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Red blood cells (RBCs) are the most abundant cell type in the blood, and play a critical role in oxygen transport. With the development of nanobiotechnology and synthetic biology, scientists have found multiple ways to take advantage of the characteristics of RBCs, such as their long circulation time, to construct universal RBCs, develop drug delivery systems, and transform cell therapies for cancer and other diseases. This article reviews the component and aging mystery of RBCs, the methods for the applied universal RBCs, and the application prospects of RBCs, such as the engineering modification of RBCs used in cytopharmaceuticals for drug delivery and immunotherapy. Finally, we summarize some perspectives on the biological features of RBCs and provide further insights into translational medicine.

Liquid biopsy is a convenient, fast, non-invasive and reproducible sampling method that can dynamically reflect the changes in tumor gene expression profile, and provide a robust basis for individualized therapy and early diagnosis of cancer. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) are the currently approved diagnostic biomarkers for screening cancer patients. In addition, tumor-derived extracellular vesicles (tdEVs), circulating tumor-derived proteins, circulating tumor RNA (ctRNA) and tumor-bearing platelets (TEPs) are other components of liquid biopsies with diagnostic potential. In this review, we have discussed the clinical applications of these biomarkers, and the factors that limit their implementation in routine clinical practice. In addition, the most recent developments in the isolation and analysis of circulating tumor biomarkers have been summarized, and the potential of non-blood liquid biopsies in tumor diagnostics has also been discussed.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by multilineage immune dysregulation, which subsequently causes inflammation, fibrosis, and even cirrhosis of liver. Due to the limitation of traditional assays, the local hepatic immunopathogenesis of PBC has not been fully characterized. Here, we utilize single-cell RNA sequencing technology to depict the immune cell landscape and decipher the molecular mechanisms of PBC patients. We reveal that cholangiocytes and hepatic stellate cells are involved in liver inflammation and fibrosis. Moreover, Kupffer cells show increased levels of inflammatory factors and decreased scavenger function related genes, while T cells exhibit enhanced levels of inflammatory factors and reduced cytotoxicity related genes. Interestingly, we identify a liver-resident Th1-like population with JAK-STAT activation in the livers of both PBC patients and murine PBC model. Finally, blocking the JAK-STAT pathway alleviates the liver inflammation and eliminates the liver-resident Th1-like cells in the murine PBC model. In conclusion, our comprehensive single-cell transcriptome profiling expands the understanding of pathological mechanisms of PBC and provides potential targets for the treatment of PBC in patients. Primary biliary cholangitis is a chronic autoimmune disease critically linked to immunological dysregulation but the local immune-pathogenesis is poorly understood. Here the authors present single cell transcriptomic characterisation of primary biliary cholangitis and implicates Th1 like cells in a murine model.

Stem cell‐based therapy has great potential in regenerative medicine. However, the survival and engraftment rates of transplanted stem cells in disease regions are poor and limit the effectiveness of cell therapy due to the fragility of stem cells. Here, an approach involving a single‐cell coating of surface‐anchored nanogel to regulate stem cell fate with anti‐apoptosis capacity in the hypoxic and ischemic environment of infarcted hearts is developed for the first time. A polysialic acid‐based system is used to anchor microbial transglutaminase to the external surface of the cell membrane, where it catalyzes the crosslinking of gelatin. The single‐cell coating with surface‐anchored nanogel endows mesenchymal stem cells (MSCs) with stress resistance by blocking the activity of apoptotic cytokines including the binding of tumor necrosis factor α (TNFα) to tumor necrosis factor receptor, which in turn maintains mitochondrial integrity, function and protects MSCs from TNFα‐induces apoptosis. The administration of surface engineered MSCs to hearts results in significant improvements in engraftment, cardiac function, infarct size, and vascularity compared with using uncoated MSCs in treating myocardial infarction. The surface‐anchored, biocompatible cell surface engineering with nanogel armor provides a new way to produce robust therapeutic stem cells and may explore immense potentials in cell‐based therapy. The cell surface masking of a nanogel endows individual cells with enhanced stress resistance and serves as a protective barrier to protect stem cells from apoptosis by reducing the binding between cytokines and their receptors, and improving the reparative potency of transplanted cells through paracrine effects in infarcted hearts, which will aid the development of approaches for cell‐based therapy.

