile compounds in coffee aroma were detected using self-aspiration corona discharge ionization mass spectrometry (SACDI-MS), and the acquired MS data were processed using a customized deep learning algorithm to perform origin authentication automatically. To facilitate high-throughput analysis, an air curtain sampling device was designed and coupled with SACDI-MS to prevent volatile mixing and signal overlap. An accuracy of 99.78% was achieved in the classification of coffee samples from six origins at a throughput of 1 s per sample. The proposed approach may be effective in preventing coffee fraud owing to its straightforward operation, rapidity, and high accuracy and thus benefit consumers.

Exploring nontraditional cardiorenal advantages of SGLT-2 inhibitors and GLP-1 receptor agonists.

This commentary provides an analysis of the study by Fu et al. in Kidney International, which employs 3 administrative databases to investigate the hyperkalemia protective effects of sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors. It emphasizes the methodological approach, notably the use of a fixed-effect model to aggregate pairwise comparisons from 3 data sets. In addition, we explored the broader cardiorenal and potential nonrenal benefits of these drug classes, underscoring the imperative for continued research in this domain.

Blocking pathogenic Leptospira invasion with aptamer molecules targeting outer membrane LipL32 protein.

This study aimed to develop aptamers targeting LipL32, a most abundant lipoprotein in pathogenic Leptospira, to hinder bacterial invasion. The objectives were to identify high-affinity aptamers through SELEX and evaluate their specificity and inhibitory effects. SELEX was employed to generate LipL32 aptamers (L32APs) over 15 rounds of selection. L32APs' binding affinity and specificity for pathogenic Leptospira were assessed. Their ability to inhibit LipL32-ECM interaction and Leptospira invasion was investigated. Animal studies were conducted to evaluate the impact of L32AP treatment on survival rates, Leptospira colonization, and kidney damage. Three L32APs with strong binding affinity were identified. They selectively detected pathogenic Leptospira, sparing non-pathogenic strains. L32APs inhibited LipL32-ECM interaction and Leptospira invasion. In animal studies, L32AP administration significantly improved survival rates, reduced Leptospira colonies, and mitigated kidney damage compared to infection alone. This pioneering research developed functional aptamers targeting pathogenic Leptospira. The identified L32APs exhibited high affinity, pathogen selectivity, and inhibition of invasion and ECM interaction. L32AP treatment showed promising results, enhancing survival rates and reducing Leptospira colonization and kidney damage. These findings demonstrate the potential of aptamers to impede pathogenic Leptospira invasion and aid in recovery from Leptospira-induced kidney injury (190 words).

ZBTB20 Regulates SERCA2a Activity and Myocardial Contractility Through Phospholamban.

BACKGROUND: Intracellular Ca2+ cycling determines myocardial contraction and relaxation in response to physiological demands. SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 2a) is responsible for the sequestration of cytosolic Ca2+ into intracellular stores during cardiac relaxation, and its activity is reversibly inhibited by PLN (phospholamban). However, the regulatory hierarchy of SERCA2a activity remains unclear. METHODS: Cardiomyocyte-specific ZBTB20 knockout mice were generated by crossing ZBTB20flox mice with Myh6-Cre mice. Echocardiography, blood pressure measurements, Langendorff perfusion, histological analysis and immunohistochemistry, quantitative reverse transcription-PCR, Western blot analysis, electrophysiological measurements, and chromatin immunoprecipitation assay were performed to clarify the phenotype and elucidate the molecular mechanisms. RESULTS: Specific ablation of ZBTB20 in cardiomyocyte led to a significant increase in basal myocardial contractile parameters both in vivo and in vitro, accompanied by an impairment in cardiac reserve and exercise capacity. Moreover, the cardiomyocytes lacking ZBTB20 showed an increase in sarcoplasmic reticular Ca2+ content and exhibited a remarkable enhancement in both SERCA2a activity and electrically stimulated contraction. Mechanistically, PLN expression was dramatically reduced in cardiomyocytes at the mRNA and protein levels by ZBTB20 deletion or silencing, and PLN overexpression could largely restore the basal contractility in ZBTB20-deficient cardiomyocytes. CONCLUSIONS: These data point to ZBTB20 as a fine-tuning modulator of PLN expression and SERCA2a activity, thereby offering new perspective on the regulation of basal contractility in the mammalian heart.

