Search Results (776)

Background: Obesity and its complications have increased in both adults and children, with pediatric populations developing metabolic disorders at earlier ages. Long non-coding RNAs, particularly MEG3, are involved in obesity through regulation of lipogenic genes including ATF4, FTO, SREBP1, FASN, and ACACA. However, data on MEG3 expression in pediatric obesity are limited. This study evaluated MEG3, FTO, and ATF4 expression in PBMCs from children with obesity and their associations with added sugar intake and lipid metabolism genes. Methods: In this cross-sectional study 71 children within the age range of 6 to 12 years were included (28 normal weight and 43 with obesity). Anthropometrical and clinical parameters and dietary added sugar consumption were analyzed. Real-time PCR was performed to assess MEG3, FTO, ATF4, SREBP1, FASN, and ACACA gene expression in peripheral blood mononuclear cells. Results: The expression of MEG3, ATF4, FTO, SREBP1, FASN, and ACACA was decreased in children with obesity. MEG3 and FTO showed sex-dependent expression in children without obesity, while additional sex-related differences were observed for SREBP1, FASN, ACACA, FTO, and MEG3 in children with obesity. MEG3 was associated with the expression of SREBP1, FASN, ACACA, FTO, and ATF4. In insulin-resistant (IR) children, MEG3, ATF4, FTO, ACACA, and SREBP1 were reduced, while FASN was increased. Added sugar intake negatively correlated with FTO, SREBP1, and ACACA. Conclusions: The MEG3, FTO, and ATF4 expression was altered in children with obesity, showing sex- and IR-related differences. Added sugar intake correlated negatively with lipogenic gene expression. Full article

FeCrAl exhibits excellent resistance to high temperatures, corrosion, and irradiation, making it a prime candidate material for accident-tolerant fuel (ATF) cladding. This study investigates the high-temperature creep behavior of FeCrAl alloys with grain sizes of 12.0 μm and 9.9 μm under temperatures ranging from 450 °C to 650 °C and applied stresses between 75 and 200 MPa. The texture, grain morphology, grain orientation, and dislocation density of FeCrAl were characterized by electron backscatter diffraction (EBSD). The results indicate that temperature, applied stress, and grain size are the primary factors governing high-temperature creep behavior. The material texture showed no significant difference before and after creep. Large grains tend to engulf smaller ones during the creep process at lower temperatures and stresses, reducing the proportion of low-angle grain boundaries (LAGBs). In contrast, at higher temperatures or under higher stress, dislocations proliferate within grains, leading to a significant increase in the number of LAGBs. As the applied stress increases, the dominant creep mechanism tends to convert from grain boundary sliding to dislocation motion. Moreover, higher temperatures or smaller grain sizes lower the critical stress required to activate dislocation motion and significantly increase dislocation density, severely degrading the creep resistance. Full article

Background: Protein kinase R (PKR) inhibits general mRNA translation by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). PKR also modulates NF-κB signaling during viral infections, but comparative studies of PKR-mediated NF-κB responses across mammalian species and their regulation by viral inhibitors remain largely unexplored. This study aimed to characterize the conserved antiviral and inflammatory roles of mammalian PKR orthologs and investigate their modulation by poxviral inhibitors. Methods: Using reporter gene assays and quantitative RT-PCR, we assessed the impact of 17 mammalian PKR orthologs on general translation inhibition, stress-responsive translation, and NF-κB-dependent induction of target genes. Congenic human and rabbit cell lines infected with a myxoma virus strain lacking PKR inhibitors were used to compare the effects of human and rabbit PKR on viral replication and inflammatory responses. Site-directed mutagenesis was employed to determine key residues responsible for differential sensitivity to the viral inhibitor M156. Results: All 17 mammalian PKR orthologs significantly inhibited general translation, strongly activated stress-responsive ATF4 translation, and robustly induced NF-κB target genes. Inhibition of these responses was specifically mediated by poxviral K3 orthologs that effectively suppressed PKR activation. Comparative analyses showed human and rabbit PKRs similarly inhibited virus replication and induced cytokine transcripts. Amino acid swaps between rabbit PKRs reversed their sensitivity to viral inhibitor M156 and NF-κB activation. Conclusions: Our data show that the tested PKR orthologs exhibit conserved dual antiviral and inflammatory regulatory roles, which can be antagonized by poxviral K3 orthologs that exploit eIF2α mimicry to modulate the PKR-NF-κB axis. Full article

