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Emerging evidence has unveiled heterogeneity in phenotypic and transcriptional alterations at the single-cell level during oxidative stress and senescence. Despite the pivotal roles of cellular metabolism, a comprehensive elucidation of metabolomic heterogeneity in cells and its connection with cellular oxidative and senescent status remains elusive. By integrating single-cell live imaging with mass spectrometry (SCLIMS), we establish a cross-modality technique capturing both metabolome and oxidative level in individual cells. The SCLIMS demonstrates substantial metabolomic heterogeneity among cells with diverse oxidative levels. Furthermore, the single-cell metabolome predicted heterogeneous states of cells. Remarkably, the pre-existing metabolomic heterogeneity determines the divergent cellular fate upon oxidative insult. Supplementation of key metabolites screened by SCLIMS resulted in a reduction in cellular oxidative levels and an extension of C. elegans lifespan. Altogether, SCLIMS represents a potent tool for integrative metabolomics and phenotypic profiling at the single-cell level, offering innovative approaches to investigate metabolic heterogeneity in cellular processes. Integrated analysis of metabolome and oxidative stress at single-cell level is challenging. Here, the authors develop SCLIMS, enabling simultaneous profiling of metabolome and oxidative stress levels and discoveries of key metabolites regulating oxidative stress, senescence, and healthy aging.

The nucleotide oligomerization domain (NOD)–like receptors 1 and 2 (NOD1/2) are intracellular pattern-recognition proteins that activate immune signaling pathways in response to peptidoglycans associated with microorganisms. Recruitment to bacteria-containing endosomes and other intracellular membranes is required for NOD1/2 signaling, and NOD1/2 mutations that disrupt membrane localization are associated with inflammatory bowel disease and other inflammatory conditions. However, little is known about this recruitment process. We found that NOD1/2 S-palmitoylation is required for membrane recruitment and immune signaling. ZDHHC5 was identified as the palmitoyltransferase responsible for this critical posttranslational modification, and several disease-associated mutations in NOD2 were found to be associated with defective S-palmitoylation. Thus, ZDHHC5-mediated S-palmitoylation of NOD1/2 is critical for their ability to respond to peptidoglycans and to mount an effective immune response.

Distribution grids are essential to power systems, as they ensure the safe and reliable operation of power systems. It is important to forecast the operational status of each distribution transformer. Consequently, there is an urgent need to develop load forecasting models that exhibit robust generalization and exceptional accuracy. However, distribution transformers are numerous, exhibit strong inherent features. Single-device load samples are scarce, with widespread few-shot issues. Traditional models rely on massive amounts of data and computational resources, making it challenging to balance computational costs, generalization ability, and accuracy. To address these issues, this paper analyzes the inherent features of distribution transformers and fine-tunes large language models using parameter-efficient fine-tuning methods to reduce training costs while preserving their generalization capabilities and accuracy. Experimental results demonstrate that this method achieves significantly higher accuracy than baseline models in few-shot scenarios.

Hepatocellular carcinoma (HCC) represents the majority of liver cancer and is the fourth most common cause of cancer‐related death. Although advances in molecular targeted therapy have shown promise, none of these agents has yet demonstrated significant clinical benefit. Bromo‐ and extraterminal domain (BET) protein inhibitors have been considered potential therapeutic drugs for HCC but the biological activity remains unclear. This study found that BET protein inhibition did not effectively suppress the progression of HCC, using a transgenic HCC mouse model. Mechanistically, the BET protein inhibitor JQ1 upregulated the expression of programmed cell death‐ligand 1 (PD‐L1) on the plasma membrane in vivo and in vitro. Moreover, JQ1 enhanced the expression of Rab8A, which upregulated the expression of PD‐L1 on the plasma membrane. This study also showed that JQ1 combined with anti‐PD‐L1 Ab effectively suppressed HCC progression, and this benefit was obtained by enhancing the activation and cytotoxic capabilities of CD8 T cells. These results revealed the crucial role and regulation of BET protein inhibition on the expression of PD‐L1 in HCC. Thus, combining BET protein inhibition with immune checkpoint blockade offers an efficient therapeutic approach for HCC. Treatment with JQ1 enhanced the expression of Rab8A, subsequently inducing programmed cell death‐ligand 1 (PD‐L1) expression on the plasma membrane of hepatocellular carcinoma (HCC), which sensitized the liver response to anti‐PD‐L1 blockade. Thus, a combined treatment of JQ1 and anti‐PD‐L1 Ab was an effective combination immunotherapy for HCC.