Change in neighborhood socioeconomic status and childhood weight status and body composition from birth to adolescence.

BACKGROUND: We aim to assess the associations between the change in neighborhood socioeconomic score (SES) between birth and 6 years and childhood weight status and body composition from 6 to 13 years. METHODS: Data for 3909 children from the Generation R Study, a prospective population-based cohort in the Netherlands were analyzed. The change in neighborhood SES between birth and 6 years was defined as static-high, static-middle, static-low, upward, and downward mobility. Child body mass index (BMI), overweight and obesity (OWOB), fat mass index (FMI) and lean mass index (LMI) were measured at age 6, 10, and 13 years. The associations were explored using generalized estimating equations. The effect modification by child sex was examined. RESULTS: In total, 19.5% and 18.1% of children were allocated to the upward mobility and downward mobility neighborhood SES group. The associations between the change in neighborhood SES and child weight status and body composition were moderated by child sex (p < 0.05). Compared to girls in the static-high group, girls in the static-low group had relatively higher BMI-SDS (ß, 95% confidence interval (CI): 0.24, 0.09-0.40) and higher risk of OWOB (RR, 95% CI: 1.98, 1.35-2.91), together with higher FMI-SDS (ß, 95% CI: 0.27, 0.14-0.41) and LMI-SDS (ß, 95% CI: 0.18, 0.03-0.33). The associations in boys were not significant. CONCLUSIONS: An increased BMI and fat mass, and higher risk of OWOB from 6 to 13 years were evident in girls living in a low-SES neighborhood or moving downward from a high- to a low-SES neighborhood. Support for children and families from low-SES neighborhoods is warranted.

Effect assessment of traditional Chinese medicine, Guilu Erxian Jiao, in patients with osteoporosis: A case-control study of the Chang gung memorial hospital.

BACKGROUND: Osteoporosis is a chronic skeletal disease characterized by low bone mass and increased risk of fracture. In Taiwan, Guilu Erxian Jiao (GEJ) is the commonly used formula of Chinese herbal medicines for patients with osteoporosis. However, the effect of GEJ on subsequent fractures in the long term is unclear. This is the first long-term case-control study of the effects of GEJ on the rates of fracture in patients with osteoporosis. METHODS: We collected data from January 1, 2000 to December 31, 2019 from the Chang Gung Research Database. We interpreted from the reports of DXA to confirm whether the patients met the criteria for osteoporosis (T score ≤ -2.5). Eighty-five patients were enrolled in the GEJ group. After two propensity score matchings, 425 patients were identified as the non-GEJ group. We assessed four outcomes to confirm the effects of GEJ in patients with osteoporosis, including the change in the T-score, new occurrences of fractures, cumulative rate of fracture, and how many doses of GEJ need to be administered to effectively reduce fractures RESULTS: There was no significant difference in either the improvement in the T score or the 5-year overall fracture (p = 0.335) between these two groups. At the fracture-prone sites, the fracture in lumbar vertebrae was less in the GEJ group (p = 0.034). A total of 600 GEJ pills are required to effectively reduce the incidence of fractures (p value= 0.0039). CONCLUSIONS: Patients who take at least 600 GEJ pills would have a decreased fracture risk at fracture-prone sites.

Gut flora metagenomic analysis coupled with metabolic and deep immune profiling in chronic kidney disease.

BACKGROUND AND HYPOTHESIS: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation. METHODS: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome, and deep immunotyping, in a cohort of patients and non-CKD controls. RESULTS: Our analyses on functional profiles of gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme, and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids, and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of functional profiles derived from gut microbiota, with the CAZyme genes being the top performing model to accurately predict early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster-tryptophan and B cell cluster-tryptophan metabolism). CONCLUSION: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may be of etiological and diagnostic implications in CKD.