Background Hexaploid wheat ( Triticum aestivum ) is a globally important crop. Heat, drought and their combination dramatically reduce wheat yield and quality, but the molecular mechanisms underlying wheat tolerance to extreme environments, especially stress combination, are largely unknown. As an allohexaploid, wheat consists of three closely related subgenomes (A, B, and D), and was reported to show improved tolerance to stress conditions compared to tetraploid. But so far very little is known about how wheat coordinates the expression of homeologous genes to cope with various environmental constraints on the whole-genome level. Results To explore the transcriptional response of wheat to the individual and combined stress, we performed high-throughput transcriptome sequencing of seedlings under normal condition and subjected to drought stress (DS), heat stress (HS) and their combination (HD) for 1 h and 6 h, and presented global gene expression reprograms in response to these three stresses. Gene Ontology (GO) enrichment analysis of DS, HS and HD responsive genes revealed an overlap and complexity of functional pathways between each other. Moreover, 4,375 wheat transcription factors were identified on a whole-genome scale based on the released scaffold information by IWGSC, and 1,328 were responsive to stress treatments. Then, the regulatory network analysis of HSFs and DREBs implicated they were both involved in the regulation of DS, HS and HD response and indicated a cross-talk between heat and drought stress. Finally, approximately 68.4 % of homeologous genes were found to exhibit expression partitioning in response to DS, HS or HD, which was further confirmed by using quantitative RT-PCR and Nullisomic-Tetrasomic lines. Conclusions A large proportion of wheat homeologs exhibited expression partitioning under normal and abiotic stresses, which possibly contributes to the wide adaptability and distribution of hexaploid wheat in response to various environmental constraints.

Immuno-oncology has witnessed remarkable advancements in the past decade, revolutionizing the landscape of cancer therapeutics in an encouraging manner. Among the diverse immunotherapy strategies, mRNA vaccines have ushered in a new era for the therapeutic management of malignant diseases, primarily due to their impressive impact on the COVID-19 pandemic. In this comprehensive review, we offer a systematic overview of mRNA vaccines, focusing on the optimization of structural design, the crucial role of delivery materials, and the administration route. Additionally, we summarize preclinical studies and clinical trials to provide valuable insights into the current status of mRNA vaccines in cancer treatment. Furthermore, we delve into a systematic discussion on the significant challenges facing the current development of mRNA tumor vaccines. These challenges encompass both intrinsic and external factors that are closely intertwined with the successful application of this innovative approach. To pave the way for a more promising future in cancer treatments, a deeper understanding of immunological mechanisms, an increasing number of high-quality clinical trials, and a well-established manufacturing platform are crucial. Collaborative efforts between scientists, clinicians, and industry engineers are essential to achieving these goals.

Anxiety-like behaviors in mice include social avoidance and avoidance of bright spaces. Whether these features are distinctly regulated is unclear. We demonstrate that in mice, social and anxiogenic stimuli, respectively, increase and decrease serotonin (5-HT) levels in basal amygdala (BA). In dorsal raphe nucleus (DRN), 5-HT∩vGluT3 neurons projecting to BA parvalbumin (DRN 5-HT∩vGluT3 -BA PV ) and pyramidal (DRN 5-HT∩vGluT3 -BA Pyr ) neurons have distinct intrinsic properties and gene expression and respond to anxiogenic and social stimuli, respectively. Activation of DRN 5-HT∩vGluT3 →BA PV inhibits 5-HT release via GABA B receptors on serotonergic terminals in BA, inducing social avoidance and avoidance of bright spaces. Activation of DRN 5-HT∩vGluT3 →BA neurons inhibits two subsets of BA Pyr neurons via 5-HT1A receptors (HTR1A) and 5-HT1B receptors (HTR1B). Pharmacological inhibition of HTR1A and HTR1B in BA induces avoidance of bright spaces and social avoidance, respectively. These findings highlight the functional significance of heterogenic inputs from DRN to BA subpopulations in the regulation of separate anxiety-related behaviors. Yu et al. show that at least two distinct serotonergic DRN-to-BA pathways are involved in different aspects of anxiety-related behaviors via different molecular mechanisms.

Small mammals harbor a diverse array of potentially zoonotic pathogens. To date, however, metagenomic surveys of these species have primarily focused on viruses, with limited attention directed to bacterial and eukaryotic pathogens. Additionally, the ecological determinants of pathogen diversity within these mammals have not been systematically examined. Herein, we employed a metatranscriptomics approach to survey the pathogen infectome—defined as the set of microorganisms infecting the host—across 2408 individual samples, representing lung, spleen, and gut from 858 animals in Guangdong province, China, considering the impact of host species, tissue, season, and geographic location on pathogen diversity. We identified 76 potential pathogen species, comprising 29 RNA viruses, 12 DNA viruses, five bacteria, and 30 eukaryotic pathogens, including 33 that are newly discovered. Distinct tissue tropisms were identified, suggesting varied transmission routes. Individual animals carried an average of one pathogen, with 10 pathogens widely distributed among mammalian orders. Total pathogen richness was largely influenced by geographic region, followed by host species and season, while zoonotic pathogen richness was primarily driven by host species. Collectively, these data provide insights into the structure of the pathogen infectome and the drivers of pathogen diversity and transmission in these key mammalian disease reservoirs. Less is known about the entire microbial pathogen profile of small mammals. Here, the authors analyse 2,408 tissue-resolved metatranscriptomes to map the infectome in small mammals, uncovering high viral, bacterial, fungal and parasitic diversity and showing how geography, hosts, and seasons shape zoonotic risk.

