Explore the vast range of titles available.

Background and Objectives: VPS26A, a core component of the retromer complex, is pivotal to endosomal trafficking and membrane protein recycling. However, its expression profile, prognostic significance, and clinical relevance in liver hepatocellular carcinoma (LIHC) remain unexplored. This study investigates the prognostic potential of VPS26A by extensively analyzing publicly available LIHC-related databases. Materials and Methods: Multiple databases, including TIMER, UALCAN, HPA, GSCA, KM Plotter, OSlihc, MethSurv, miRNet, OncomiR, LinkedOmics, GeneMANIA, and STRING, were used to evaluate VPS26A expression patterns, prognostic implications, correlations with tumor-infiltrating immune cells (TIICs), epigenetic modifications, drug sensitivity, co-expression networks, and protein–protein interactions in LIHC. Results: VPS26A was significantly overexpressed at both the mRNA and protein levels in LIHC tissues compared to that in normal tissues. This upregulation was strongly associated with a poor prognosis. Furthermore, VPS26A expression was both positively and negatively correlated with various TIICs. Epigenetic analysis indicated that VPS26A is regulated by promoter and regional DNA methylation. Additionally, VPS26A influences the sensitivity of LIHC cells to a broad range of anticancer agents. Functional enrichment and co-expression analyses revealed that VPS26A serves as a central regulator of the LIHC transcriptomic landscape, with positively correlated gene sets linked to poor prognosis. Additionally, VPS26A contributes to the molecular architecture governing vesicular trafficking, with potential relevance to diseases involving defects in endosomal transport and autophagy. Notably, miRNAs targeting VPS26A-associated gene networks have emerged as potential prognostic biomarkers for LIHC. VPS26A was found to be integrated into a highly interconnected signaling network comprising proteins in cancer progression, immune regulation, and cellular metabolism. Conclusions: Overall, VPS26A may serve as a potential prognostic biomarker and therapeutic target in LIHC. This study provides novel insights into the molecular mechanisms underlying LIHC progression, and highlights the multifaceted role of VPS26A in tumor biology.

Background and Objectives: Chromobox 1 (CBX1), a key epigenetic regulator involved in chromatin remodeling, has been implicated in various cancers; however, its role in liver hepatocellular carcinoma (LIHC) remains underexplored. This study aimed to investigate the expression patterns, epigenetic regulation, and non-coding RNA (ncRNA) networks involving CBX1 in LIHC, assess their potential as diagnostic and prognostic biomarkers, and explore their relevance as a putative therapeutic target. Materials and Methods: A multi-omics bioinformatics approach was employed using datasets from GEPIA2, OncoDB, UALCAN, Human Protein Atlas, KM Plotter, MethSurv, miRNet, and ENCORI. These databases were used to analyze mRNA and protein expression, DNA methylation, prognosis, and interaction networks involving CBX1 and ncRNAs. Results: CBX1 was significantly upregulated in both the mRNA and protein expression in LIHC. Upregulated CBX1 expression was associated with poor prognosis. DNA methylation analysis revealed that both hypermethylated and hypomethylated probes were significantly associated with CBX1 expression and poor prognosis. hsa-miR-212-3p and hsa-miR-132-3p were significantly upregulated in LIHC and were positively correlated with CBX1 expression and poor prognosis. The ncRNA network was identified, including long ncRNAs, circular RNAs, and pseudogenes, many of which were linked to tumor progression and poor prognosis, and competing endogenous RNAs were associated with tumor progression and poor prognosis in LIHC. Conclusions: CBX1 was significantly overexpressed in LIHC and was regulated by both DNA methylation and ncRNA interactions. Its expression is closely associated with a poor prognosis. The CBX1–micro-RNA–long ncRNA/circular RNA axis is a promising avenue for the development of novel diagnostic and therapeutic strategies. This study provides system-level insights into the regulatory landscape of CBX1 in LIHC and supports its potential role in precision medicine.

Microvilli on T cells have been proposed to survey surfaces of antigen-presenting cells (APC) or facilitate adhesion under flow; however, whether they serve essential functions during T cell activation remains unclear. Here we show that antigen-specific T cells deposit membrane particles derived from microvilli onto the surface of cognate antigen-bearing APCs. Microvilli carry T cell receptors (TCR) at all stages of T cell activation and are released as large TCR-enriched, T cell microvilli particles (TMP) in a process of trogocytosis. These microvilli exclusively contain protein arrestin-domain-containing protein 1, which is directly involved in membrane budding and, in combination with vacuolar protein-sorting-associated protein 4, transforms large TMPs into smaller, exosome-sized TMPs. Notably, TMPs from CD4 + T cells are enriched with LFA-2/CD2 and various cytokines involved in activating dendritic cells. Collectively, these results demonstrate that T cell microvilli constitute “immunological synaptosomes” that carry T cell messages to APCs. Microvilli can participate in adhesion or migration of T cells, but whether they are involved in function regulation is unclear. Here the authors show that T cell microvilli form budding vesicles containing T cell signalling components for deposition onto antigen presenting cells (APC) and modulation of APC functions.

