Search Results (181)

Eukaryotic elongation factor 1A (eEF1A), the second most abundant intracellular protein, not only plays a key role in peptide elongation, but is also capable of numerous moonlighting functions. Within malignant cells, eEF1A is by no means a neutral bystander but instead actively participates in oncogenic transformations via a myriad of molecular pathways. Thus far, a broad range of small-molecule inhibitors have been identified, which, despite their structural diversity, suppress tumor growth by targeting eEF1A. Interestingly, just as eEF1A enables its oncogenic potential far beyond boosting protein translation, these targeted agents disrupt this oncoprotein via multiple axes distinct from mere protein synthesis inhibition. Whereas the oncogenic mechanisms of eEF1A has been well documented, there lacks a systemic survey of the eEF1A-targeting agents in terms of their mechanisms. Accordingly, the present work aims to examine their multifaceted modes of action more than just blocking protein synthesis. By unveiling these insights, our deepened knowledge of these eEF1A-binding inhibitors will inform the development of future eEF1A-targeted drugs for cancer treatment. Full article

Glioblastoma multiforme (GBM) is an aggressive and molecularly heterogeneous brain cancer with a poor prognosis. Despite advancements in standard-of-care therapies, including surgery, radiotherapy, and temozolomide (TMZ), the median survival remains approximately 15 months, with a 5-year survival rate of less than 10%. We and others have demonstrated that FOXM1 is a critical oncogenic driver of GBM cell proliferation. However, the role of FOXM1 and its interaction with other oncogenic signaling pathways in GBM remains incompletely understood. In this study, we identified FOXM1, AXL, and eEF2K as highly upregulated oncogenes in GBM patient tumors. We demonstrated, for the first time, that FOXM1 directly interacts with AXL and eEF2K, regulating their expression and promoting GBM cell proliferation, migration, and invasion. Knockdown of these genes disrupted cell proliferation, spheroid formation, migration, and invasion, and induced apoptosis and ferroptosis. Additionally, inhibiting the FOXM1–AXL/eEF2K signaling axis sensitized GBM cells to TMZ, further enhancing apoptotic and ferroptotic responses. These findings highlight the critical role of the FOXM1–AXL/eEF2K signaling pathway in GBM progression and suggest that targeting this axis may offer a novel multitargeted therapeutic strategy in GBM. Full article

Marine-derived compounds represent a rich source of structurally diverse molecules with therapeutic potential for cancer, renal disorders, metabolic-associated fatty liver disease (MAFLD), and atherosclerosis. This review systematically evaluates recent advances, highlighting compounds such as Microcolin H, Benzosceptrin C, S14, HN-001, Equisetin, glycosides (e.g., cucumarioside A₂-2), ilimaquinone, and Aplidin (plitidepsin). Key mechanisms include autophagy modulation, immune checkpoint inhibition, anti-inflammatory effects, and mitochondrial homeostasis. Novel findings reveal glycosides’ dual role in cytotoxicity and immunomodulation, ilimaquinone’s induction of the DNA damage response, and Aplidin’s disruption of protein synthesis via eEF1A2 binding. Pharmacokinetic challenges and structure–activity relationships are critically analyzed, emphasizing nanodelivery systems and synthetic analog development. This review bridges mechanistic insights with translational potential, offering a cohesive framework for future drug development. Full article

Background/Objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis. Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools. Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype–phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome. Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes. Full article