Altitude Test Facility (ATF) compressor systems are widely used in aero-engine tests. These systems achieve the control of gas pressure and transport through complex operation processes. With advancements in the aviation industry, there is a growing demand for higher performance, greater safety, and more energy efficiency in digital ATF systems. Hybrid modeling is a technology that combines many methods and can meet these requirements. The Modular Dynamic System Greitzer (MDSG) compressor model, including mechanistic and data-driven modeling approaches, is combined with a neural network to obtain a BPNN-MDSG hybrid modeling method for the digital turbine system. The digital simulation is linked with the physical sensors of the ATF system to realize real-time simulation and monitoring. The steady and dynamic conditions of the actual system are simulated in virtual space. Compared with the actual results, the average error of steady mass flow is less than 3%, and the error of pressure is less than 1%. The average error of dynamic mass flow is less than 5%, and the error of pressure is less than 3%. The simulation and characteristic predictions are carried out in BPNN-MDSG virtual space. The anti-surge characteristics of the ATF system under start-up conditions are obtained. The full-condition anti-surge operation map of the system is obtained, which provides guidance for the actual operation of the ATF system. Full article

Human leukocyte extract (HLE), a non-immunogenic dialyzable leukocyte preparation (<10 kDa), may serve as a safe adjuvant in immunotherapy. We investigated the effects of albendazole (ABZ), HLE, and their combination in Mesocestoides vogae infected mice, focusing on lymphoid cells in the peritoneal cavity, the site of larval proliferation and parasite-induced immunosuppression. Peritoneal lymphoid cells were analysed by flow cytometry and qPCR. Cells proliferative responses to ConA, LPS, and parasite excretory/secretory (E/S) antigens, cytokine production (ELISA), IgM and IgG isotypes in exudates and parasite antigen recognition (Western blot) were assessed. Efficacy was measured by larval burden and 14-3-3 gene expression in larvae. HLE combined with ABZ enhanced larval clearance and suppressed 14-3-3 gene expression in larvae. HLE and combination therapy increased CD3⁺ T cell frequencies, especially CD3^+high, reduced regulatory CD3+/IL-10 Tregs and expression of Foxp3⁺. All treatments diminished CD19⁺/IL-10⁺ Bregs, correlating with lower CD9 and Atf3 mRNA levels compared to infected mice. Transcription factors T-bet expression was strongly upregulated, while GATA3 was moderately elevated. IFN-γ production and T/B cell proliferation were restored after HLE and combination therapy, partially, even in the presence of E/S antigens. IgM and total IgG levels against parasite antigens declined, while Th1-associated IgG2a increased in ABZ+HLE and HLE-treated groups. Albendazole failed to reverse the immunosuppressive Treg-type immunity but was more effective in reducing Breg populations and their functions. HLE enhanced ABZ efficacy by restoring Th1 responsiveness, reducing Treg/Breg activity, and modulating antibody profiles. It represents a promising immunomodulatory adjuvant in the treatment of the infections associated with Th2/Treg-driven immunosuppression. Full article

Background: Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease characterized by abnormal prenatal development of the left ventricle that has an aberrantly thick trabecular layer and a thinner compacted myocardial layer. However, the underlying molecular mechanisms of LVNC regulated by mitochondrial phosphatase genes remain largely unresolved. Methods: We generated a mouse model with cardiac-specific deletion (CKO) of Ptpmt1, a type of mitochondrial phosphatase gene, using the αMHC-Cre, and investigated the effects of cardiac-specific Ptpmt1 deficiency on cardiac development. Morphological, histological, and immunofluorescent analyses were conducted in Ptpmt1 CKO and littermate controls. A transcriptional atlas was identified by RNA sequencing (RNA-seq) analysis. Results: We found that CKO mice were born at the Mendelian ratio with normal body weights. However, most of the CKO mice died within 24 h after birth, developing spontaneous ventricular tachycardia. Morphological and histological analysis further revealed that newborn CKO mice developed an LVNC phenotype, evidenced by a thicker trabecular layer and a thinner myocardium layer, when compared with the littermate control. We then examined the embryonic hearts and found that such an LVNC phenotype could also be observed in CKO hearts at E15.5 but not at E13.5. We also performed the EdU incorporation assay and demonstrated that cardiac cell proliferation in both myocardium and trabecular layers was significantly reduced in CKO hearts at E15.5, which is also consistent with the dysregulation of genes associated with heart development and cardiomyocyte proliferation in CKO hearts at the same stage, as revealed by both the transcriptome analysis and the quantitative real-time PCR. Deletion of Ptpmt1 in mouse cardiomyocytes also induced an increase in phosphorylated eIF2α and ATF4 levels, indicating a mitochondrial stress response in CKO hearts. Conclusions: Our results demonstrated that Ptpmt1 may play an essential role in regulating left ventricular compaction during mouse heart development. Full article

