Advances in experimental medicine and biology最新文献

Immunoglobulin (Ig) is traditionally believed to be produced solely by B cells. Nonetheless, mounting evidence has demonstrated that various types of Igs are extensively expressed in many cell types. Among them, IgG is found to be highly expressed in cancer cells and is thus labeled as cancer-derived IgG. Cancer-derived IgG shares identical fundamental structures with B cell-derived IgG, but displays several unique characteristics, including restricted variable region sequences and unique glycosylation modifications for those expressed by epithelial cancers. Cancer-derived IgG plays multiple crucial roles in carcinogenesis, including facilitating cancer invasion and metastasis, enhancing cancer stemness, contributing to chemoresistance, and remodeling the tumour microenvironment. Recent studies have discovered that cancer-derived sialylated IgG (SIA-IgG) is extensively expressed in pancreatic cancer cells and is predominantly located in the cytoplasm and on the cell membrane. Cancer-derived IgG expressed by pancreatic cancer presents a restrictive variable region sequence and contains a unique sialylation site of the Fab region. Functionally, cancer-derived IgG participates in pancreatic cancer progression via different mechanisms, such as promoting proliferation, facilitating migration and invasion, resisting apoptosis, inducing inflammation, and modulating the tumour microenvironment. SIA-IgG has shown potential as a clinical biomarker. The expression of SIA-IgG is associated with poor tumour differentiation, metastasis, and chemoresistance in pancreatic cancer. High expression of SIA-IgG can serve as an independent prognostic factor for pancreatic cancer. Additionally, SIA-IgG expression elevated with malignant progression for the precursor lesions of pancreatic cancer. These findings present a prospect of applying cancer-derived IgG as a novel diagnostic and therapeutic target in the management of pancreatic cancer, and aiding in overcoming the challenge in the treatment of this stubborn malignancy.

The electrical impulses that coordinate the sequential, rhythmic contractions of the atria and ventricles are initiated and tightly regulated by the specialized tissues of the cardiac conduction system. In the mature heart, these impulses are generated by the pacemaker cardiomyocytes of the sinoatrial node, propagated through the atria to the atrioventricular node where they are delayed and then rapidly propagated to the atrioventricular bundle, right and left bundle branches, and finally, the peripheral ventricular conduction system. Each of these specialized components arise by complex patterning events during embryonic development. This chapter addresses the origins and transcriptional networks and signaling pathways that drive the development and maintain the function of the cardiac conduction system.

Mammalian cardiac development is a complex, multistage process. Though traditional lineage tracing studies have characterized the broad trajectories of cardiac progenitors, the advent and rapid optimization of single-cell RNA sequencing methods have yielded an ever-expanding toolkit for characterizing heterogeneous cell populations in the developing heart. Importantly, they have allowed for a robust profiling of the spatiotemporal transcriptomic landscape of the human and mouse heart, revealing the diversity of cardiac cells-myocyte and non-myocyte-over the course of development. These studies have yielded insights into novel cardiac progenitor populations, chamber-specific developmental signatures, the gene regulatory networks governing cardiac development, and, thus, the etiologies of congenital heart diseases. Furthermore, single-cell RNA sequencing has allowed for the exquisite characterization of distinct cardiac populations such as the hard-to-capture cardiac conduction system and the intracardiac immune population. Therefore, single-cell profiling has also resulted in new insights into the regulation of cardiac regeneration and injury repair. Single-cell multiomics approaches combining transcriptomics, genomics, and epigenomics may uncover an even more comprehensive atlas of human cardiac biology. Single-cell analyses of the developing and adult mammalian heart offer an unprecedented look into the fundamental mechanisms of cardiac development and the complex diseases that may arise from it.

The development of the inflow tract is undoubtedly one of the most complex remodeling events in the formation of the four-chambered heart. It involves the creation of two separate atrial chambers, the formation of an atrial/atrioventricular (AV) septal complex, the incorporation of the caval veins and coronary sinus into the right atrium, and the remodeling events that result in pulmonary venous return draining into the left atrium. In these processes, the atrioventricular mesenchymal complex, consisting of the major atrioventricular (AV) cushions, the mesenchymal cap on the primary atrial septum (pAS), and the dorsal mesenchymal protrusion (DMP), plays a crucial role.

