Yongwen Chen

MS4A (membrane-spanning 4-domain, subfamily A) molecules are categorized into tetraspanins, which possess four-transmembrane structures. To date, eighteen MS4A members have been identified in humans, whereas twenty-three different molecules have been identified in mice. MS4A proteins are selectively expressed on the surfaces of various immune cells, such as B cells (MS4A1), mast cells (MS4A2), macrophages (MS4A4A), Foxp3⁺CD4⁺ regulatory T cells (MS4A4B), and type 3 innate lymphoid cells (TMEM176A and TMEM176B). Early research confirmed that most MS4A molecules function as ion channels that regulate the transport of calcium ions. Recent studies have revealed that some MS4A proteins also function as chaperones that interact with various immune molecules, such as pattern recognition receptors and/or immunoglobulin receptors, to form immune complexes and transmit downstream signals, leading to cell activation, growth, and development. Evidence from preclinical animal models and human genetic studies suggests that the MS4A superfamily plays critical roles in the pathogenesis of various diseases, including cancer, infection, allergies, neurodegenerative diseases and autoimmune diseases. We review recent progress in this field and focus on elucidating the molecular mechanisms by which different MS4A molecules regulate the progression of tumors, Alzheimer’s disease, and autoimmune diseases. Therefore, in-depth research into MS4A superfamily members may clarify their ability to act as candidate biomarkers and therapeutic targets for these diseases. Eighteen distinct members of the MS4A (membrane-spanning four-domain subfamily A) superfamily of four-transmembrane proteins have been identified in humans, whereas the MS4A genes are translated into twenty-three different molecules in mice. These proteins are selectively expressed on the surface of various immune cells, such as B cells (MS4A1), macrophages (MS4A4A), mast cells (MS4A2), Foxp3⁺CD4⁺ regulatory T cells (MS4A4B), type 3 innate lymphoid cells (TMEM176A and TMEM176B) and colonic epithelial cells (MS4A12). Functionally, most MS4A molecules function as ion channels that regulate the flow of calcium ions [Ca²⁺] across cell membranes. Recent studies have revealed that some MS4A proteins also act as molecular chaperones and interact with various types of immune receptors, including pattern recognition receptors (PRRs) and immunoglobulin receptors (IgRs), to form signaling complexes, thereby modulating intracellular signaling and cellular activity. Evidence from preclinical animal models and human genetic studies suggests that MS4A proteins play critical roles in various diseases (2). Therefore, we reviewed the recent progress in understanding the role of the MS4A superfamily in diseases, particularly in elucidating its function as a candidate biomarker and therapeutic target for cancer.

Background: Cell death plays an essential role in carcinogenesis, but its function in the recurrence and postoperative prognosis of head and neck cancer (HNC), which ranks as the 7^th most common malignancy globally, remains unclear.Methods: Data from five main subtypes of HNC related single-cell RNA sequencing (scRNA-seq) were recruited to establish a single-cell atlas, and the distribution of cell death models (CDMs) across different tissues as well as cell subtypes were analyzed. Bulk RNA-seq from the Cancer Genome Atlas Program (TCGA) dataset was subjected to a machine learning-based integrative procedure for constructing a consensus cell death-related signature risk score (CDRscore) model and validated by external data. The biofunctions including different expression analysis, immune cell infiltration, genomic mutations, enrichment analysis as well as cellchat analysis were compared between the high- and low- risk score groups categorized by this CDRscore model. Finally, samples from laryngeal squamous cell cancer (LSCC) were conducted by spatial transcriptomics (ST) to further validate the results of CDRscore model.Results: T cells from HNC patients manifested the highest levels of cell death while HPV infection attenuates malignant cell death based on single-cell atlas. CDMs are positively correlated with the tumor-cell stemness, immune-related score and T cells are infiltrated. A CDRscore model was established based on the transcription of ten cell death prognostic genes (MRPL10, DDX19A, NDFIP1, PCMT1, HPRT1, SLC2A3, EFNB2, HK1, BTG3 and MAP2K7). It functions as an independent prognostic factor for overall survival in HNC and displays stable and powerful performance validated by GSE41613 and GSE65858 datasets. Patients in high CDRscore manifested worse overall survival, more active of epithelial mesenchymal transition, TGF-β-related pathways and hypoxia, higher transcription of T cell exhausted markers, and stronger TP53 mutation. ST from LSCC showed that spots with high-risk scores were colocalized with TGF-β and the proliferating malignant cells, additionally, the risk scores have a negative correlation with TCR signaling but positive association with LAG3 transcription.Conclusion: The CDRscore model could be utilized as a powerful prognostic indicator for HNC.

