Rheumatic diseases exhibit insidious onset and non-specific early manifestations, causing substantial diagnostic delays in primary care. This delay is closely linked to a prolonged subclinical inflammation phase, where pathogenic immune processes are active yet clinically inapparent. The mechanistic basis of this early disease concealment remains incompletely synthesized. Subclinical inflammation represents a state of persistent, low-grade immune activation in the absence of overt clinical signs, structural damage, or marked laboratory abnormalities. This phase is driven primarily by innate immune priming, sterile inflammation, and low-intensity cytokine signaling, which together sustain immune dysregulation below conventional diagnostic thresholds. Key processes include pattern recognition receptor activation, inflammasome signaling, modest but chronic cytokine production, and gradual erosion of immune tolerance. These mechanisms precede adaptive immune engagement, autoantibody maturation, and tissue-specific inflammation, thereby creating a temporal dissociation between molecular pathology and clinical expression. Disease-specific evidence from rheumatoid arthritis and systemic lupus erythematosus how subclinical inflammation constitutes a common early pathogenic state across diverse rheumatic conditions. Importantly, the heterogeneity and compartmentalization of early immune activation explain why routine clinical assessment and standard inflammatory markers frequently fail to detect active disease in primary care. By integrating current mechanistic insights, this review reframes diagnostic delay as a biologically driven phenomenon rather than a limitation of clinical practice. Understanding the mechanisms of subclinical inflammation provides a rational framework for risk-informed recognition and timely referral in primary care, with potential implications for improving long-term outcomes in rheumatic diseases.

Lactiplantibacillus plantarum (formerly Lactobacillus plantarum) Lp05, a strain isolated from pickled vegetables, is widely used as a probiotic in the food industry. However, its impact on the host immune system, especially the adaptive immune system, remains poorly understood. In this study, we systematically evaluated the influence of Lp05 on T cell immunity under both homeostatic and inflammatory conditions in mice. First, we showed that early life exposure to Lp05 does not compromise the development or maturation of the adaptive immune system, as evidenced by normal thymic T cell development and unaltered immune cell profiles in the spleen and lymph nodes of offspring from Lp05-treated dams. Second, in an inflammatory setting of an inflammatory bowel disease model, Lp05 supplementation protected mice against dextran sulfate sodium-induced colitis. Mechanistically, this protection was correlated with an increased differentiation of CD4[+]Foxp3[+] Treg cells, likely associated with enhancement of microbial amino acid biosynthesis and metabolic pathways in the gut. Taken together, our findings demonstrate that Lp05 administration is safe for T cell development and exhibits therapeutic potential in colitis, primarily by promoting Treg cell differentiation.

Preeclampsia is a multisystem hypertensive disorder of pregnancy that significantly increases maternal and fetal morbidity and long‑term cardiovascular risk. Growth differentiation factor 15 (GDF‑15) is a stress‑responsive member of the TGF‑β superfamily that is highly expressed in the placenta and secreted into the maternal circulation, where levels rise markedly during gestation. Emerging evidence has positioned GDF‑15 as a potential biomarker for preeclampsia, with multiple studies reporting elevated concentrations in affected women, particularly in early‑onset disease. This review comprehensively examines the molecular mechanisms governing GDF‑15 generation, maturation, and secretion, and delineates its functional roles in placental physiology, including trophoblast invasion, syncytiotrophoblast renewal, endothelial protection, and metabolic regulation. We further explore the genetic architecture of the GDF15 locus, highlighting functional variants such as rs888663 that influence expression levels and may modulate disease susceptibility. The clinical utility of GDF‑15 is critically appraised in the context of established angiogenic markers, with emphasis on its additive predictive value, temporal limitations relative to the aspirin preventive window, and the need for assay standardization. Finally, key unresolved questions are identified, including whether GDF‑15 elevation is pathogenic or compensatory, and how it interacts with the broader network of angiogenic, inflammatory, and metabolic pathways in preeclampsia.

Brain organoids, as pioneering three-dimensional (3D) in vitro platforms, have profoundly advanced our understanding of human brain development and disease mechanisms. This review summarizes recent progress in enhancing cellular diversity, structural organization, and functional complexity within brain organoids. A key application of these models lies in disease modelling, encompassing neurodevelopmental and neurodegenerative disorders as well as brain tumours, which enables personalized drug screening and mechanistic studies. Despite persistent challenges related to neuronal maturation, vascularization, reproducibility, and functional integration, we highlight emerging bioengineering strategies, multi-organ integration approaches, and ethical considerations that provide a roadmap for next-generation organoid platforms. Collectively, brain organoids hold transformative potential for both fundamental neuroscience and translational research, bridging critical gaps between conventional experimental models and human-specific pathophysiology.

