Advances in biological regulation最新文献

The pancreatic islet, historically described as a binary system of insulin-secreting beta cells and glucagon-secreting alpha cells, is increasingly recognized as a complex paracrine network contributing to glucose homeostasis. Alpha-to-beta cell communication is not merely modulatory but a decisive mechanism sustaining islet function under metabolic stress. Alpha cell distribution, structural specializations at the alpha-beta interface, and adaptations in signaling pathways collectively shape glycemic set points and beta cell resilience. Recent studies highlight the context-dependent nature of this intra-islet crosstalk. Visa et al. demonstrated that prediabetic stress in Western diet-fed mice remodels islet cytoarchitecture in a sex-dependent manner, enhancing alpha-to-beta signaling and Ca²⁺ dynamics, and thereby preserving insulin secretion more effectively in females than in males. Experiments using a glucagon receptor antagonist in human islets confirmed that glucagon paracrine signaling is essential for this adaptive enhancement, particularly the increased Ca²⁺ dynamics in female islets under high metabolic demand. Mechanistic studies further revealed that the GLP-1 receptor forms specialized nanodomains at the alpha-beta junction that undergo pre-internalization, priming beta cells for rapid Ca²⁺ influx and heightened metabolic responsiveness. Collectively, these findings highlight intra-islet communication as a critical determinant of adaptation or failure in diabetes progression. However, conflicting evidence from beta cell-only islets, which display enhanced glucose-stimulated insulin secretion, together with reports that long-term exposure to the GLP-1 analog liraglutide can compromise beta cell function, presents a paradox that challenges current models of intra-islet regulation. Understanding these nuances is crucial for translating intra-islet signaling into targeted therapeutic strategies and regenerative tissue engineering.

CD19 is a central regulator of B-cell biology, acting both as a lineage marker and a critical modulator of signaling thresholds that govern development, activation, and tolerance. Structurally, CD19 is a heavily glycosylated transmembrane protein whose cytoplasmic domain harbors multiple tyrosine motifs serving as docking sites for key signaling molecules, including PI3K. Its expression is tightly regulated by transcriptional, post-transcriptional, and post-translational mechanisms, as well as by interactions with CD21 and CD81 in surface complexes. Genetic studies in mice and humans demonstrate that CD19 acts as a molecular rheostat, with both deficiency and overexpression leading to profound immunological dysfunctions ranging from hypogammaglobulinemia to autoimmunity. Importantly, recent work has revealed an additional level of CD19 signaling regulation mediated by conformational control of the CD19 cytoplasmic domain. A basic CD19 cytoplasmic juxtamembrane region engages in ionic interactions with PtdIns(4,5)P2, thereby influencing CD19 activation state. Loss of the 5-phosphatase INPP5K increases PtdIns(4,5)P2 levels, leading to constitutive CD19 signaling, impaired B-cell development and hypogammaglobulinemia. This discovery underscores the role of lipid-protein interactions in restraining inappropriate CD19 activation. Clinically, CD19 has emerged as a validated therapeutic target, with CAR T cells, bispecific antibodies, and monoclonal antibodies achieving remarkable efficacy in B-cell malignancies and autoimmune disorders. Understanding the fine regulation of CD19 expression, structure, and signaling remains essential to optimize therapeutic strategies.

The myelodysplastic syndromes (MDS) are common myeloid malignancies that develop from the successive acquisition of driver mutations in hematopoietic stem cells residing in the bone marrow. Around a third of MDS patients will develop secondary acute myeloid leukemia (sAML) and patients with high-risk MDS or sAML have a dismal prognosis. The study of disease progression in myeloid malignancy has been enhanced in recent years by the use of induced pluripotent stem cells (iPSCs) technology. iPSCs offer the advantage of indefinite expansion and the potential for genetic modification, with reprogramming enabling the capture of the full complement of genetic lesions found in primary patient bone marrow samples. The power of iPSC and CRISPR-Cas9 gene editing technologies have been harnessed to generate a range of iPSC-based cellular models of MDS, reflecting the genetic and biologic heterogeneity of the disease. Stage-specific patient iPSC lines have been produced and sequential gene editing in normal human iPSCs has been performed to map the evolution of MDS to AML. These studies have increased our understanding of the impact of driver mutations, and co-mutations, on disease phenotype and revealed mechanisms underlying disease stage transitions in myeloid malignancy. iPSC-based models of MDS have also proven important tools in high throughput drug screening and have empowered drug testing and drug discovery, offering a new platform to develop personalized therapy.

Genetic alterations in genes encoding components of the PI3K/AKT/mTOR signaling pathway are frequently observed in head and neck squamous cell carcinoma (HNSCC), breast cancer, and a variety of other human malignancies. In particular, PIK3CA, encoding the p110α catalytic subunit of PI3K enzyme, is altered in approximately 30 % of HNSCC tumors and 37 % of breast cancer tumors. In addition, loss of PTEN protein, a negative regulator of PI3K signaling, occurs in roughly one-third of HNSCC. Here, we review the impact of these alterations on the growth and metabolism of cancer cells and summarize progress that has been made in the development and clinical evaluation of inhibitors that directly target p110α and related proteins. We also describe emerging approaches that are identifying unique vulnerabilities and targeting opportunities in tumors characterized by PIK3CA or PTEN alterations.