The myelin sheath is an essential structure for the rapid transmission of electrical impulses through axons, and peripheral myelination is a well-programmed postnatal process of Schwann cells (SCs), the myelin-forming peripheral glia. SCs transdifferentiate into demyelinating SCs (DSCs) to remove the myelin sheath during Wallerian degeneration after axonal injury and demyelinating neuropathies, and macrophages are responsible for the degradation of myelin under both conditions. In this study, the mechanism by which DSCs acquire the ability of myelin exocytosis was investigated. Using serial ultrastructural evaluation, we found that autophagy-related gene 7-dependent formation of a “secretory phagophore (SP)” and tubular phagophore was necessary for exocytosis of large myelin chambers by DSCs. DSCs seemed to utilize myelin membranes for SP formation and employed p62/sequestosome-1 (p62) as an autophagy receptor for myelin excretion. In addition, the acquisition of the myelin exocytosis ability of DSCs was associated with the decrease in canonical autolysosomal flux and was demonstrated by p62 secretion. Finally, this SC demyelination mechanism appeared to also function in inflammatory demyelinating neuropathies. Our findings show a novel autophagy-mediated myelin clearance mechanism by DSCs in response to nerve damage.

Although T cell activation is known to involve the internalization of the T cell antigen receptor (TCR), much less is known regarding the release of TCRs following T cell interaction with cognate antigen-presenting cells. In this study, we examine the physiological mechanisms underlying TCR release following T cell activation. We show that T cell activation results in the shedding of TCRs in T cell microvilli, which involves a combined process of trogocytosis and enzymatic vesiculation, leading to the loss of membrane TCRs and microvilli-associated proteins and lipids. Surprisingly, unlike TCR internalization, this event results in the rapid upregulation of surface TCR expression and metabolic reprogramming of cholesterol and fatty acid synthesis to support cell division and survival. These results demonstrate that TCRs are lost through trogocytic ‘molting’ following T cell activation and highlight this mechanism as an important regulator of clonal expansion. Following interaction with antigen-presenting cells, T cell receptors (TCR) can be internalized via endocytosis. In contrast to this established mechanism, this study shows that T cell activation can be followed by TCR shedding, leading to enhanced TCR expression, metabolic activity and proliferation.

As high temperature and relative humidity (RH) are the main environmental factors causing heat stress, the temperature–humidity index (THI) serves as an indicator of heat stress in livestock animals. This study aimed to determine the effects of heat stress on the laying performance, physiological responses, egg quality, and blood profile of laying hens by subjecting them to environmental conditions with varying THI levels (68–85) for 28 days. The indicators of laying performance, such as feed intake (−30%) and egg production rate (−11%), significantly decreased in the hens exposed to severe heat stress (33 °C, 66% RH) compared to those exposed to thermoneutral conditions (21 °C, 68% RH). Moreover, severe heat stress reduced the egg yolk color, eggshell thickness and strength, and Haugh units of the eggs produced by the laying hens. Furthermore, a significant increase in serum K+ and a decrease in Na+ levels were observed in the hens subjected to severe heat stress compared with those under thermoneutral conditions. Our results indicate that heat stress alters the physiological responses and metabolism of laying hens, resulting in a lower egg quality and production rate.

Communication between cells is essential for multicellular life. During cognate immune interactions, T cells communicate with antigen-presenting cells (APC) via direct cell-cell contact or the release of molecules and vesicles containing T cell messages. A wide variety of mechanisms have been reported and among them a process called \"trogocytosis\" has traditionally been thought to be the fastest way to directly transfer membrane portions containing intact proteins from one cell to another; however, the mechanism is unverified. Trogocytosis has been distinguished from the generation of extracellular vesicles (EVs), a term that encompasses exosomes and microvesicles, as EVs are released via a contact-independent manner and are suggested to potentially send molecular messages over a distance. However, some previous reports regarding EVs in T cells may be misleading in terms of explaining their cellular origins. In addition, there is little evidence on how EVs are generated from T cells and function to regulate complex immune responses. A recent work demonstrated that T cell microvilli-thin and finger-like membrane protrusions-are highly fragile and easily separated as membrane particles by trogocytosis, forming a new class of EVs. Surprisingly, released T cell microvilli-derived particles act as vectors, transmitting T cell messages to cognate APCs. This review focuses on how T cell microvilli vesicles are connected with immune regulation mechanisms discovered previously.