CD4[+] T cells are the principal cellular targets of HIV-1, yet the extent to which viral proteins reshape their transcriptional identity remains incompletely understood. Here, using an integrated multi-omics approach, we identified a distinct population of HIV-1 RNA-positive CD4[+] T cells that localized within transcriptionally defined B-cell clusters and expressed multiple canonical B cell-associated genes during acute infection. Mechanistic analyses revealed that this phenotype was driven by the HIV-1 accessory protein Vpr. Both Vpr overexpression and Vpr-deficient viral systems demonstrated that Vpr induces the expression of CD19, MS4A1, CD22, and PAX5 in primary CD4[+] T cells. Single-cell RNA sequencing, bulk RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq) further showed that Vpr promotes extensive transcriptional and epigenetic remodeling, accompanied by increased accessibility and expression of genes involved in B-cell differentiation and development, including PAX5, EBF1, and PRDM1. Notably, this B cell-like transcriptional program was transient and gradually diminished during prolonged culture. Together, our findings uncover an unexpected role of Vpr in inducing lineage-associated transcriptional reprogramming in mature CD4[+] T cells and provide new insight into how HIV-1 manipulates host-cell identity during infection.

ABCC8 pathogenic variants have been found to cause neonatal diabetes mellitus (NDM), maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI), depending on the nature of the mutation. Few studies have reported on the carrier frequency of CHI-related ABCC8 variants. In Singapore, the carrier rate is 1 in 754. Paternally inherited ABCC8 recessive variants have been classically associated with focal lesions causing CHI. In our case series of five patients with paternally inherited ABCC8 variants, one patient had a second maternally inherited recessive variant, making him a compound heterozygous genotype presenting with severe, neonatal onset, diffuse disease that was not responsive to diazoxide. The remaining four patients had a single paternally inherited ABCC8 variant, of which three were previously reported to be recessive variants-only 1 had a focal lesion while the rest had diffuse disease. A comprehensive review of our cases suggests that patients with paternally inherited ABCC8 variants, whether autosomal recessive, heterozygous, or associated with genetic syndromes, were heterogeneous in their clinical manifestations and cannot be reliably distinguished based on their initial clinical presentation. A deeper understanding of the genotype-phenotype correlation of ABCC8-related CHI will require further research and functional analyses. Both a genetic diagnosis and imaging using [18]F-DOPA-PET should be pursued in a timely manner once diazoxide unresponsiveness has been established. Single-stage near-total pancreatectomy may be considered for patients with diffuse disease.

Most cancer therapeutics that show preclinical promise fail in clinical trials, underscoring the need for complementary disease models. Over the past two decades, zebrafish models have matured from a tool for studying vertebrate development into a versatile platform spanning the translational cancer pipeline. Transgenic and transplantation zebrafish models have dissected fundamental mechanisms of tumor initiation and metastasis. Beyond mechanistic insight, phenotypic chemical and genetic screens provide a rapid, whole-organism filter to prioritize and repurpose therapeutic candidates, several of which have reached the clinic. Most recently, zebrafish patient-derived xenografts have begun to predict individual patient treatment responses within clinically actionable timeframes. Tracing this evolution, we argue that zebrafish models are not a replacement for other systems but earn their translational value when applied to the questions they answer best and when embedded in co-clinical workflows alongside oncology teams.

This article critically examines ADAM19-mediated inflammatory remodeling within five distinct subtypes of solid tumors prone to inflammation, employing non-neoplastic inflammatory states strictly as a comparative reference. As a transmembrane protease belonging to the ADAM family, ADAM19 undergoes maturation through plasmin-dependent cleavage, with its expression tightly regulated by both transcriptional and epigenetic controls. Although dysregulated ADAM19 levels are evident in various inflammatory lesions and malignancies, its context-specific dual biological roles necessitate a systematic synthesis.

Precise extracellular matrix (ECM) coordination is essential for cardiac septation, yet the molecular etiology of human isolated perimembranous ventricular septal defects (VSD) remains elusive. Here, we constructed a high-resolution single-cell transcriptomic atlas of human VSD, benchmarking the pathological state against a 7-22 week developmental trajectory. Integrating these single-cell profiles with a reference-based spatial transcriptomic map, we deconvolved the distinct molecular signatures of membranous and muscular septal regions. We found that aberrant cardiomyocyte hypertrophy operates alongside a systemic failure in the non-myocyte microenvironment. Crucially, the ECM regulatory network is dysregulated, driven by attenuated endothelial-fibroblast crosstalk and downregulated THBS1-integrin signaling. Supported by in vitro assays, this dysregulation impairs key endothelial-to-mesenchymal transition (EndoMT) programs and transcriptionally suppresses MMP2. Spatial reconstruction confirmed this maturation block compromises both septal regions, indicating a global remodeling arrest that precludes physical closure. Validated by in situ immunofluorescence and a robust correlation between reduced maternal serum MMP2 levels and defect size, our study portrays VSD as a disease driven by microenvironmental insufficiency and arrested remodeling, providing an integrative framework for understanding human cardiac dysmorphogenesis.