The tribological tests of a ferritic stainless steel (FSS) 445 in contact with high-speed steel (HSS) were performed on a high-temperature pin-on-disc tribometer. Wear exhibited significant difference when the FSS 445 was oxidised with a Cr-rich oxide scale on the surface. The HSS pin displayed adhesive wear when there was no oxide scale on the stainless steel disc, and in the early stages, the coefficient of friction fluctuated significantly, but the level of wear changed as Cr 2 O 3 particles formed. The wear was then reduced, and the coefficient of friction remained stable. The Cr-rich oxide scale which formed on the stainless steel was able to stabilise the coefficient of friction, to reduce the wear rate and to help form a glazed layer on the HSS surface. The abrasive wear of the HSS pin took place at 850 °C, indicating that the hardness of the Cr-rich oxide scale increased as the temperature decreased.

: Biological mechanisms that control liver regeneration remain poorly defined. However, these mechanisms are remarkable issues in the clinic that affect management of hepatic loss caused by liver surgery, traumatic injury, chronic infection, or liver poisoning. Increasing evidence has shown that various growth factors, cytokines, and metabolic signaling pathways affect the liver regenerative process. Our aim is to study the effect of bromodomain and extraterminal (BET) protein inhibition on liver regeneration and its mechanism. : We studied the role of BET protein inhibitor, JQ1, in liver regeneration in a mouse model after 70% partial hepatectomy (PH). We evaluated yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) and Notch signaling pathways, which were affected by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes and AML12 cell lines . We evaluated the relationship of YAP/TAZ and Notch signaling pathway using YAP/TAZ pathway inhibitor in liver regeneration . Moreover, we analyzed the relationship of YAP/TAZ and Notch signaling pathways via overexpression or RNA silencing of in AML12 cells. Furthermore, we used overexpression mouse model to examine whether it can rescue liver regeneration damage caused by inhibition of BET proteins. : In this study, we report that BET protein inhibitor JQ1 molecule impairs the early phase of liver regeneration in a mouse model after 70% PH. Mechanistically, YAP/TAZ and Notch1-NICD pathways were suppressed by BET protein inhibitor in mouse hepatic tissues and primary hepatocytes and mouse AML12 cell lines . By using YAP/TAZ pathway inhibitor, we confirmed that the liver regeneration and the activation of Notch pathway were impaired by the inhibition of YAP/TAZ pathway . Furthermore, the study showed that knockdown by shRNA in normal mouse hepatic cell line downregulated Notch1 signal transduction, whereas overexpression promoted Notch1-NICD signals. Specific overexpression of in mouse liver could rescue the effect of BET protein inhibition on liver regeneration injury. : These results revealed the crucial role of the YAP/TAZ-Notch1-NICD axis in liver regeneration. Therefore, BET protein inhibitors must be used in caution in the treatment of hepatic diseases by reason of its suppressive roles in liver regeneration.

The high temperature oxidation behaviour of ferritic stainless steel SUS 430 was investigated over the temperature range from 1000 to 1150 °C in humid air containing 18% water vapour. Isothermal thermogravimetric analyses were performed to study the oxidation kinetics. The microstructure, composition and thickness of the oxide scale formed were investigated via optical microscopy (OM), X-ray diffraction and a scanning electron microscope equipped with an energy dispersive spectrometer. The results indicate that breakaway oxidation occurs at all temperatures and that its onset is accelerated by increasing temperature. The growth rate of the multilayer oxide scale follows a parabolic law with apparent activation energy of 240.69 kJ/mol, and the formation of FeO is decreased when the temperature is higher than 1120°C. The inner oxide scale, Fe-Cr spinel, grows mainly inward and internal oxidation is observed even in a short oxidation test at 1150°C for 105 s. The mechanism of high temperature oxidation of SUS 430 in humid air containing 18% water vapour is discussed.

