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Therapeutic mRNAs and vaccines are being developed for a broad range of human diseases, including COVID-19. However, their optimization is hindered by mRNA instability and inefficient protein expression. Here, we describe design principles that overcome these barriers. We develop an RNA sequencing-based platform called PERSIST-seq to systematically delineate in-cell mRNA stability, ribosome load, as well as in-solution stability of a library of diverse mRNAs. We find that, surprisingly, in-cell stability is a greater driver of protein output than high ribosome load. We further introduce a method called In-line-seq, applied to thousands of diverse RNAs, that reveals sequence and structure-based rules for mitigating hydrolytic degradation. Our findings show that highly structured “superfolder” mRNAs can be designed to improve both stability and expression with further enhancement through pseudouridine nucleoside modification. Together, our study demonstrates simultaneous improvement of mRNA stability and protein expression and provides a computational-experimental platform for the enhancement of mRNA medicines. The authors develop an RNA sequencing-based platform, PERSIST-seq, to simultaneously delineate in-cell mRNA stability, ribosome load, and in-solution stability of a diverse mRNA library to derive design principles for improved mRNA therapeutics.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide, and it is always the consequence of chronic hepatitis and liver cirrhosis. The nucleotide-binding domain, leucine-rich family (NLR), pyrin-containing 3 (NLRP3) inflammasome has been shown to orchestrate multiple innate and adaptive immune responses. However, little is known about its role in cancer. This study was performed to investigate the role of the NLRP3 inflammasome in the development and progression of HCC. The expression of NLRP3 inflammasome components was analyzed in HCC tissues and corresponding non-cancerous liver tissues at both the mRNA and protein levels. Our data demonstrate that the expression of all of the NLRP3 inflammasome components was either completely lost or significantly downregulated in human HCC, and that the deficiency correlated significantly with advanced stages and poor pathological differentiation. In addition, our data provide an overview of the expression of NLRP3 inflammasome components in the multi-stage development of HCC and indicate a surprising link between deregulation of the NLRP3 inflammasome molecular platform and HCC progression. In conclusion, this study presents a dynamic expression pattern of NLRP3 inflammasome components in multi-stage hepatocarcinogenesis and demonstrates that deregulated expression of the inflammasome is involved in HCC progression.

Gender differences exist in the susceptibility, incidence, progression, and prognosis of bacterial infections in males and females, influenced by various factors including lifestyle and habits. Multiple reports have indicated that estrogen plays a crucial immunomodulatory role in many pathogenic microbial infections, highlighting a complex relationship between estrogen, its receptors, and bacterial infections. Estrogen and its receptors regulate host immune responses, affecting the host’s ability to clear bacteria and thus influencing the likelihood and difficulty of infection eradication. Variations in estrogen levels may lead to differences in the occurrence and progression of bacterial infections, with estrogen playing varied roles in diseases caused by the same bacterial pathogens. The interaction between estrogen and bacterial infections represents a complex and crucial aspect of human physiology and clinical medicine. Understanding this interaction is essential for advancing infection prevention and treatment strategies. This article reviews the correlation and mechanisms between estrogen and bacterial infections, emphasizing the importance of further research in this field.

Respiratory infectious diseases, particularly those caused by respiratory viruses, have the potential to lead to global pandemics, thereby posing significant threats to public and human health. Historically, the primary treatment for respiratory bacterial infections has been antibiotic therapy, while severe cases of respiratory viral infections have predominantly been managed by controlling inflammatory cytokine storms. Ferroptosis is a novel form of programmed cell death that is distinct from apoptosis and autophagy. In recent years, Recent studies have demonstrated that ferroptosis plays a significant regulatory role in various respiratory infectious diseases, indicating that targeting ferroptosis may represent a novel approach for the treatment of these conditions. This article summarized the toxic mechanisms underlying ferroptosis, its relationship with respiratory infectious diseases, the mechanisms of action, and current treatment strategies. Particular attentions were given to the interplay between ferroptosis and Mycobacterium tuberculosis, Epstein-Barr virus, severe acute respiratory syndrome coronavirus-2, Pseudomonas aeruginosa, dengue virus, influenza virus and herpes simplex virus type1infection. A deeper understanding of the regulatory mechanisms of ferroptosis in respiratory infections will not only advance our knowledge of infection-related pathophysiology but also provide a theoretical foundation for the development of novel therapeutic strategies. Targeting ferroptosis pathways represents a promising therapeutic approach for respiratory infections, with significant clinical and translational implications.