All-cause and immune checkpoint inhibitor-associated acute kidney injury in immune checkpoint inhibitor users: a meta-analysis of occurrence rate, risk factors and mortality.

Background: Immune checkpoint inhibitors (ICIs) have been associated with acute kidney injury (AKI). However, the occurrence rate of ICI-related AKI has not been systematically examined. Additionally, exposure to proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs) were considered as risk factors for AKI, but with inconclusive results in ICI-related AKI. Our aim was to analyse the occurrence rate of all-cause AKI and ICI-related AKI and the occurrence rates of severe AKI and dialysis-requiring AKI, and to determine whether exposure to PPIs and NSAIDs poses a risk for all-cause and ICI-related AKI. Methods: This study population was adult ICI recipients. A systematic review was conducted by searching MEDLINE, Embase and PubMed through October 2023. We included prospective trials and observational studies that reported any of the following outcomes: the occurrence rate of all-cause or ICI-related AKI, the relationship between PPI or NSAID exposure and AKI development or the mortality rate in the AKI or non-AKI group. Proportional meta-analysis and pairwise meta-analysis were performed. The evidence certainty was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Results: A total of 120 studies comprising 46 417 patients were included. The occurrence rates of all-cause AKI were 7.4% (14.6% from retrospective studies and 1.2% from prospective clinical trials). The occurrence rate of ICI-related AKI was 3.2%. The use of PPIs was associated with an odds ratio (OR) of 1.77 [95% confidence interval (CI) 1.43-2.18] for all-cause AKI and an OR of 2.42 (95% CI 1.96-2.97) for ICI-related AKI. The use of NSAIDs was associated with an OR of 1.77 (95% CI 1.10-2.83) for all-cause AKI and an OR of 2.57 (95% CI 1.68-3.93) for ICI-related AKI. Conclusions: Our analysis revealed that approximately 1 in 13 adult ICI recipients may experience all-cause AKI, while 1 in 33 adult ICI recipients may experience ICI-related AKI. Exposure to PPIs and NSAIDs was associated with an increased OR risk for AKI in the current meta-analysis.

Self-assembly of maltose-albumin nanoparticles for efficient targeting delivery and therapy in liver cancer.

The effective delivery and targeted release of drugs within tumor cells are critical factors in determining the therapeutic efficacy of nanomedicine. To achieve this objective, a conjugate of maltose (Mal) and bovine serum albumin (BSA) was synthesized by the Maillard reaction and self-assembled into nanoparticles with active-targeting capabilities upon pH/heating induction. This nanoparticle could be effectively loaded with doxorubicin (DOX) to form stable nanodrugs (Mal-BSA/DOX) that were sensitive to low pH or high glutathione (GSH), thereby achieving a rapid drug release (96.82 % within 24 h). In vitro cell experiments indicated that maltose-modified BSA particles efficiently enhance cellular internalization via glucose transporters (GLUT)-mediated endocytosis, resulting in increased intracellular DOX levels and heightened expression of γ-H2AX. Consequently, these results ultimately lead to selective tumor cells death, as evidenced by an IC50 value of 3.83 µg/mL in HepG2 cells compared to 5.87 µg/mL in 293t cells. The efficacy of Mal-BSA/DOX in tumor targeting therapy has been further confirmed by in vivo studies, as it effectively delivered a higher concentration of DOX to tumor tissue. This targeted delivery approach not only reduces the systemic toxicity of DOX but also effectively inhibits tumor growth (TGI, 75.95 %). These findings contribute valuable insights into the advancement of targeting-albumin nanomedicine and further support its potential in tumor treatment.

Engineering Clinically Relevant Probiotics with Switchable "Nano-Promoter" and "Nano-Effector" for Precision Tumor Therapy.