The development of a fully functional four-chambered heart is critically dependent on the correct formation of the structures that separate the atrial and ventricular chambers. Perturbation of this process typically results in defects that allow mixing of oxygenated and deoxygenated blood. Atrioventricular septal defects (AVSD) form a class of congenital heart malformations that are characterized by the presence of a primary atrial septal defect (pASD), a common atrioventricular valve (cAVV), and frequently also a ventricular septal defect (VSD). While AVSD were historically considered to result from failure of the endocardial atrioventricular cushions to properly develop and fuse, more recent studies have determined that inhibition of the development of other components of the atrioventricular mesenchymal complex can lead to AVSDs as well. The role of the dorsal mesenchymal protrusion (DMP) in AVSD pathogenesis has been well-documented in studies using animal models for AVSDs, and in addition, preliminary data suggest that the mesenchymal cap situated on the leading edge of the primary atrial septum may be involved in certain situations as well. In this chapter, we review what is currently known about the molecular mechanisms and animal models that are associated with the pathogenesis of AVSD.

Natural killer (NK) cells are innate immune lymphocytes that rapidly produce cytokines upon activation and kill target cells. NK cells have been of particular interest in primary hemophagocytic lymphohistiocytosis (pHLH) since all of the genetic defects associated with this disorder cause diminished cytotoxic capacity of NK cells and T lymphocytes, and assays of NK cell killing are used clinically for the diagnosis of HLH. Herein, we review human NK cell biology and the significance of alterations in NK cell function in the diagnosis and pathogenesis of HLH.

Combined use of a surgical mask and oxygen mask might decrease the inspired oxygen concentration and increase the risk of hypercapnia. We investigated the fraction of inspired oxygen (FiO₂) and end-tidal carbon dioxide (ETCO₂) under different combinations of masks and oxygen flows. Five healthy volunteers were administered oxygen using the following methods: oxygen mask alone (O group), oxygen mask over a surgical mask (S group), and oxygen mask over an N95 mask (N group). FiO₂ and ETCO₂ were measured at oxygen flow rates of 0, 5, and 8 L/min under each mask condition. At oxygen flow rates of 5 and 8 L/min, FiO₂ was lower in the order of N group (0.32 at 5 L/min, 0.36 at 8 L/min), S group (0.45 at 5 L/min, 0.52 at 8 L/min), and O group (0.61 at 5 L/min, 0.73 at 8 L/min). ETCO₂ was higher in the order of N, S, and O groups. In conclusion, wearing the oxygen mask over the surgical mask or N95 mask reduces FiO₂ and increases ETCO₂ in healthy volunteers. Since patients who have emerged from general anaesthesia are more likely to have worse respiratory conditions, they need close observation to avoid hypoxemia and hypercapnia.

Sleep apnea syndrome (SAS) is associated with cardiopulmonary and dental nasopharyngeal diseases. The blood oxygen saturation (SpO₂) detected using pulse oximetry is a diagnostic screening method for SAS. SAS severity is assessed using the oxygen desaturation index (ODI), which measures the number of times the SpO₂ decreases by more than 3% for longer than 10 s. This study investigated the association between reduced SpO₂ and parasympathetic nervous system activity (PSNA) during night sleep in young adults (n = 63; aged 20-32 years). Changes in PSNA were measured every minute for 24 h during a free-moving day using an ActiveTracer accelerometer. Pulse oximetry was performed simultaneously during sleep. All participants had significantly lower PSNA when the SpO₂ decreased by 3% or more than when it did not. There were no significant differences in PSNA when an ODI cutoff of 5 events/h was used. However, participants with an ODI >5 events/h had significantly lower PSNA during normal SpO₂ than those with an ODI <5 events/h, suggesting an association between SpO₂ desaturation and PSNA decline during sleep. A high ODI may indicate reduced PSNA levels during sleep, affecting sleep efficiency. Treatment aimed at reducing the ODI may improve sleep quality, even in young adults.

The "oxygen paradox" embodies the delicate interplay between two opposing biological processes involving oxygen (O₂). O₂ is indispensable for aerobic metabolism, fuelling oxidative phosphorylation in mitochondria. However, excess O₂ can generate reactive species that harm cells. Thus, maintaining O₂ balance is paramount, requiring the prioritisation of its benefits while minimising potential harm. Previous research hypothesised that caveolae, specialised cholesterol-rich membrane structures with a curved morphology, regulate cellular O₂ levels. Their role in absorbing and controlling O₂ release to mitochondria remains unclear. To address this gap, we aim to explore how the structural features of caveolae, particularly membrane curvature, influence local O₂ levels. Using coarse-grained (CG) molecular dynamics simulations, we simulate a caveola-like curved membrane and select a CG bead as the O₂ model. Comparing a flat bilayer and a liposome of 10 nm diameter, composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), allows us to study changes in the O₂ free energy profile. Our findings reveal that curvature has a contrasting effect on the free energy of the outer and inner layers. These findings show the membrane curvature's impact on O₂ partitioning in the membrane and O₂ permeation barriers, paving the way towards our understanding of the role of caveolae curvature in O₂ homeostasis.