Exploring Cellular Gateways: Unraveling the Secrets of Disordered Proteins within Live Nuclear Pores.

Understanding the spatial organization of nucleoporins (Nups) with intrinsically disordered domains within the nuclear pore complex (NPC) is crucial for deciphering eukaryotic nucleocytoplasmic transport. Leveraging high-speed 2D single-molecule tracking and virtual 3D super-resolution microscopy in live HeLa cells, we investigated the spatial distribution of all eleven phenylalanine-glycine (FG)-rich Nups within individual NPCs. Our study reveals a nuanced landscape of FG-Nup conformations and arrangements. Five FG-Nups are steadfastly anchored at the NPC scaffold, collectively shaping a central doughnut-shaped channel, while six others exhibit heightened flexibility, extending towards the cytoplasmic and nucleoplasmic regions. Intriguingly, Nup214 and Nup153 contribute to cap-like structures that dynamically alternate between open and closed states along the nucleocytoplasmic transport axis, impacting the cytoplasmic and nuclear sides, respectively. Furthermore, Nup98, concentrated at the scaffold region, extends throughout the entire NPC while overlapping with other FG-Nups. Together, these eleven FG-Nups compose a versatile, capped trichoid channel spanning approximately 270 nm across the nuclear envelope. This adaptable trichoid channel facilitates a spectrum of pathways for passive diffusion and facilitated nucleocytoplasmic transport. Our comprehensive mapping of FG-Nup organization within live NPCs offers a unifying mechanism accommodating multiple transport pathways, thereby advancing our understanding of cellular transport processes.

Unveiling the complexity: assessing models describing the structure and function of the nuclear pore complex.

The nuclear pore complex (NPC) serves as a pivotal subcellular structure, acting as a gateway that orchestrates nucleocytoplasmic transport through a selectively permeable barrier. Nucleoporins (Nups), particularly those containing phenylalanine-glycine (FG) motifs, play indispensable roles within this barrier. Recent advancements in technology have significantly deepened our understanding of the NPC's architecture and operational intricacies, owing to comprehensive investigations. Nevertheless, the conspicuous presence of intrinsically disordered regions within FG-Nups continues to present a formidable challenge to conventional static characterization techniques. Historically, a multitude of strategies have been employed to unravel the intricate organization and behavior of FG-Nups within the NPC. These endeavors have given rise to multiple models that strive to elucidate the structural layout and functional significance of FG-Nups. Within this exhaustive review, we present a comprehensive overview of these prominent models, underscoring their proposed dynamic and structural attributes, supported by pertinent research. Through a comparative analysis, we endeavor to shed light on the distinct characteristics and contributions inherent in each model. Simultaneously, it remains crucial to acknowledge the scarcity of unequivocal validation for any of these models, as substantiated by empirical evidence.

GSDME-dependent pyroptosis signaling pathway in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the serious chronic microvascular complications of diabetes, and leads to the increased morbidity and mortality in diabetic patients. Gasdermin E (GSDME)-dependent pyroptosis signaling pathway plays important roles in a variety of physiological and pathological processes. However, its role and mechanism in DN are still unclear. In this study, we established a rat DN model by intraperitoneal injection of streptozotocin (STZ) successfully. Structural and functional disorders in the kidney were exhibited on the 12th week after STZ injection; the expressions of caspase-3 and GSDME at protein level in renal cortex were significantly up-regulated. At the 20th week, GSDME-N increased significantly, accompanied by the upregulation of caspase-1 in renal cortex and the release of mature IL-1ß (mIL-1ß) in serum. Furthermore, we found the protein levels of GSDME, caspase-3, caspase-1 and IL-1ß were all increased in HK2 and HBZY-1 cells under high-glucose conditions. We also found that the expression of GSDME-N significantly decreased when caspase-3 was knockdown. In contrast, knockdown of GSDME has no effect on caspase-3. Interestingly, either caspase-3, caspase-1 or GSDME knockdown reduced the release of mIL-1ß. Finally, injection of adeno-associated virus (AAV) 9-shGSDME into the rat kidney reduced kidney damage and renal cell pyroptosis in comparison with wild-type diabetic rats. These results indicated that the activation of caspase-1 induced IL-1ß maturation, and the activation of caspase-3 mediated cleavage of GSDME responsible for the formation of plasma membrane pore, followed by cytoplasmic release of mIL-1ß. Overall, we identified a pro-pyroptosis role for GSDME in DN, which does provide an important basis for clinical therapeutic studies.

Transcriptome Analysis Reveals the Inducing Effect of Bacillus siamensis on Disease Resistance in Postharvest Mango Fruit.