Protein functions are often revealed by their localization to specialized cellular sites. Recent reports demonstrated that swiprosin-1 is found together with actin and actin-binding proteins in the cytoskeleton fraction of human mast cells and NK-like cells. However, direct evidence of whether swiprosin-1 regulates actin dynamics is currently lacking. We found that swiprosin-1 localizes to microvilli-like membrane protrusions and lamellipodia and exhibits actin-binding activity. Overexpression of swiprosin-1 enhanced lamellipodia formation and cell spreading. In contrast, swiprosin-1 knockdown showed reduced cell spreading and migration. Swiprosin-1 induced actin bundling in the presence of Ca(2+), and deletion of the EF-hand motifs partially reduced bundling activity. Swiprosin-1 dimerized in the presence of Ca(2+) via its coiled-coil domain, and a lysine (Lys)-rich region in the coiled-coil domain was essential for regulation of actin bundling. Consistent with these observations, mutations of the EF-hand motifs and coiled-coil region significantly reduced cell spreading and lamellipodia formation. We provide new evidence of how swiprosin-1 influences cytoskeleton reorganization and cell spreading.

This study aims to characterize the influence of short-term heat stress (HS; 4 day) in early lactating Holstein dairy cows, in terms of triggering blood metabolomics and parameters, milk yield and composition, and milk microRNA expression. Eight cows (milk yield = 30 ± 1.5 kg/day, parity = 1.09 ± 0.05) were homogeneously housed in environmentally controlled chambers, assigned into two groups with respect to the temperature humidity index (THI) at two distinct levels: approximately ~71 (low-temperature, low-humidity; LTLH) and ~86 (high-temperature, high-humidity; HTHH). Average feed intake (FI) dropped about 10 kg in the HTHH group, compared with the LTLH group (p = 0.001), whereas water intake was only numerically higher (p = 0.183) in the HTHH group than in the LTLH group. Physiological parameters, including rectal temperature (p = 0.001) and heart rate (p = 0.038), were significantly higher in the HTHH group than in the LTLH group. Plasma cortisol and haptoglobin were higher (p < 0.05) in the HTHH group, compared to the LTLH group. Milk yield, milk fat yield, 3.5% fat-corrected milk (FCM), and energy-corrected milk (ECM) were lower (p < 0.05) in the HTHH group than in the LTLH group. Higher relative expression of milk miRNA-216 was observed in the HTHH group (p < 0.05). Valine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, lactic acid, 3-phenylpropionic acid, 1,5-anhydro-D-sorbitol, myo-inositol, and urea were decreased (p < 0.05). These results suggest that early lactating cows are more vulnerable to short-term (4 day) high THI levels—that is, HTHH conditions—compared with LTLH, considering the enormous negative effects observed in measured blood metabolomics and parameters, milk yield and compositions, and milk miRNA-216 expression.

Brain derived neurotrophic factor (BDNF) has been shown to play an important role in poststroke recovery. BDNF secretion is influenced by genetic and epigenetic profiles. This study aimed to investigate whether BDNF val66met polymorphism and promoter methylation status were associated with outcomes at two weeks and one year after stroke. A total of 286 patients were evaluated at the time of admission and two weeks after stroke, and 222 (78%) were followed one year later in order to evaluate consequences of stroke at both acute and chronic stages. Stroke outcomes were dichotomised into good and poor by the modified Rankin Scale. Stroke severity (National Institutes of Health Stroke Scale), physical disability (Barthel Index), and cognitive function (Mini-Mental State Examination) were measured. Associations of BDNF genotype and methylation status on stroke outcomes and assessment scale scores were investigated using logistic regression, repeated measures ANOVA and partial correlation tests. BDNF val66met polymorphism was independently associated with poor outcome at 2 weeks and at 1 year, and with worsening physical disability and cognitive function over that period. Higher BDNF promoter methylation status was independently associated with worse outcomes at 1 year, and with the worsening of physical disability and cognitive function. No significant genotype-methylation interactions were found. A role for BDNF in poststroke recovery was supported, and clinical utility of BDNF genetic and epigenetic profile as prognostic biomarkers and a target for drug development was suggested.