Improving nitrogen use efficiency (NUE) is critical to advancing sustainable cereal production, particularly under Mediterranean conditions where environmental pressures challenge input-intensive practises. This study evaluates NUE in Tritordeum, a climate-resilient wheat–barley hybrid, using a holistic experimental approach that integrates pre- and post-harvest soil analyses, including an electrical conductivity (EC) assessment, plant and seed nutrient profiling, and an evaluation of yield performance and nitrogen ratio dynamics. Four treatments were tested: conventional urea (T1), urea with an urease inhibitor (NBPT) (T2), urea with a nitrification inhibitor (DCD) (T3), and an unfertilised control (C). While conventional urea achieved the highest yield (1366 kg ha⁻¹), enhanced-efficiency fertilisers (EEFs) improved nutrient synchronisation and seed nutritional quality. Specifically, EEFs increased seed zinc (T2: 34.93 mg/kg), iron (T1: 33.77 mg/kg), and plant potassium (T2: 1.66%; T3: 1.61%) content, and also improved nitrogen remobilisation (elevated Nplant/Nseed ratios). EEFs also influenced soil properties, increasing organic matter (T3: 2.75%) and EC (T3: 290.78 μS/cm). These findings suggest that while EEFs may not always boost yield in the short term, they contribute to long-term soil fertility and nutrient density in grain. This study underscores the importance of synchronising nitrogen availability with Tritordeum’s phenological stages and highlights the crop’s suitability for sustainable, low-input agriculture under climate variability. Full article

Multi-floored grain warehouses are widely used in China due to their efficient space utilization and high storage capacity. This study evaluates the seismic performance of such structures using a Composite Structure of Steel and Concrete (CSSC) system under various grain-loading conditions. A finite element model was developed in OpenSees based on actual loading scenarios, with both pushover and time history analyses conducted. Results show that the EEF condition (E = Empty, F = Full; top–middle–bottom = Empty–Empty–Full) leads to a 35.14% increase in peak base shear compared to the FEE condition (grain on the top floor only). Capacity spectrum analysis indicates that EEF provides higher initial stiffness and lower displacement across all performance points. Time history results reveal that configurations with lighter upper mass (EFF, EEE) are more prone to top-floor acceleration amplification, while FFF and FFE demonstrate more stable responses due to balanced mass distribution. The maximum inter-story drift consistently occurs at the second floor, with FFF and FFE showing the most significant deformation. All drift ratios meet code limits, confirming the safety and applicability of the CSSC system under various storage scenarios. Full article

Translational control is crucial for maintaining cellular homeostasis, yet the distinct features and regulatory requirements governing protein synthesis during erythropoiesis remain unclear. Here, we reveal that erythroid cells exhibit an extraordinarily high demand for protein synthesis, which is required for their differentiation but also implies the need for tight regulation to prevent excessive erythropoiesis. Notably, we identify significant phosphorylation of eukaryotic elongation factor 2 (eEF2) at threonine 56 during erythroid differentiation, which reduces protein synthesis and acts as a molecular brake to limit unchecked erythropoiesis. This is evidenced by elevated red blood cell counts in peripheral blood and increased incidence of blood hyperviscosity and thrombosis in eEF2_T56M mice, which are deficient in eEF2 phosphorylation. Mechanistic studies demonstrate that eEF2 phosphorylation selectively regulates the translation of a subset of proteins, including NFE2, which partially mediates the effects of eEF2 modification. Collectively, our findings highlight a previously unappreciated role for translational control in achieving efficient and balanced erythropoiesis, with eEF2 phosphorylation serving as a critical protective mechanism against hyperactive erythropoiesis and offering a potential therapeutic target for hematologic disorders such as polycythemia vera. Full article

The eukaryotic translation elongation factor 1 (eEF1) family exhibits critical roles in RNA viral infection beyond its canonical function in protein synthesis. This review analyzes the structural characteristics of eEF1A and the eEF1B complex, and their regulatory mechanisms during viral infection. eEF1A impacts viral replication by stabilizing viral RNA-dependent RNA polymerase (RdRp) complexes, modulating genomic RNA synthesis, and facilitating viral assembly through cytoskeletal regulation. eEF1B subunits contribute through enhancing viral mRNA translation, regulating nuclear transport of viral components, and mediating post-translational modifications. The high conservation of eEF1 proteins across species and their involvement in multiple stages of viral replication establish them as promising broad-spectrum antiviral targets. Current eEF1-targeting compounds like plitidepsin demonstrate efficacy against diverse viral families, though therapeutic development faces challenges in balancing antiviral activity with host toxicity. This review provides a theoretical foundation for developing novel antiviral strategies targeting host–virus interaction interfaces and offers insights into addressing emerging infectious diseases. Full article

