Nawal Abdul-Baki, Reimi Navarro, Jieh-Juen Yu
et al.
Coccidioidomycosis (CM) is a fungal infection caused by the inhalation of airborne arthroconidia released by Coccidioides spp. Endemic areas include the southwestern United States, Mexico, and parts of South America. The estimated CM cases exceed 300,000 per year. Current treatment for CM is limited and primarily relies on antifungals such as azoles and Amphotericin B. Moreover, concerns about drug cytotoxicity and rising of azole-resistance underscore the need for alternative or adjunctive immune-based prevention and therapies. This review presents recent advances in immune CM intervention and discusses the potential application of emerging antifungal immunotherapy to treat invasive CM. For preventive vaccination, we reviewed the recent development of subunit protein vaccines and mRNA-based vaccines. Prospects for formulating vaccines with potent adjuvants and delivery systems to enhance protective immunity against CM are also provided. For immunotherapy, we reviewed recent reports of antifungal treatment with immunomodulators, CAR-cells and checkpoint inhibitors. Finally, we discuss the application of experimental animal and in vitro models for advancing vaccine and immunotherapeutic development for CM.
There is growing interest in pre-training antibody language models ( AbLMs ) with a mixture of unpaired and natively paired sequences, seeking to combine the proven benefits of training with natively paired sequences with the massive scale of unpaired antibody sequence datasets. However, given the novelty of this strategy, the field lacks a systematic evaluation of data processing methods and training strategies that maximize the benefits of mixed training data while accommodating the significant imbalance in the size of existing paired and unpaired datasets. Here, we introduce a method of curriculum learning for AbLMs, which facilitates a gradual transition from unpaired to paired sequences during training. We optimize this method and compare it to other data sampling strategies for AbLMs, including a constant mix and a fine-tuning approach. We observe that the curriculum and constant approaches show improved performance compared to the fine-tuning approach in large-scale models, likely due to their ability to prevent catastrophic forgetting and slow overfitting. Finally, we show that a 650M-parameter curriculum model, CurrAb, outperforms existing mixed AbLMs in downstream residue prediction and classification tasks.
BackgroundAging is accompanied by profound changes in immune regulation and epigenetic landscapes, yet the molecular drivers underlying these alterations are not fully understood.MethodsTranscriptional profiles of peripheral blood samples from young and elderly individuals, together with aging-associated methylation probe data, were used to identify aging biomarkers. Transcriptomics and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to explore potential regulatory mechanisms. Functional validation was performed via knockdown in immune and microglial cell lines, assessing inflammatory responses and reactive oxygen species (ROS) levels. Finally, an independent cohort was recruited to validate expression and promoter methylation, with ChIP-seq and the assay for transposase-accessible chromatin with sequencing (ATAC-seq) analyses supporting epigenetic repression as the underlying mechanism.ResultsLEF1 expression was significantly downregulated in elderly individuals, accompanied by increased promoter methylation, indicating age-related epigenetic repression. Integrated multi-omics analysis linked LEF1 to immune inflammation and neurodegenerative pathways. LEF1 knockdown enhanced inflammatory responses and ROS production in vitro. ChIP-seq and ATAC-seq data supported epigenetic repression as a mechanism for age-related LEF1 silencing.ConclusionsAge-related epigenetic repression of LEF1 contributes to immune-inflammatory activation and may underlie neurodegenerative processes.
Mitochondrial antiviral signaling (MAVS) was first discovered as an activator of NF-κB and IRF3 in response to viral infection in 2005. As a key innate immune adapter that acts as an ‘on/off’ switch in immune signaling against most RNA viruses. Upon interaction with RIG-I, MAVS aggregates to activate downstream signaling pathway. The MAVS gene, located on chromosome 20p13, encodes a 540-amino acid protein that located in the outer membrane of mitochondria. MAVS protein was ubiquitously expressed with higher levels in heart, skeletal muscle, liver, placenta and peripheral blood leukocytes. Recent studies have reported MAVS to be associated with various conditions including cancers, systemic lupus erythematosus, kidney disease, and cardiovascular disease. This article provides a comprehensive summary and description of MAVS research in cardiac disease, encompassing structure, expression, protein-protein interactions, modifications, as well as the role of MAVS in heart disease. It is aimed to establish a scientific foundation for the identification of potential therapeutic target.