Attenuated Salmonella typhimurium (S. typhimurium) strains can selectively grow and express exogenous genes in tumors for targeted therapy. We engineered S. typhimurium strain VNP20009 to secrete tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) under the control of a hypoxia‐induced nirB promoter and examined the efficacy of Salmonella‐mediated targeted expression of TRAIL in mice bearing melanoma tumor and in TRAIL‐resistant RM‐1 tumor. We found that VNP preferentially accumulated in tumor tissues and the nirB promoter effectively drove targeted expression of TRAIL. Compared with recombinant TRAIL protein and VNP20009 combination therapy, VNP20009 expressing TRAIL significantly suppressed melanoma growth but failed to suppress RM‐1 tumor growth. Furthermore, we confirmed that VNP20009 expressing TRAIL yielded its antitumor effect by inducing melanoma apoptosis. Our findings indicate that Salmonella‐mediated tumor‐targeted therapy with TRAIL could reduce tumor growth and extend host survival. (Cancer Sci 2012; 103: 325–333)

Motor proteins, encoded by Kinesin superfamily (KIF) genes, are critical for brain development and plasticity. Increasing studies reported KIF’s roles in neurodevelopmental disorders. Here, a 6 years and 3 months‐old Chinese boy with markedly symptomatic epilepsy, intellectual disability, brain atrophy, and psychomotor retardation was investigated. His parents and younger sister were phenotypically normal and had no disease‐related family history. Whole exome sequencing identified a novel heterozygous in‐frame deletion (c.265_267delTCA) in exon 3 of the KIF5C in the proband, resulting in the removal of evolutionarily highly conserved p.Ser90, located in its ATP‐binding domain. Sanger sequencing excluded the proband's parents and family members from harboring this variant. The activity of ATP hydrolysis in vitro was significantly reduced as predicted. Immunofluorescence studies showed wild‐type KIF5C was widely distributed throughout the cytoplasm, while mutant KIF5C was colocalized with microtubules. The live‐cell imaging of the cargo‐trafficking assay revealed that mutant KIF5C lost the peroxisome‐transporting ability. Drosophila models also confirmed p.Ser90del's essential role in nervous system development. This study emphasized the importance of the KIF5C gene in intracellular cargo‐transport as well as germline variants that lead to neurodevelopmental disorders and might enable clinicians for timely and accurate diagnosis and disease management in the future. We identified a novel heterozygous in‐frame deletion (c.265_267delTCA) in exon 3 of KIF5C in a 6 years and 3 months‐old Chinese boy with markedly symptomatic epilepsy, intellectual disability, and psychomotor retardation, resulting in the removal of evolutionarily highly conserved p.Ser90 in its ATP‐binding domain. This study emphasized the importance of the KIF5C in intracellular cargo‐transport as well as germline variants leading to neurodevelopmental disorders.

In response to the current challenges of limited monitoring methods and underutilization of data in distribution networks, this paper proposes a study on intelligent distribution network operation and anomaly detection using information technology. This article begins by analyzing the technical characteristics and data flow within the current power supply enterprise distribution network scheduling support system. It selects extensive historical telemetry data as the subject of research and employs the C-means fuzzy clustering algorithm to identify distribution line load patterns and conduct load prediction. A mismatch degree index, taking into account membership degree and Euclidean distance factors, serves as the criterion for assessing line faults. A 12 kV distribution line (L) in a certain area was chosen and tested using real operational data to see if the proposed big data-based method for monitoring distribution network faults works. The test results show that this study can correctly find patterns in distribution line loads, reliably find line faults, and, to some extent, lessen the problems that come up when loads change normally. The application results reveal that this study offers a straightforward and practical monitoring approach that effectively assesses the fault status of distribution networks that cannot be monitored using existing methods.