Background Cervical cancer, prevalent in low- and middle-income countries, is primarily caused by high-risk HPV16. Vesicle-Associated Membrane Protein 8 (VAMP8), involved in vesicle trafficking and autophagy, may influence HPV16-related cervical cancer progression. Methods VAMP8 expression was evaluated in cervical tissue specimens from patients with HPV16-positive lesions (including low- and high-grade squamous intraepithelial lesions and cancer) and HPV-negative normal controls using proteomics, qPCR, and immunohistochemistry. A Cox proportional hazards model for prognosis was developed using immunohistochemical data from a cohort of cervical cancer patients. The clinical significance of VAMP8 was further assessed using RNA-seq and clinical data from The Cancer Genome Atlas-Cervical Cancer (TCGA-CESC) cohort. The effects of VAMP8 on autophagy and tumor progression were examined in HPV16 E6/E7-immortalized cervical epithelial cells (Ect1/E6E7) and cervical cancer cell lines (SiHa, HeLa, C-33A) in vitro, and in a SiHa xenograft model in vivo. Transcriptomic analysis of Ect1/E6E7 and SiHa cells identified VAMP8-regulated pathways. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays in SiHa cells were used to confirm the regulation of the HIF-1 pathway. Results VAMP8 was upregulated in HPV16-positive samples, particularly in low-grade squamous intraepithelial lesions (LSIL). Elevated VAMP8 correlated with poor survival outcomes and advanced tumor stages. VAMP8 enhanced autophagy and reduced proliferation and invasiveness in HPV16-positive cervical cells but increased in established cancer cell lines. In vivo, VAMP8 overexpression promoted tumor growth and autophagy. The HIF-1 pathway emerged as a key regulatory axis of VAMP8, enhancing hypoxic responses and angiogenesis. Conclusion Elevated VAMP8 in HPV16-associated cervical cancer promotes tumor progression by enhancing autophagy via the HIF-1 pathway, suggesting its potential as a diagnostic and prognostic biomarker. Highlights 1. VAMP8 is upregulated in HPV16-positive tissues, especially in LSIL. 2. Elevated VAMP8 correlates with poor survival and advanced tumor stages. 3. VAMP8 enhances autophagy and promotes tumor progression in cervical cancer. 4. VAMP8 interacts with HIF-1 pathway, enhancing hypoxic response and angiogenesis.

Photodetectors (PDs) based on perovskite nanowires are among the most promising next‐generation photodetection technologies; however, their poor long‐term stability is the biggest challenge limiting their commercial application. Herein, an ionic liquid, 1‐butyl‐3‐methylimidazolium tetrafluoroborate (BMIMBF4), is incorporated as an additive into methylammonium lead triiodide (MAPbI3) nanowires; this not only effectively passivates defects to inhibit perovskite degradation but also leads to the formation of nanochannels, enabling fast charge transfer. As a result, the long‐term stability and performance of MAPbI3 nanowires are considerably improved. The detectivity, linear detection range, and noise equivalent power of the MAPbI3 nanowire PD reach 2.06 × 1013 Jones, 160 dB, and 1.38 × 10−15 W Hz−1/2, respectively, comparable to the highest performance of perovskite nanowire PDs reported to date. Moreover, the unencapsulated PD can maintain 100% of its initial performance after being exposed to an open‐air environment for more than 5000 h, establishing it as the most stable perovskite nanowire PD reported to date. Notably, the PD exhibits improved diffuse reflection imaging ability when compared with commercial silicon photodiode S2386. This study provides a new strategy for constructing sensitive, stable, and flexible perovskite PDs and will accelerate their commercial application in the future. The poor long‐term stability of perovskite nanowires photodetectors (PDs) hinders its future commercial application. Here, an ionic liquid (BMIMBF4) is incorporated into methylammonium lead triiodide (MAPbI3) nanowires, resulting in reduced defects, enhanced charge carrier transfer, and improved stability and performance. Remarkably, the unencapsulated MAPbI3 nanowire PDs exhibit ultra‐high stability with no performance attenuation after stored in air for more than 5000 h.