Boyang Dong,1 Liangzhen Xie,2 Yan Li2 1Graduate School, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China; 2Ear-Nose-Throat Department, the First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of ChinaCorrespondence: Yan Li, Ear-Nose-Throat Department, the First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China, Email liyan888111@163.comAbstract: Allergic rhinitis (AR) is a prevalent chronic inflammatory allergic disease, characterized by paroxysmal nasal congestion, itching, sneezing, and rhinorrhea, which affects mental health in severe cases. Western medical treatments primarily rely on glucocorticoids and antihistamines, which, while providing symptomatic relief, are associated with varying degrees of side effects and fail to ensure long-term efficacy. The pathogenesis of AR is intricately related to immune system dysregulation, and the treatment of AR has not yet been fully clarified. Natural products, having co-evolved with humans over millennia, boast structural diversity and rich biological activity, and they can precisely interact with intracellular targets such as enzymes, receptors, and ion channels, positioning them as a vital resource for therapeutic interventions. Notably, validated natural products often contain multiple active constituents, which confer broader therapeutic effects compared to single-component compounds. These constituents also exhibit lower acute toxicity than synthetic drugs, ensuring superior long-term. The synergistic interactions among their components endow them with dual potential for both prevention and treatment. Natural products modulate AR pathogenesis through various signaling pathways, addressing key etiological factors such as immune dysregulation, inflammatory responses, as well as oxidative stress. These developments will drive research and application of natural products in AR management, unlocking their untapped potential. This review systematically examines the mechanisms by which natural products regulate AR pathogenesis through signaling pathways, drawing on both animal studies and laboratory research, though clinical data are still relatively limited. By elucidating their specific mechanisms of action, this work not only provides novel insights for developing effective, long-term AR management drugs but also offers scientific guidance for experimental research and clinical application in AR therapeutics.Keywords: allergic rhinitis, natural products, pathogenesis, signaling pathways, therapeutic mechanism
Amanda Brady, Taylor M. Garrison, Robert K. Ernst
et al.
ABSTRACT Yersinia pestis is the etiological agent of human plague. However, certain evolutionarily divergent subspecies have different host specificities and virulence capacity compared to the more commonly studied strains with pandemic potential. This resource examines 10 diverse isolates representing some of the most understudied subspecies commonly referred to as Yersinia pestis Pestoides.
CAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.
BackgroundGlucose-to-lymphocyte ratio (GLR) plays an important role in the prognosis of various tumors. The aim of this study was to comprehensively evaluate the prognostic value of GLR in solid tumors through the meta-analysis.MethodsA comprehensive search of eligible studies was performed by scrutinizing the Pubmed, Embase and Web of science databases until May 30, 2024. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to evaluate overall survival (OS), disease-free survival (DFS) and recurrence free survival (RFS).ResultsA total of 22 studies from 14 articles involving 9472 patients were included in the study. The pooled analysis showed that cancer patients with high GLR was significantly associated with unfavorable OS (HR:1.48,95% CI:1.34-1.63) and DFS/RFS (HR:2.20,95% CI:1.66-2.92). Subgroup analysis further showed that high GLR had better predictive value in liver cancer (HR:2.66, 95%CI:1.80-3.93), breast cancer (HR:2.13, 95%CI:1.10-4.13) and pancreatic cancer (HR:1.92, 95%CI:1.30-2.84).ConclusionsGLR can be used as an effective prognostic marker in patients with solid tumors.
Tumor mutation burden (TMB) is a widely recognized biomarker for predicting the efficacy of immunotherapy. However, its use still remains highly controversial. In this study, we examine the underlying causes of this controversy based on clinical needs. By tracing the source of the TMB errors and analyzing the design philosophy behind variant callers, we identify the conflict between the incompleteness of biostatistics rules and the variety of clinical samples as the critical issue that renders TMB an ambivalent biomarker. A series of experiments were conducted to illustrate the challenges of mutation detection in clinical practice. Additionally, we also discuss potential strategies for overcoming these conflict issues to enable the application of TMB in guiding decision-making in real clinical settings.