Background/Objectives: The HOX genes encode a family of homeodomain-containing transcription factors that have important roles in defining cell and tissue identity in embryonic development, but which also show deregulated expression in many cancers and have been shown to have pro-oncogenic roles. Due to their functionally redundant nature, strategies to target HOX protein function in cancer have focused on their interaction with their PBX cofactor using competitive peptides such as HXR9. HOX/PBX inhibition triggers apoptosis through a sudden increase in target gene expression, including Fos, DUSP1, and ATF3, which are otherwise repressed by HOX/PBX binding. Methods: We analyzed publicly available transcriptomic data in the R2 platform. Results: We show that a specific subgroup of HOX genes is negatively correlated with Fos, DUSP1, and ATF3 expression in prostate cancer, and that this subgroup also shows a strong positive corelation with pathways that support tumour growth, most notably DNA repair and aminoacyl tRNA biosynthesis, and a negative correlation with genes that promote cell adhesion and prevent motility. In addition, this set of HOX genes strongly correlates with patient age, reflecting a previously identified progressive loss of regulation of HOX expression in normal peripheral blood cells. Conclusions: Our findings indicate these HOX genes may have pro-oncogenic functions in prostate cancer. Full article

The growth of tumor cells is accompanied by an increased rate of endoplasmic reticulum stress (ERS), the accumulation of misfolded proteins, and the activation of a network of adaptive signaling pathways known as the unfolded protein response (UPR). Although the UPR is an adaptive reaction aiming to restore ER proteostasis, prolonged and severe ERS leads to cell death. Taking into account that the components of the ERS/UPR machinery in cancers of different types can be overexpressed or downregulated, both the induction of excessive ERS and suppression of UPR have been proposed as therapeutic strategies to sensitize cells to conventional chemotherapy. This narrative review presents a several examples of using natural and synthetic compounds that can either induce persistent ERS by selectively blocking ER Ca²⁺ pumps (SERCA) to disrupt ER Ca²⁺ homeostasis, or altering the activity of UPR chaperones and sensors (GRP78, PERK, IRE1α, and ATF6) to impair protein degradation signaling. The molecular alterations induced by miscellaneous inhibitors of ERS/UPR effectors are described as well. These agents showed promising therapeutic effects as a part of combination therapy in preclinical experimental settings; however, the number of clinical trials is still limited, while their results are inconsistent. Multiple side effects, high toxicity to normal cells, or poor bioavailability also hampers their clinical application. Since the pharmacological modulation of ERS/UPR is a valuable approach to sensitize cancer cells to standard chemotherapy, the search for more selective agents with better stability and low toxicity, as well as the development of more efficient delivery systems that can increase their therapeutic specificity, are highly required goals for future studies. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality despite advances in treatments, necessitating more effective therapeutic strategies. Single-cell RNA sequencing (scRNA-seq) technology has revolutionized our ability to dissect the cellular complexity of cancers, which is often obscured in conventional bulk transcriptomic experiments. Methods: In this study, we performed an integrative analysis of scRNA-seq data from multiple LUAD patient cohorts to investigate cell-type-specific transcriptomic changes across disease stages. Clustering, lineage trajectory analysis, and transcriptional regulatory network reconstruction were employed to identify stage-specific gene markers and their upstream regulators. Additionally, we constructed intercellular communication networks to evaluate signaling changes within the tumor microenvironment (TME) during LUAD progression. Results: Our analysis revealed that epithelial cells from stage IV tumors exhibited a distinct transcriptional profile compared to earlier stages, a separation not observed in immune or stromal cell populations. We identified a panel of gene markers that differentiated epithelial cells across disease stages and effectively stratified patients into subgroups with distinct survival outcomes and TME compositions. Regulatory network analysis uncovered key transcription factors, including ATF3, ATF4, HSF1, KLF4, and NFIC, as potential upstream regulators of these stage-specific genes. Moreover, cell–cell communication analysis revealed a significant increase in signaling originating from epithelial cells and a concomitant decrease in immune-derived signals in late-stage LUAD. We identified several signaling pathways enriched in stage-specific crosstalk, including Wnt, PTN, and PDGF pathways, which may play critical roles in LUAD progression. Conclusions: This study provides a comprehensive single-cell resolution map of LUAD progression, highlighting epithelial-driven regulatory programs and dynamic intercellular communication within the TME. Our findings uncover novel molecular markers and regulatory mechanisms with potential prognostic and therapeutic value for more precise treatment. Full article