It is unclear whether enhanced efficiency fertilizer (EEF) or deep fertilization strategies (DF) can simultaneously improve crop productivity and reduce gaseous nitrogen losses. The DF strategy’s investment cost is lower than that of EEF’s, with more potential for large-scale promotion. However, there is still a need for a comprehensive comparison and evaluation of DF and EEF’s effects on crop productivity and gaseous nitrogen losses. Here, we examine the effects of DF and EEF on crop yield, nitrogen use efficiency (NUE), and nitrous oxide (N₂O) and ammonia (NH₃) emissions by a meta-analysis of published studies. We collected peer-reviewed articles on EEF and DF published in recent decades and conducted a global meta-analysis, and explored their responses to different climatic, field management practices, and environmental factors. The results showed that compared with urea application on the surface, EEF and DF significantly increased yields by 7.52% and 13.88% and NUE by 25.84% and 36.27% and reduced N₂O emissions by 37.98% and 34.18% and NH₃ emissions by 42.37% and 69.68%, respectively. The DF strategy is superior to that of the EEF. Due to differences in climatic factors, soil properties, and management practices, the effects of DF and EEF in improving crop productivity and gaseous nitrogen loss vary. However, in most cases, DF is more beneficial than EEF. Compared with EEF, DF significantly increased the yield by 84.63% and reduced NH₃ volatilization by 64.47%, yield-scaled N₂O emission by 13.32%, and yield-scaled NH₃ emission by 60.23%. Therefore, we emphasize that DF can achieve higher yields, nitrogen fertilizer utilization efficiency, lower emissions of gaseous nitrogen, and lower yield-scaled N₂O and NH₃ emissions than EEF, which is beneficial for the sustainable development of global agricultural ecosystems. The research results provide valuable information on crop productivity and environmental costs under an effective fertilizer type and fertilization strategy management. Full article

In “no-bleed” engine architectures, bleed air is replaced by shaft power extraction to run the subsystems, avoiding the inefficiencies of traditional bleed systems. This approach is increasingly used in small turbofan engines, prompting analysis of its impact on engine performance and exergy efficiency. A small high-bypass turbofan engine was modeled in software under two control strategies: constant thrust (CT) and constant speed (CS), with shaft power extraction up to 18 kW. Exergy analysis evaluated efficiency losses and sustainability metrics (exergy efficiency, environmental effect factor, and exergetic sustainability index). Simulations indicate that an 18 kW shaft power extraction increases SFC by 13.6% (CT) and 42.1% (CS). Exergy efficiency rises from 47.3% to 50.7% (CT) and 54.2% (CS). However, these power draws also increase irreversibility and the environmental effect factor (EEF) grows from 0.678 to 0.732 (CT) and 0.744 (CS), while the exergetic sustainability index (ESI) drops from 1.48 to 1.34, signaling reduced sustainability at high extraction. Maintaining constant thrust during extraction incurs smaller fuel consumption and exergy efficiency penalties than constant speed control. The findings highlight the need for adaptive control strategies (e.g., limiting extraction levels or using variable-geometry components) to mitigate losses and enhance sustainability in no-bleed engine designs. Full article

Functional gene expression is closely linked to an organism’s physiology and can be quantified using Real-Time Quantitative Reverse Transcription PCR (RT-qPCR). However, the stability of reference gene expression is not absolute, which may impact the accuracy of RT-qPCR results. In this study, we evaluated the suitability of nine genes including receptor for activated protein kinase c1 (rack1), ribosomal protein L6 (rpl6), ribosomal protein L9 (rpl9), ribosomal protein S2 (rps2), ribosomal protein S18 (rps18), ribosomal protein lateral stalk subunit P0 (rplp0), eukaryotic translation elongation factor 1β (eef1b), eukaryotic translation initiation factor 4a (eif4a), eukaryotic translation initiation factor 5a (eif5a) analyzed from RNA sequencing (RNA-Seq) data in addition to three genes including eukaryotic elongation factor 1α (eef1a), β-actin (actb), and glyceraldehyde 3-phosphate dehydrogenase (gapdh) selected from the literature to obtain the best internal controls in the RT-qPCR analysis of M. rosenbergii under overmating stress and natural aging. RefFinder was used to comprehensively evaluate the stability of the candidate reference genes. The initial results showed that three genes (eif5a, rps18, and rplp0) from the RNA-Seq data had relatively stable expression levels, which were more stable than those of the three commonly used reference genes. Eif5a and rps18 were the best combination for the RT-qPCR analysis of M. rosenbergii under overmating stress and aging. Further analysis indicated that eif5a might be the best reference gene for the study of M. rosenbergii. Full article

