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Abstract Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homoeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.

Objective: Solid tumor cells utilize amino acid transporters (AATs) to increase amino acid uptake in response tonutrient-insufficiency. The upregulation of AATs is therefore critical for tumor development and progression. This studyidentifies the upregulated AATs under amino acid deprived conditions, and further determines the clinicopathologicalimportance of these AATs in evaluating the prognosis of patients with cancers.Materials and Methods: In this experimental study, the Gene Expression Omnibus (GEO) datasets (GSE62673,GSE26370, GSE125782 and GSE150874) were downloaded from the NCBI website and utilized for integrateddifferential expression and pathway analysis v0.96, Gene Set Enrichment Analysis (GSEA), and REACTOME analysesto identify the AATs upregulated in response to amino acid deprivation. In addition, The Cancer Genome Atlas (TCGA)datasets with prognostic information were assessed and employed to evaluate the association of identified AATs withpatients’ prognoses using SurvExpress analysis.Results: Using analysis of NCBI GEO data, this study shows that amino acid deprivation leads to the upregulationof six AAT genes; SLC3A2, SLC7A5, SLC7A1, SLC1A4, SLC7A11 and SLC1A5. GSEA and REACTOME analysesidentified altered signaling in cells exposed to amino acid deprivation, such as pathways related to stress responses,the cell cycle and apoptosis. In addition, Principal Component Analysis showed these six AAT genes to be well dividedinto two distinct clusters in relation to TCGA tumor tissues versus normal counterparts. Finally, Log-Rank analysisconfirmed the upregulation of this panel of six AAT genes is correlated with poor prognosis in patients with colorectal,esophageal, kidney and lung cancers.Conclusion: The upregulation of a panel of six AATs is common in several human cancers and may provide a valuablediagnostic tool to evaluate the prognosis of patients with colorectal, esophageal, kidney and lung cancers.

Abstract Background Immunocheckpoint inhibitors (ICIs) have been widely used in the clinical treatment of lung cancer. Although clinical studies and trials have shown that patients can benefit significantly after PD-1/PD-L1 blocking therapy, less than 20% of patients can benefit from ICIs therapy due to tumor heterogeneity and the complexity of immune microenvironment. Several recent studies have explored the immunosuppression of PD-L1 expression and activity by post-translational regulation. Our published articles demonstrate that ISG15 inhibits lung adenocarcinoma progression. Whether ISG15 can enhance the efficacy of ICIs by modulating PD-L1 remains unknown. Methods The relationship between ISG15 and lymphocyte infiltration was identified by IHC. The effects of ISG15 on tumor cells and T lymphocytes were assessed using RT-qPCR and Western Blot and in vivo experiments. The underlying mechanism of PD-L1 post-translational modification by ISG15 was revealed by Western blot, RT-qPCR, flow cytometry, and Co-IP. Finally, we performed validation in C57 mice as well as in lung adenocarcinoma tissues. Results ISG15 promotes the infiltration of CD4+ T lymphocytes. In vivo and in vitro experiments demonstrated that ISG15 induces CD4+ T cell proliferation and invalidity and immune responses against tumors. Mechanistically, we demonstrated that the ubiquitination-like modifying effect of ISG15 on PD-L1 increased the modification of K48-linked ubiquitin chains thus increasing the degradation rate of glycosylated PD-L1 targeting proteasomal pathway. The expression of ISG15 and PD-L1 was negatively correlated in NSCLC tissues. In addition, reduced accumulation of PD-L1 by ISG15 in mice also increased splenic lymphocyte infiltration as well as promoted cytotoxic T cell infiltration in the tumor microenvironment, thereby enhancing anti-tumor immunity. Conclusions The ubiquitination modification of PD-L1 by ISG15 increases K48-linked ubiquitin chain modification, thereby increasing the degradation rate of glycosylated PD-L1-targeted proteasome pathway. More importantly, ISG15 enhanced the sensitivity to immunosuppressive therapy. Our study shows that ISG15, as a post-translational modifier of PD-L1, reduces the stability of PD-L1 and may be a potential therapeutic target for cancer immunotherapy.

Currently, the alteration of external factors during crude oil extraction easily disrupts the thermodynamic equilibrium of asphaltene, resulting in the continuous flocculation and deposition of asphaltene molecules in crude oil. This accumulation within the pores of reservoir rocks obstructs the pore throat, hindering the efficient extraction of oil and gas, and consequently, affecting the recovery of oil and gas resources. Therefore, it is crucial to investigate the principles of asphaltene deposition inhibition and the synthesis of asphaltene inhibitors. In recent years, the development of nanotechnology has garnered significant attention due to its unique surface and volume effects. Nanoparticles possess a large specific surface area, high adsorption capacity, and excellent suspension and catalytic abilities, exhibiting unparalleled advantages compared with traditional organic asphaltene inhibitors, such as sodium dodecyl benzene sulfonate and salicylic acid. At present, there are three primary types of nanoparticle inhibitors: metal oxide nanoparticles, organic nanoparticles, and inorganic nonmetal nanoparticles. This paper reviews the recent advancements and application challenges of nanoparticle asphaltene deposition inhibition technology based on the mechanism of asphaltene deposition and nano-inhibitors. The aim was to provide insights for ongoing research in this field and to identify potential future research directions.