Gender differences exist in the susceptibility, incidence, progression, and prognosis of diseases caused by viral infections. These differences are influenced by various factors, including lifestyle and habits between males and females. Some reports have pointed out that estrogen plays an important immune-modulatory role in many viral infections. In certain viral infections, estrogen exhibits a protective and regulatory effect, while in others, it has a synergistic and promoting effect. The action of estrogen and its receptors affect the occurrence and prognosis of viral infections to some extent. This article reviews the correlation and the related mechanisms between estrogen and viral infections.

Background Mycoplasma pneumoniae can be divided into different subtypes on the basis of the sequence differences of adhesive protein P1, but the relationship between different subtypes, macrolide resistance and clinical manifestations are still unclear. In the present study, we established a molecular beacon based real-time polymerase chain reaction (real-time PCR) p1 gene genotyping method, analyzed the macrolide resistance gene mutations and the relationship of clinical characteristics with the genotypes. Methods A molecular beacon based real-time PCR p1 gene genotyping method was established, the mutation sites of macrolide resistance genes were analyzed by PCR and sequenced, and the relationship of clinical characteristics with the genotypes was analyzed. Results The detection limit was 1–100 copies/reaction. No cross-reactivity was observed in the two subtypes. In total, samples from 100 patients with positive M. pneumoniae detection results in 2019 and 2021 were genotyped using the beacon based real-time PCR method and P1-1 M. pneumoniae accounted for 69.0%. All the patients had the A2063G mutation in the macrolide resistance related 23S rRNA gene. Novel mutations were also found, which were C2622T, C2150A, C2202G and C2443A mutations. The relationship between p1 gene genotyping and the clinical characteristics were not statistically related. Conclusion A rapid and easy clinical application molecular beacon based real-time PCR genotyping method targeting the p1 gene was established. A shift from type 1 to type 2 was found and 100.0% macrolide resistance was detected. Our study provided an efficient method for genotyping M. pneumoniae , valuable epidemiological monitoring information and clinical treatment guidance to control high macrolide resistance.

The diagnosis and treatment of non-small cell lung cancer in clinical settings face serious challenges, particularly due to the lack of integration between the two processes, which limit real-time adjustments in treatment plans based on the patient’s condition and drive-up treatment costs. Here, we present a multifunctional pH-sensitive core-shell nanoparticle containing quercetin (QCT), termed AHA@MnP/QCT NPs, designed for the simultaneous diagnosis and treatment of non-small cell lung cancer. Mechanistic studies indicated that QCT and Mn 2+ exhibited excellent peroxidase-like (POD-like) activity, catalysing the conversion of endogenous hydrogen peroxide into highly toxic hydroxyl radicals through a Fenton-like reaction, depleting glutathione (GSH), promoting reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum, and inducing ferroptosis. Additionally, Mn 2+ could activate the cGAS-STING signalling pathway and promote the maturation of dendritic cells and infiltration of activated T cells, thus inducing tumor immunogenic cell death (ICD). Furthermore, it exhibited effective T2-weighted MRI enhancement for tumor imaging, making them valuable for clinical diagnosis. In vitro and in vivo experiments demonstrated that AHA@MnP/QCT NPs enabled non-invasive imaging and tumor treatment, which presented a one-stone-for-two-birds strategy for combining tumor diagnosis and treatment, with broad potential for clinical application in non-small cell lung cancer therapy. Graphical Abstract