Background: Natural infection or vaccination have provided robust immune defense against SARS-CoV-2 invasion, nevertheless, Omicron variants still successfully cause breakthrough infection, and the underlying mechanisms are poorly understood.Methods: Sequential blood samples were continuously collected at different time points from 252 volunteers who were received the CanSino Ad5-nCoV (n= 183) vaccine or the Sinovac CoronaVac inactivated vaccine (n= 69). The anti-SARS-CoV-2 prototype and Omicron BA.5.2 as well as XBB.1.16 variant neutralizing antibodies (Nab) in sera were detected by ELISA. Sera were also used to measure pseudo and live virus neutralization assay. The associations between the anti-prototype Nab levels and different HLA-ABC alleles were analyzed using artificial intelligence (AI)-deep learning techniques. The frequency of B cells in PBMCs was investigated by flow cytometry assay (FACs).Results: Individuals carrying the HLA-B^*15 allele manifested the highest concentrations of anti-SARS-CoV-2 prototype Nab after vax administration. Unfortunately, these volunteers are more susceptible to Omicron BA.5.2 breakthrough infection due to their sera have poorer anti-BA.5.2 Nab and lower levels of viral neutralization efficacy. FACs confirmed that a significant decrease in CD19⁺CD27⁺RBD⁺ memory B cells in these HLA-B^*15 population compared to other cohorts. Importantly, generating lower concentrations of cross-reactive anti-XBB.1.16 Nab post-BA.5.2 infection caused HLA-B^*15 individuals to be further infected by XBB.1.16 variant.Conclusions: Individuals carrying the HLA-B^*15 allele respond better to COVID-19 vax including the CanSino Ad5-nCoV and the Sinovac CoronaVac inactivated vaccines, but are more susceptible to Omicron variant infection, thus, a novel vaccine against this population is necessary for COVID-19 pandemic control in the future.

Purposes STAT1 is a transduction and transcriptional regulator that functions within the classical JAK/STAT pathway. In addition to chronic mucocutaneous candidiasis, bacterial infections are a common occurrence in patients with STAT1 gain-of-function (GOF) mutations. These patients often exhibit skewing of B cell subsets; however, the impact of STAT1-GOF mutations on B cell-mediated humoral immunity remains largely unexplored. It is also unclear whether these patients with IgG within normal range require regular intravenous immunoglobulin (IVIG) therapy. Methods Eleven patients (harboring nine different STAT1-GOF mutations) were enrolled. Reporter assays and immunoblot analyses were performed to confirm STAT1 mutations. Flow cytometry, deep sequencing, ELISA, and ELISpot were conducted to assess the impact of STAT1-GOF on humoral immunity. Results All patients exhibited increased levels of phospho-STAT1 and total STAT1 protein, with two patients carrying novel mutations. In vitro assays showed that these two novel mutations were GOF mutations. Three patients with normal total IgG levels received regular IVIG infusions, resulting in effective control of bacterial infections. Four cases showed impaired affinity and specificity of pertussis toxin-specific antibodies, accompanied by reduced generation of class-switched memory B cells. Patients also had a disrupted immunoglobulin heavy chain (IGH) repertoire, coupled with a marked reduction in the somatic hypermutation frequency of switched Ig transcripts. Conclusion STAT1-GOF mutations disrupt B cell compartments and skew IGH characteristics, resulting in impaired affinity and antigen-specificity of antibodies and recurrent bacterial infections. Regular IVIG therapy can control these infections in patients, even those with normal total IgG levels.

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has diverse clinical manifestations, which is the main feature of the disease, and the fundamental reason is the different immune responses in different bodies among the population. The damage mechanisms of critical illness by SARS-CoV-2 and its variants, such as hyperinflammatory response, a double-edged function of type I interferon, and hyperactivation of the complement system, are the same as other critical illnesses. Targeting specific immune damage mechanisms of COVID-19, we scored the first to put forward that the responses of T cells induced by acute virus infection result in “acute T-cell exhaustion” in elderly patients, which is not only the peripheral exhaustion with quantity reduction and dysfunction of T cells but also the central exhaustion that central immune organs lost immune homeostasis over peripheral immune organs, whereas the increased thymic output could alleviate the severity and reduce the mortality of the disease with the help of medication. We discovered that immune responses raised by SARS-CoV-2 could also attack secondary lymphoid organs, such as the spleen, lymphoid nodes, and kidneys, in addition to the lung, which we generally recognize. Integrated with the knowledge of mechanisms of immune protection, we developed a coronavirus antigen diagnostic kit and therapeutic monoclonal antibody. In the future, we will further investigate the mechanisms of immune damage and protection raised by coronavirus infection to provide more scientific strategies for developing new vaccines and immunotherapies.

The topic of this paper is the impact of Chinese monetary policy on stock price, and the importance of this study is mainly reflected with capital market gradually becomes a crucial feature of China's future economic development, the stock market, as a vital component of the capital market, is attracting more and more attention from the monetary authorities for its importance. In light of the aforementioned, this paper uses the M0, M1 and M2 data from 2010-2021, THE closing price of CSI 300 and the Shanghai interbank lending rate to build the VAR model to investigate how monetary policy affects stock prices. and the data in this paper are obtained from the CSMAR database and the Flush database. The study finds that although the money supply has a positive effect on stock prices and interest rates have a negative one, stock prices are still mostly controlled by their own fluctuations. This research offers some policy ideas based on this result.

Many encapsulated bacteria use capsules to cause invasive diseases. However, it remains largely unknown how the capsules enhance bacterial virulence under in vivo infection conditions. Here we show that the capsules primarily target the liver to enhance bacterial survival at the onset of blood-borne infections. In a mouse sepsis model, the capsules enabled human pathogens Streptococcus pneumoniae and Escherichia coli to circumvent the recognition of liver-resident macrophage Kupffer cells (KCs) in a capsular serotype-dependent manner. In contrast to effective capture of acapsular bacteria by KCs, the encapsulated bacteria are partially (low-virulence types) or completely (high-virulence types) “untouchable” for KCs. We finally identified the asialoglycoprotein receptor (ASGR) as the first known capsule receptor on KCs to recognize the low-virulence serotype-7F and -14 pneumococcal capsules. Our data identify the molecular interplay between the capsules and KCs as a master controller of the fate and virulence of encapsulated bacteria, and suggest that the interplay is targetable for therapeutic control of septic infections.