The axial skeleton, with the exception of spondyloarthropathy, is the most neglected aspect of rheumatology training and, as a result, perhaps the most complex. The clinical “problem” of back/neck pain could be considered the “orphan child” of medicine, and our perspective as rheumatologists is often sought for such entities. Sources of back/neck pain are myriad, and not all phenomena affecting the back are symptomatic. Perhaps the one that has most concerned rheumatologists is the cervical instability associated with rheumatoid arthritis. The current review examines intrinsic and extrinsic alterations in axial skeletal components, providing a guide to discriminating the causes (e.g., Scheuermann’s disease versus osteoporotic compression and the various forms of axial joint ankylosis) and the implications of vertebral endplate alterations. The specificity and sensitivity (limitations) of radiologic findings are reviewed, with a reminder that vertebral body osteophytes do not represent osteoarthritis and are therefore unlikely to explain back or neck complaints and that it is our clinical examination which will likely suggest symptom origin.
BackgroundThe role of immune checkpoint inhibitors (ICIs) in NSCLC patients with EGFR mutations are controversial. In this study, we aim to investigate the therapeutic efficacy of ICIs alone or in combination in patients with EGFR mutated NSCLC in late-line settings, and explore the factors that may predict the efficacy of ICIs.Patients and MethodsWe retrospectively collected the clinical and pathological information of 75 patients with confirmed EGFR mutations. All patients have developed acquired resistance to EGFR-TKIs, and were treated with ICIs in late line settings from January 2019 to January 2021, at Shandong Caner Hospital and Institute. Therapeutic efficacy was evaluated by tumor response and survival.ResultsThe median follow-up period was 7.3months (range 1.8-31.8 months). The overall response rate (ORR) was 8.0%, and the disease control rate (DCR) was 78.7%. The median PFS for all patients was 3.9 months (95% CI, 2.7-5.0), while the median OS was 9.9 months (95% CI, 5.3-14.6). We found that patients with longer response duration to EGFR-TKIs (≥10 months) showed a longer PFS when treated with immunotherapy compared with patients with shorter PFS-TKI (<10 months), the median PFS in two groups were 5.2 months [95%CI 4.2-6.2] and 2.8 months [2.0-3.6]) respectively (HR, 0.53, 95%CI, 0.31-0.91, P=0.005). In exploratory analysis, we found that concurrent extracranial radiotherapy and higher body mass index (BMI) are associated with longer PFS (P values are 0.006 and 0.021 respectively).ConclusionsWe found that combination regimen of immunotherapy plus chemotherapy plus antiangiogenetic agents may yield longer survival in patients with EGFR mutated NSCLC. We also found that patients with longer PFS-TKI, concurrent extracranial radiotherapy and higher BMI may benefit more from immunotherapy.
BackgroundIn this study, we investigated the prediction and prognostic value of SDF-1 for triple-negative breast cancer (TNBC) patients who underwent neoadjuvant chemotherapy (NAC) following standard radical surgery.MethodsA total of 303 TNBC patients were included in this study. The NAC regimen was weekly paclitaxel plus carboplatin (PC) for all patients. SDF-1 and CXCR4 expression were measured at baseline and surgery via enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC), respectively. Correlations between variables and treatment response were studied, and Cox proportional hazards regression analysis was implemented for prognostic evaluation.ResultsOf the 303 patients, 103 (34.0%) experienced pathological complete response (pCR) after completion of NAC. Serum SDF-1 expression before NAC was significantly correlated with the abundance of TILs. A higher pCR rate was more likely to be observed in patients with lower serum SDF-1 levels before NAC (P=0.001, OR=0.997, 95% CI: 0.996-0.999) and higher levels of TILs (P=0.005). In the multivariate survival model for nonpCR patients, serum SDF-1 expression at surgery served as an independent prognostic value for survival (high level, HR=1.980, 95% CI: 1.170-3.350, low level was used as a reference; P=0.011). Additionally, the predictive and prognostic value of serum SDF-1 expression was significant in patients with high abundance of TILs but not in patients with low abundance of TILs.ConclusionsThis study contributes to the clarification of the value of serum SDF-1 to predict pCR and survival for TNBC patients who underwent NAC. This new serum marker, together with TILs, might help identify clinical subtypes of TNBC with different treatment responses and survival and play an important role in tailoring and modifying the NAC strategy for advanced TNBCs in the future.