Human respiratory syncytial virus (HRSV) is a leading cause of acute respiratory infections in children. COVID-19 NPIs significantly suppressed HRSV transmission. This study analyzed six-year epidemiological dynamics of pediatric HRSV infections in Henan Province, China, focusing on NPI suppression effects, the 2023 resurgence, and \"Immune debt\" impact. We retrospectively collected respiratory specimens from 80,920 children with acute respiratory diseases at Henan Children's Hospital (2019-2024). HRSV was detected using RT-qPCR. Positivity rates were analyzed by year, season, and age group. During 2019-2024, HRSV positivity fluctuated markedly: 14.65% (2019), 16.34% (2021), 3.27% (2022 under strict NPIs), 21.47% (2023 post-NPIs), and 6.80% (2024). Interrupted time-series analysis indicated that NPI lifting in 2023 was associated with a significant surge in infection risk (OR = 668.77, 95% CI: 47.03-9509.28). Seasonal patterns shifted substantially, with the characteristic winter peak replaced by an off-season spring outbreak in April 2023 (57.41%). Multivariable logistic regression identified age as the strongest predictor, with infants <1 year having the highest risk (aOR = 9.02, 95% CI: 8.31-9.79) and a 4.91-fold higher positivity rate than school-aged children (22.98% vs. 4.68%; 95% CI: 4.59-5.25; P < 0.001). NPIs dramatically affected HRSV epidemiology. The intense post-suppression rebound strongly supports the \"Immune debt\" theory-accumulation of susceptible children driving resurgence. Establishing year-round, multi-pathogen surveillance systems is crucial for post-pandemic public health challenges.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is closely associated with mitochondrial damage, diminished glutathione peroxidase 4 activity, dysfunction of the System Xc − cystine/glutamate antiporter, and disruptions in iron metabolism. Infections of the human reproductive system and associated reproductive disorders pose a significant global public health challenge, characterized by diverse pathogens and complex pathogenic mechanisms. Recent research has revealed that ferroptosis plays a critical role in the pathological processes of many of these infections. This review systematically elaborates on the central mechanistic role of ferroptosis in various pathologies of the reproductive system. These include CD4 + T cell depletion and immunological non-response in Human Immunodeficiency Virus (HIV) infection, the development of Human Papillomavirus (HPV)-associated cervical cancer, Staphylococcus aureus -induced endometritis and mastitis, as well as male infertility, pre-eclampsia, and ovarian cancer linked to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Despite the diversity of the pathogens, they can all trigger ferroptosis through common mechanisms, such as disrupting the Nrf2/GPX4 antioxidant axis, impairing the System Xc − –GSH–GPX4 pathway, and inducing dysregulation of iron metabolism. Furthermore, ferroptosis interacts intricately with pyroptosis and apoptosis, forming a complex network that collectively regulates the outcome of infections and the extent of tissue damage. Notably, ferroptosis plays a context-dependent dual role in various reproductive system infections. During the initial phases of infection, it exerts a protective effect by eliminating pathogens and curbing infection progression. In contrast, during advanced or chronic stages, ferroptosis exacerbates tissue injury and promotes disease pathogenesis. The ferroptosis pathway holds great therapeutic promise, either through inhibitors that safeguard host cells or inducers that eradicate drug-resistant bacteria by triggering a “ferroptosis-like” state. Nevertheless, challenges remain for clinical translation, as the ferroptosis network is incompletely understood, and the tissue selectivity and long-term safety of targeted drugs are unverified. Future studies must elucidate host-pathogen interactions to develop precise targeted therapies.

The immunosuppressive tumor microenvironment (TME) is a pivotal contributor to therapeutic resistance in triple-negative breast cancer (TNBC). Immunogenic cell death (ICD), which activates antitumor immunity through damage-associated molecular pattern (DAMP) release, represents a promising therapeutic strategy for TNBC. Although gambogic acid (GA) triggers ICD by inducing synergistic apoptosis/ferroptosis and DAMP secretion, its clinical translation is hindered by non-specific targeting, poor solubility, and systemic toxicity. To overcome these limitations, we engineered homologous tumor cell membrane-coated GA/Ga³⁺ nanoparticles (M@GAGa NPs) that operate through a triple-functionality: (1) Tumor-targeted delivery: Homologous membrane coating enables immune evasion and precise TNBC tissue accumulation. (2) TME-responsive synergy: Acidic TME-triggered release of GA and Ga³⁺ permits Ga³⁺-mediated disruption of tumor metabolism via ferric ion mimicry, synergistically enhancing GA-induced cytotoxicity. (3) Immunomodulation: GA-induced ICD releases immune signalling molecules such as calreticulin (CRT) and high mobility group protein B1 (HMGB1), while Ga³⁺ reprograms immunosuppressive cells, collectively activating dendritic cell (DC) antigen presentation and CD8⁺ T cell-mediated antitumor immunity. M@GAGa NPs remodel the immunosuppressive TNBC microenvironment through multimodal synergy, offering an innovative precision immunotherapy platform to overcome current therapeutic constraints.