Postharvest anthracnose, caused by the fungus Colletotrichum gloeosporioides, is one of the most important postharvest diseases of mangoes worldwide. Bacillus siamensis (B. siamensis), as a biocontrol bacteria, has significant effects on inhibiting disease and improving the quality of fruits and vegetables. In this study, pre-storage application of B. siamensis significantly induced disease resistance and decreased disease index (DI) of stored mango fruit. To investigate the induction mechanisms of B. siamensis, comparative transcriptome analysis of mango fruit samples during the storage were established. In total, 234,808 unique transcripts were assembled and 56,704 differentially expressed genes (DEGs) were identified by comparative transcriptome analysis. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs showed that most of the DEGs involved in plant-pathogen interaction, plant hormone signal transduction, and biosynthesis of resistant substances were enriched. Fourteen DEGs related to disease-resistance were validated by qRT-PCR, which well corresponded to the FPKM value obtained from the transcriptome data. These results indicate that B. siamensis treatment may act to induce disease resistance of mango fruit by affecting multiple pathways. These findings not only reveal the transcriptional regulatory mechanisms that govern postharvest disease, but also develop a biological strategy to maintain quality of post-harvest mango fruit.

Chronic stress promotes breast carcinoma metastasis by accumulating myeloid-derived suppressor cells through activating ß-adrenergic signaling.

Numerous studies have found that chronic stress could promote tumor progression and this may be related to inhibtion of immune system. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells with immunosuppressive activity. MDSCs may represent a key link between chronic stress and tumor progression. However, the role of stress-induced MDSCs in breast cancer progression is unclear. The present study showed that pre-exposure of chronic stress could lead to MDSCs elevation and facilitated breast cancer metastasis in tumor-bearing mice. Adoptive transfer of MDSCs could significantly increase lung metastatic foci. In contrast, lung metastasis could be alleviated by depleting endogenous MDSCs with Gr-1 antibody. The concentration of norepinephrine in serum and the expression of tyrosine hydroxylase in bone marrow could be significantly elevated by chronic stress. Moreover, propranolol, an inhibitor of ß-adrenergic signaling, could inhibit breast carcinoma metastasis and prevent the expansion of chronic stress-induced MDSCs. Further study revealed that the expressions of IL-6 and JAK/STAT3 signaling pathways were upregulated by chronic stress in mice, and this upregulation could be inhibited by propranolol. Blocking the IL-6 signal or inhibiting the activation of the JAK/STAT3 signaling pathway could reduce tumor growth and metastasis by attenuating the accumulation of MDSCs in vivo. Besides, propranolol inhibited the expression of IL-6 in supernatant of 4T1 cells induced by isoproterenol and reduced the proportion of inducible MDSCs in vitro. Taken together, these data indicated that chronic stress may accumulate MDSCs via activation of ß-adrenergic signaling and IL-6/STAT3 pathway, thereby promoting breast carcinoma metastasis.

Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Mitochondrial dysfunction - including increased apoptosis, calcium and protein dyshomeostasis within the organelle, and dysfunctional bioenergetics and oxidative status - is a common, early feature in all the major neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD). However, the exact molecular mechanisms that drive the organelle to dysfunction and ultimately to failure in these conditions are still not well described. Different authors have shown that inorganic polyphosphate (polyP), an ancient and well-conserved molecule, plays a key role in the regulation of mitochondrial physiology under basal conditions. PolyP, which is present in all studied organisms, is composed of chains of orthophosphates linked together by highly energetic phosphoanhydride bonds, similar to those found in ATP. This polymer shows a ubiquitous distribution, even if a high co-localization with mitochondria has been reported. It has been proposed that polyP might be an alternative to ATP for cellular energy storage in different organisms, as well as the implication of polyP in the regulation of many of the mitochondrial processes affected in AD and PD, including protein and calcium homeostasis. Here, we conduct a comprehensive review and discussion of the bibliography available regarding the role of polyP in the mitochondrial dysfunction present in AD and PD. Taking into account the data presented in this review, we postulate that polyP could be a valid, innovative and, plausible pharmacological target against mitochondrial dysfunction in AD and PD. However, further research should be conducted to better understand the exact role of polyP in neurodegeneration, as well as the metabolism of the polymer, and the effect of different lengths of polyP on cellular and mitochondrial physiology.

The Function, Regulation and Mechanism of Programmed Cell Death of Macrophages in Atherosclerosis.

Atherosclerosis is a chronic progressive inflammatory vascular disease, which is an important pathological basis for inducing a variety of cardio-cerebrovascular diseases. As a kind of inflammatory cells, macrophages are the most abundant immune cells in atherosclerotic plaques and participate in the whole process of atherosclerosis and are the most abundant immune cells in atherosclerotic plaques. Recent studies have shown that programmed cell death plays a critical role in the progression of many diseases. At present, it is generally believed that the programmed death of macrophages can affect the development and stability of atherosclerotic vulnerable plaques, and the intervention of macrophage death may become the target of atherosclerotic therapy. This article reviews the role of macrophage programmed cell death in the progression of atherosclerosis and the latest therapeutic strategies targeting macrophage death within plaques.