With the rapid growth of Internet applications and network traffic, existing routing algorithms are usually difficult to guarantee the quality of service (QoS) indicators such as delay, bandwidth, and packet loss rate as well as network energy consumption for various data flows with business characteristics. They have problems such as unbalanced traffic scheduling and unreasonable network resource allocation. Aiming at the above problems, this paper proposes a QoS-oriented energy-saving routing algorithm A3C-R in the software-defined network (SDN) environment. Based on the asynchronous update advantages of the asynchronous advantage Actor-Critic (A3C) algorithm and the advantages of independent interaction between multiple agents and the environment, the A3C-R algorithm can effectively improve the convergence of the routing algorithm. The process of the A3C-R algorithm first takes QoS indicators such as delay, bandwidth, and packet loss rate and the network energy consumption of the link as input. Then, it creates multiple agents to start asynchronous training, through the continuous updating of Actors and Critics in each agent and periodically synchronizes the model parameters to the global model. After the algorithm training converges, it can output the link weights of the network topology to facilitate the calculation of intelligent routing strategies that meet QoS requirements and lower network energy consumption. The experimental results indicate that the A3C-R algorithm, compared to the baseline algorithms ECMP, I-DQN, and DDPG-EEFS, reduces delay by approximately 9.4%, increases throughput by approximately 7.0%, decreases the packet loss rate by approximately 9.5%, and improves energy-saving percentage by approximately 10.8%. Full article

This study aimed to evaluate the effects of encapsulated postbiotics derived from various probiotic microorganisms, alone or in combination with inulin, on the growth performance, carcass traits, organ weights, blood parameters, and mRNA expression of selected hormones in broilers. A total of 588 one-day-old male Ross-308 chicks were randomly designated to six replicates of seven dietary treatments (initial body weight: 40.85 ± 0.56 g, per replicate, n = 14 chicks). The treatments consisted of a basal diet (C), supplemented with encapsulated postbiotics (0.30%) derived from Lactobacillus plantarum (ELP), Bacillus subtilis (EBS), or Enterococcus faecium (EEF), as well as combinations of these encapsulated postbiotics with 1.0% inulin (ELPI, EBSI, and EEFI) for six weeks. The results demonstrated that the body weight and body weight gain of birds that were fed diets supplemented with encapsulated postbiotics or their combinations with inulin significantly increased in comparison to the C group (p < 0.001). Feed intake (FI) remained unaffected during days 1–21, as did feed conversion ratios (FCR) during days 22–42, and days 1–42 demonstrated no significant differences (p > 0.05). However, FCR improved during days 1–21, and FI increased during days 22–42 and 1–42 (p < 0.05). Carcass yield, including breast, thigh, and abdominal fat yields, was enhanced (p < 0.001). Although the relative weights of the heart, spleen, pancreas, and liver were unaffected (p > 0.05), the relative weight of the bursa of Fabricius increased (p < 0.001). Serum antioxidant status and immunoglobulin A and M levels were higher, while liver enzymes, cholesterol, triglycerides, and total oxidant status were lower in the supplemented groups compared to the control group (p < 0.001). Serum glucose and protein levels remained unchanged (p > 0.05). The mRNA expression of growth hormone and insulin-like growth factor was upregulated in the supplemented groups (p < 0.001). In conclusion, encapsulated postbiotics (0.30%) derived from different probiotics, alone or combined with inulin (1.0%), positively influenced growth performance, carcass traits, and immunity in male broilers. Full article