Background/Objectives: Hidradenitis suppurativa (HS) is a complicated chronic inflammatory skin disorder characterized by recurrent and painful deep-seated nodules, abscesses, fistulae, scarring, and sinus tracts. HS most commonly affects high-density hair follicles and apocrine gland-rich regions of the body, including the axillae, inguinal folds, breasts, and perianal areas. Although genetic predisposition and environmental factors are known to contribute to the development and the severity of HS, the molecular mechanisms of HS are largely unknown. Methods: In this study, we employed global epigenetic and genomic data analysis and single-nucleus ATAC-seq (snATAC-seq) to profile the heterogeneity of HS-associated chromatin accessibility and define the underlying disease drivers. We additionally performed high-resolution immunofluorescence staining to confirm a novel candidate regulator. Results: We found that multiple skin development modules and molecular signal pathways were epigenetically dysregulated in HS basal CD49f^high cells. Importantly, our snATAC-seq revealed a previously unraveled role for a transcription factor, ATF3, in transcriptionally regulating HS-associated genes. We also delineated the specific ATF3 expression pattern across the HS lesional skin. Conclusions: We characterize HS-specific epigenetic plasticity and chromatin state at the single-nucleus level and further underscore a possible mechanism for HS pathogenesis. Full article

Lysosomal dysfunction and endoplasmic reticulum (ER) stress play essential roles in cancer cell survival, growth, and stress adaptation. Among the various stressors in the tumor microenvironment, oxidative stress (OS) is a central driver that exacerbates both lysosomal and ER dysfunction. In healthy cells, the ER manages protein folding and redox balance, while lysosomes regulate autophagy and degradation. Cancer cells, however, are frequently exposed to elevated levels of reactive oxygen species (ROS), which disrupt protein folding in the ER and damage lysosomal membranes and enzymes, promoting dysfunction. Persistent OS activates the unfolded protein response (UPR) and contributes to lysosomal membrane permeabilization (LMP), leading to pro-survival autophagy or cell death depending on the context and on the modulation of pathways like PERK, IRE1, and ATF6. Cancer cells exploit these pathways by enhancing their tolerance to OS and shifting UPR signaling toward survival. Moreover, lysosomal impairment due to ROS accumulation compromises autophagy, resulting in the buildup of damaged organelles and further amplifying oxidative damage. This vicious cycle of ROS-induced ER stress and lysosomal dysfunction contributes to tumor progression, therapy resistance, and metabolic adaptation. Thus, targeting lysosomal and ER stress responses offers potential as cancer therapy, particularly in increasing oxidative stress and promoting apoptosis. This review explores the interconnected roles of lysosomal dysfunction, ER stress, and OS in cancer, focusing on the mechanisms driving their crosstalk and its implications for tumor progression and therapeutic resistance. Full article

Extreme weather events such as heavy rainfall significantly reduce surface salinity in coastal waters, presenting considerable challenges to the aquaculture of Japanese scallops (Mizuhopecten yessoensis) in shallow cage systems. This study investigated the effects of chronic low-salinity stress on the growth performance, antioxidant capacity, and gene expression profile of M. yessoensis using a 60-day salinity gradient experiment. S33 represents the control treatment with normal seawater salinity (33‰), while S30, S28, and S26 represent experimental groups with progressively lower salinities of 30‰, 28‰, and 26‰, respectively. A decline in salinity was accompanied by an increase in oxygen consumption. The S26 group exhibited a higher ammonia excretion rate (2.73 μg/g·h) than other groups, indicating intensified nitrogen metabolism. Growth was inhibited under low-salinity conditions. The S33 group exhibited greater weight gain (16.7%) and shell growth (8.4%) compared to the S26 group (11.6% and 6%), which also showed a substantially higher mortality rate (46%) compared to the control (13%). At 28‰, antioxidant enzyme activities (T-AOC, SOD, CAT, POD) were elevated, indicating a moderate level of stress. However, at the lowest salinity (26‰), these indicators decreased, reflecting the exhaustion of the antioxidant systems and indicating that the mollusks’ adaptive capacity had been exceeded, leading to a state of stress fatigue. NAD-MDH activity was elevated in the S26 group, reflecting enhanced aerobic metabolism under stress. Transcriptome analysis revealed 564 differentially expressed genes (DEGs) between the S33 and S26 groups. Functional enrichment analysis indicated that these DEGs were mainly associated with immune and stress response pathways, including NF-κB, TNF, apoptosis, and Toll/Imd signaling. These genes are involved in key metabolic processes, such as alanine, aspartate, and glutamate metabolism. Genes such as GADD45, ATF4, TRAF3, and XBP1 were upregulated, contributing to stress repair and antioxidant responses. Conversely, the expressions of CASP3, IKBKA, BIRC2/3, and LBP were downregulated, potentially mitigating apoptosis and inflammatory responses. These findings suggest that M. yessoensis adapts to chronic low-salinity stress through the activation of antioxidant systems, modulation of immune responses, and suppression of excessive apoptosis. This study provides new insights into the molecular mechanisms underlying salinity adaptation in bivalves and offers valuable references for scallop aquaculture and selective breeding programs. Full article