Small antibacterial effectors, including lysozymes, lectins, and antimicrobial peptides, are key regulators of intestinal immunity. However, whether there is coordination among them during regulation is an interesting, but largely unknown, issue. In the present study, we revealed that small effectors synergistically regulate peptidoglycan-derived intestinal immunity in the kuruma shrimp, Marsupenaeus japonicus. A C-type lysozyme (LysC) was screened as a responsive factor for the intestine-bacteria interaction. LysC functions to restrict intestinal bacteria, mainly by cleaving Photobacterium damselae peptidoglycan to generate muropeptides which are powerful stimulators that induce anti-lipopolysaccharides factor B1 (AlfB1), an effective bactericidal peptide. The muropeptides also induce a C-type lectin (Ctl24), which recognizes peptidoglycan and coats bacteria. By counteracting LysC-mediated muropeptide release and AlfB1’s bactericidal activity, Ctl24 prevents the continuous elimination of intestinal bacteria. Therefore, this study demonstrates a mechanism by which small immune effectors coordinate to achieve intestinal homeostasis, and provides new insights into peptidoglycan-derived intestinal immunity in invertebrates. Author summary Intestinal homeostasis largely determines the healthy status of metazoan animals. Uncovering the mechanism for intestinal homeostasis would be helpful to develop new strategies for disease control. In this study, we demonstrated that small immune effectors, including lysozyme, lectin, and bactericidal peptide, collaborate to regulate shrimp intestinal homeostasis in shrimp. Intestinal bacterial peptidoglycan is digested by a lysozyme into muropeptides, which induce the expression of this lysozyme, a bactericidal peptide and a lectin. The former two effectors are able to restrict intestinal bacteria by generating muropeptides and killing bacteria, respectively, while the latter one counteracts their functions. By coating peptidoglycan, this lectin inhibits lysozyme-mediated muropeptides release, and bactericidal peptide-mediated killing of bacteria. Through controlling, but not eliminating intestinal bacteria, these small effectors together achieve a dynamic balance of intestinal bacteria in shrimp. Therefore, this study emphasized the significance of peptidoglycan as the driving force for intestinal homeostasis, and provides insights into generating a healthy intestinal microbiota by utilizing the synergy among small immune effectors.
Jasmine C. Labuda, Oanh H. Pham, Claire E. Depew
et al.
Significance Sexually transmitted infections are widespread and cause irreparable harm to young women. After infection of the female reproductive tract, lymphoid clusters are generated with fully resident lymphocytes that do not recirculate via blood or lymphatic vessels. However, the protective value of tissue-resident lymphocytes or cluster formation has not been determined for important reproductive pathogens. Our study demonstrates that these local immune structures are unnecessary for robust protective immunity to Chlamydia . Instead, efficient tissue surveillance is provided by circulating memory lymphocytes generated outside reproductive tissues. These findings reinforce the value of assessing circulating, rather than local, immune parameters of Chlamydia immunity and suggest that future vaccine efforts should focus on the elicitation of robust systemic immunity to provide local mucosal protection.
Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian cells, the ubiquitous palmitoyltransferases (PATs) and serine hydrolases, including acyl protein thioesterases (APTs), catalyze the addition and removal of palmitate, respectively. The attachment of palmitoyl groups alters the membrane affinity of the substrate protein changing its subcellular localization, stability, and protein-protein interactions. Forty years of research has led to the understanding of the role of protein palmitoylation in significantly regulating protein function in a variety of biological processes. Recent global profiling of immune cells has identified a large body of S-palmitoylated immunity-associated proteins. Localization of many immune molecules to the cellular membrane is required for the proper activation of innate and adaptive immune signaling. Emerging evidence has unveiled the crucial roles that palmitoylation plays to immune function, especially in partitioning immune signaling proteins to the membrane as well as to lipid rafts. More importantly, aberrant PAT activity and fluctuations in palmitoylation levels are strongly correlated with human immunologic diseases, such as sensory incompetence or over-response to pathogens. Therefore, targeting palmitoylation is a novel therapeutic approach for treating human immunologic diseases. In this review, we discuss the role that palmitoylation plays in both immunity and immunologic diseases as well as the significant potential of targeting palmitoylation in disease treatment.