Probiotics have the potential as biotherapeutic agents for cancer management in preclinical models and human trials by secreting antineoplastic or immunoregulatory agents in the tumor microenvironment (TME). However, current probiotics lack the ability to dynamically respond to unique TME characteristics, leading to limited therapeutic accuracy and efficacy. Although progress has been made in customizing controllable probiotics through synthetic biology, the engineering process is complex and the predictability of production is relatively low. To address this, here, for the first time, this work adopts pH-dependent peroxidase-like (POD-like) artificial enzymes as both an inducible "nano-promoter" and "nano-effector" to engineer clinically relevant probiotics to achieve switchable control of probiotic therapy. The nanozyme initially serves as an inducible "nano-promoter," generating trace amounts of nonlethal reactive oxygen species (ROS) stress to upregulate acidic metabolites in probiotics. Once metabolites acidify the TME to a threshold, the nanozyme switches to a "nano-effector," producing a great deal of lethal ROS to fight cancer. This approach shows promise in subcutaneous, orthotopic, and colitis-associated colorectal cancer tumors, offering a new methodology for modulating probiotic metabolism in a pathological environment.

Interferon-alpha and MxA inhibit BK polyomavirus replication by interaction with polyomavirus large T antigen.

INTRODUCTION: BK Polyomavirus (BKPyV) infection is a common complication in kidney transplant recipients and can result in poor outcome and graft failure. Currently, there is no known effective antiviral agent. This study investigated the possible antiviral effects of Interferon alpha (IFNα) and its induced protein, MxA, against BKPyV. METHODS: In vitro cell culture experiments were conducted using human primary renal proximal tubular epithelial cells (HRPTECs). We also did animal studies using Balb/c mice with unilateral kidney ischemic reperfusion injury. RESULTS: Our results demonstrated that IFNα effectively inhibited BKPyV in vitro and murine polyomavirus in animal models. Additionally, IFNα and MxA were found to suppress BKPyV TAg and VP1 production. Silencing MxA attenuated the antiviral efficacy of IFNα.We observed that MxA interacted with BKPyV TAg, causing it to remain in the cytosol and preventing its nuclear translocation. To determine MxA's essential domain for its antiviral activities, different mutant MxA constructs were generated. The MxA mutant K83A retained its interaction with BKPyV TAg, and its antiviral effects were intact. The MxA T103A mutant, on the other hand, abolished GTPase activity and lost its protein-protein interaction with BKPyV TAg, and lost its antiviral effect. CONCLUSION: IFNα and its downstream protein, MxA, have potent antiviral properties against BKPyV. Furthermore, our findings indicate that the interaction between MxA and BKVPyV TAg plays a crucial role in determining the anti-BKPyV effects of MxA.

Base editing of the mutated TERT promoter inhibits liver tumor growth.

BACKGROUND AND AIMS: Base editing has shown great potential for treating human diseases with mutated genes. However, its potential for treating HCC has not yet been explored. APPROACH AND RESULTS: We employed adenine base editors (ABEs) to correct a telomerase reverse transcriptase ( TERT ) promoter mutation, which frequently occurs in various human cancers, including HCC. The mutated TERT promoter -124 C>T is corrected to -124 C by a single guide (sg) RNA-guided and deactivated Campylobacter jejuni Cas9 (CjCas9)-fused adenine base editor (CjABE). This edit impairs the binding of the E-twenty six/ternary complex factor transcription factor family, including E-twenty six-1 and GABPA, to the TERT promoter, leading to suppressed TERT promoter and telomerase activity, decreased TERT expression and cell proliferation, and increased cell senescence. Importantly, injection of adeno-associated viruses expressing sgRNA-guided CjABE or employment of lipid nanoparticle-mediated delivery of CjABE mRNA and sgRNA inhibits the growth of liver tumors harboring TERT promoter mutations. CONCLUSIONS: These findings demonstrate that a sgRNA-guided CjABE efficiently converts the mutated TERT promoter -124 C>T to -124 C in HCC cells and underscore the potential to treat HCC by the base editing-mediated correction of TERT promoter mutations.