Cortisol, the main glucocorticoid in teleost, plays a central role in mediating the physiological response to stress by regulating metabolism, immune function, and growth. While its transcriptional effects are well known, its role in modulating chromatin accessibility in fish skeletal muscle remains poorly understood. In this study, we investigated the epigenomic and transcriptomic changes induced by cortisol in a juvenile rainbow trout’s (Oncorhynchus mykiss) skeletal muscle using ATAC-seq and RNA-seq. Fish were treated with a single intraperitoneal dose of cortisol (10 mg/kg) or vehicle, and muscle samples were collected 3 h post-treatment. ATAC-seq analysis revealed a total of 163,802 differentially accessible regions (DARs), with an important enrichment of open regions near transcription start sites and promoters. A total of 1612 and 1746 differentially accessible genes (DAGs) were identified in the cortisol and control groups, respectively. Motif enrichment analysis identified 89 transcription factors to be significantly enriched, among which key stress-responsive regulators such as Fos, AP-1, FoxO1/3, Mef2a/b/c, Klf5/10, and ATF4 were prominently represented. RNA-seq analysis identified 4050 differentially expressed genes (DEGs), with 2204 upregulated genes involved in autophagy, mitophagy, and FoxO signaling, while 1864 downregulated genes were enriched in spliceosome and chromatin remodeling pathways. Integrative analysis revealed 174 overlapping genes between ATAC-seq and RNA-seq datasets, highlighting pathways linked to autophagy and ATP-dependent chromatin remodeling. Four selected DEGs (sesn1, sesn2, cullin3, samtor) were validated by qPCR, showing high concordance with transcriptomic data. These findings provide new insights into cortisol-mediated regulation of chromatin dynamics and gene expression in teleost skeletal muscle and underscore the importance of epigenetic mechanisms in fish stress responses. Full article

Background/Objectives: Acute lung injury (ALI) is an inflammatory condition characterized by tissue barrier damage, which leads to vascular leakage, pulmonary edema, and compromised gas exchange. Lipopolysaccharides (LPS) are a component of Gram-negative bacteria, which trigger inflammation by Toll-like receptor 4 (TLR4) activation. Herein, we investigated the possibility that Pasireotide (PAS) exerts protective effects in an experimental model of ALI. Methods: C57BL/6 male mice received an intratracheal injection of saline or LPS, followed by PAS or vehicle treatment. Bronchoalveolar lavage fluid (BALF) was collected via tracheal catheterization, and Western blot analysis was used to detect protein expression variations. Results: Our results suggest that PAS treatment alleviates LPS-induced mouse lung injury and inflammation. JAK/STAT and MAPK activation levels in the inflamed lungs were suppressed due to PAS treatment, as well as BALF protein concentration. Additionally, PAS counteracted LPS-induced Grp94 protein reduction, suggesting the involvement of ATF6 in PAS-triggered barrier-protective effects. Grp94 is a downstream ATF6 target. Conclusions: Our data demonstrate that PAS protects mouse lungs against LPS in an experimental model of ALI. Full article

The application of multiple parametric arays (MPAs) has been increasingly prominent in recent years due to the high directivity of parametric arrays. However, existing beamforming methods for MPAs are limited to special scenarios, such as narrow-edged beamforming, or have high complexity, such as requiring numerous acoustic transfer function (ATF) identifications. This paper proposes a low-complexity versatile beamforming method based on the transitive relationship among ATFs. For N parametric arrays, the number of identified ATFs can be reduced from N² to N through interpolation and flipping. Moreover, by neglecting the less affected part in the acoustic field structure, the number of identified ATFs can be reduced to less than N. On the basis of ATF matrix estimated, the desired acoustic field can be generated by optimizing the emission weight coefficient. The accuracy of ATF estimation is verified through the precise reconstruction of the acoustic field. Even when the number of identified ATFs does not exceed N, the desired acoustic field of different types of beam patterns can be formed correctly. The beamforming effects of MPAs confirm the low-complexity and versatility of the proposed method, offering a highly feasible solution for acoustic field control. Full article