This study utilized MAC-T cells cultured in vitro as a model to investigate the effects of varying concentrations of valine on α-casein synthesis and its underlying regulatory mechanisms. In this experiment, MAC-T cells were subjected to a 12 h starvation period, followed by the addition of valine in a range of concentrations (a total of seven concentrations: 0.000, 1.596, 3.192, 6.384, 12.768, 25.536, and 51.072 mM, as well as in 10% Fetal Bovine Serum). The suitable range of valine concentrations was determined using enzyme-linked immunosorbent assays (ELISAs). Real-time fluorescent quantitative PCR (RT-qPCR) and Western blot analyses were employed to evaluate the expression levels and phosphorylation states of the casein alpha s1 gene (CSN1S1), casein alpha s2 gene (CSN1S2) and mTOR signaling pathway-related genes. The functionality of the mTOR signaling pathway was further validated through rapamycin (100.000 nM) inhibition experiments. Results indicated that 1× Val (6.384 mM), 2× Val (12.768 mM), 4× Val (25.536 mM), and 8× Val (51.072 mM) significantly enhanced α-casein synthesis (p < 0.01). Within this concentration range, valine significantly upregulated the expression of CSN1S1, CSN1S2, and mTOR signaling pathway-related genes including the RagA gene (RRAGA), RagB gene (RRAGB), RagC gene (RRAGC), RagD gene (RRAGD), mTOR, raptor gene (RPTOR), and 4EBP1 gene (EIF4EBP1), eukaryotic initiation factor 4E (EIF4E), and S6 Kinase 1 (S6K1) (p < 0.01). Notably, the expression of the eukaryotic elongation factor 2 (EEF2) gene peaked at 1× Val (6.384 mM), while the expression of other genes reached their maximum at 4× Val (25.536 mM). Additionally, valine significantly increased the phosphorylation levels of mTOR, S6K1, 4E-binding protein-1 (4EBP1), ribosomal protein S6 (RPS6), and eEF2 (p < 0.01), with the highest phosphorylation levels of mTOR, S6K1, and RPS6 observed at 4× Val (25.536 mM). Rapamycin treatment significantly inhibited mTOR phosphorylation and α-casein synthesis (p < 0.01); however, the addition of 4× Val (25.536 mM) partially mitigated this inhibitory effect. In conclusion, valine promotes α-casein synthesis by activating the mTOR signaling pathway, with an optimal concentration of 4× Val (25.536 mM). Full article

Cellular metabolism must adapt rapidly to environmental alterations and adjust nutrient uptake. Low glucose availability activates the AMP-dependent kinase (AMPK) pathway. We demonstrate that activation of AMPK or the downstream Unc-51-like autophagy-activating kinase (ULK1) inhibits receptor-mediated endocytosis. Beyond limiting dextran uptake, this activation prevents endocytic uptake of human pathogenic enveloped and non-enveloped, positive- and negative-stranded RNA viruses, such as yellow fever, dengue, tick-borne encephalitis, chikungunya, polio, rubella, rabies lyssavirus, and SARS-CoV-2, not only in mammalian and insect cells but also in precision-cut lung slices and neuronal organoids. ULK1 activation inhibited enveloped viruses but not EV71. However, receptor presentation at the cytoplasmic membrane remained unaffected, indicating that receptor binding was unchanged, while later stages of endocytosis were targeted via two distinct pathways. Drug-induced activation of the AMPK pathway reduced early endocytic factor TXNIP by suppressing translation. In contrast, the amounts of Rab5 and the late endosomal marker Rab7 decreased due to translation inactivation and ULK1-dependent proteasome activation within minutes. Furthermore, activation of AMPK hindered the late replication steps of SARS-CoV-2 by reducing viral RNAs and proteins and the endo-lysosomal markers LAMP1 and GRP78, suggesting a reduction in early and late endosomes and lysosomes. Inhibition of the PI3K and mTORC2 pathways, which sense amino acid and growth factor availability, promotes AMPK activity and blocks viral entry. Our results indicate that AMPK and ULK1 emerge as restriction factors of cellular endocytosis, impeding the receptor-mediated endocytic entry of enveloped and non-enveloped RNA viruses. Full article