With the development of modern communication technology and the large number of new controllable loads connected to the power grid, the new controllable loads with flexible regulation characteristics can participate in the emergency frequency stability control. However, the communication state differences and spatial distribution characteristics of controllable load will affect the actual effect of frequency control. In this paper, an emergency frequency control method based on deep reinforcement learning is proposed considering the response time of controllable load shedding. The proposed method evaluates response ability for emergency control of controlled loads through load response time, controllable load amount and controllable load buses. Then, the controllable load with smaller response time is cut out preferentially to ensure rapid control, and the Markov Decision Process (MDP) is used to model the emergency frequency control problem. Finally, Rainbow algorithm of Deep Reinforcement Learning (DRL) is used to optimize the emergency frequency stability control strategy involving controllable load resources. The formation of emergency load shedding instruction is directly driven by high-dimensional operation state data after power grid failure, so that, the aim of minimizing the economic cost is achieved under the constraint of system stability. The effectiveness of the proposed method is verified in the IEEE 39-bus system.

How photoexcitations influence superconductivity at the FeSe/SrTiO3 interface remains elusive. Here, the authors report fast optical generation of a metastable superconducting state and its reversal by voltage pulses at the FeSe monolayer/SrTiO3 interface.

Water-in-oil-in-water (W1/O/W2) double emulsions must resist W1–W1, O–O and W1–W2 coalescence to be suitable for applications. This work isolates the stability of the oil droplets in a double emulsion, focusing on the impact of the concentration of the hydrophilic surfactant. The stability against coalescence was measured on droplets ranging in size from millimeters to micrometers, evaluating three different measurement methods. The time between the contact and coalescence of millimeter-sized droplets at a planar interface was compared to the number of coalescence events in a microfluidic emulsion and to the change in the droplet size distributions of micrometer-sized single and double emulsions. For the examined formulations, the same stability trends were found in all three droplet sizes. When the concentration of the hydrophilic surfactant is reduced drastically, lipophilic surfactants can help to increase the oil droplets’ stability against coalescence. This article also provides recommendations as to which purpose each of the model experiments is suited and discusses advantages and limitations compared to previous research carried out directly on double emulsions.

Abstract The incidence of patients diagnosed with either breast cancer (BC) or inflammatory bowel disease (IBD) is increasing each year. IBD has been shown to be strongly associated with the development of a variety of solid tumors, but the relationship with breast cancer is not yet definitive. We explored the causative relationship between IBD and BC using a Mendelian randomization (MR) strategy. MR-Egger regression, weighted median (WM), simple median (SM), maximum likelihood (ML), and inverse variance weighting (IVW) methods were among the analytical techniques used in this work. The examination of heterogeneity was conducted by the use of Cochran's Q test and Rucker's Q test. The sensitivity analysis in this study used the IVW and MR-Egger methodologies. The results of our investigation suggested that IBD had a beneficial impact on estrogen receptor-negative (ER-) breast cancer (odds ratio (OR) = 0.92, P = 0.02). The study did not find a significant association between IBD and the risk of developing overall breast cancer (OR = 0.99, P = 0.60), as well as estrogen receptor-positive (ER+) breast cancer (OR = 1.02, P = 0.60) specifically. In addition, our study findings indicated that there was a detrimental association between ER+ breast cancer and IBD as determined using reverse MR analysis (OR = 1.07, P = 0.04). Furthermore, this analysis failed to observe any significant association between overall breast cancer (OR = 1.07, P = 0.07) or ER- breast cancer (OR = 0.99, P = 0.89) and IBD. Our bidirectional MR study yielded a correlation between IBD and some specific hormone receptor status of BC.

Abstract Background Telomere length (TL), mitochondrial DNA copy number (mtDNAcn), and DNA methylation age (DNAmAge) are common aging biomarkers. However, research on the associations between these three markers at birth and subsequent metabolic status was limited. This study aimed to evaluate the association between TL, mtDNAcn, and DNAmAge in newborns and the variation in metabolic hormones of children at 3 years old. Methods This research involved 895 mother–child pairs from a birth cohort in China, with TL and mtDNAcn measured using quantitative real-time PCR, DNA methylation (DNAm) assessed using Infinium MethylationEPIC Beadchip, and DNAm age (DNAmAge) determined using Horvath’s epigenetic clock. Insulin and leptin levels were measured via electrochemiluminescence assay. Multivariable adjusted linear regression and restricted cubic spline (RCS) analysis were utilized to examine the association between aging markers and metabolic hormones. Results The linear regression analysis indicated the percentage change of metabolism hormones for per doubling of aging biomarkers alterations and found significant associations between DNAmAge and insulin levels (adjusted percent change (95% CI), − 13.22 (− 23.21 to − 1.94)), TL and leptin levels (adjusted percent change (95% CI), 15.32 (1.32 to 31.24)), and mtDNAcn and leptin levels (adjusted percent change (95% CI), − 14.13 (− 21.59 to − 5.95)). The RCS analysis revealed significant non-linear associations between TL (Ln transformed) and insulin (Ln transformed) (P = 0.024 for nonlinearity), as well as DNAmAge (Ln transformed) and leptin (Ln transformed) (P = 0.043 for nonlinearity). Specifically, for TL and insulin, a positive association was observed when TL (Ln transformed) was less than − 0.05, which transitioned to an inverse association when TL (Ln transformed) was greater than − 0.05. Regarding DNAmAge and leptin, there was a sharp decline when DNAmAge (Ln transformed) was less than − 1.35, followed by a plateau between − 1.35 and − 0.67 and then a further decline when DNAmAge (Ln transformed) was greater than − 0.67. Conclusions In this prospective birth cohort study, variation in metabolic hormones of children at 3 years old was associated with TL, mtDNAcn, and DNAmAge at birth. These findings suggested that TL, mtDNAcn, and DNAmAge might play a role in the biological programming of metabolic health from birth.

Abstract Articular cartilage damage and wear can result in cartilage degeneration, ultimately culminating in osteoarthritis. Current surgical interventions offer limited capacity for cartilage tissue regeneration and offer only temporary alleviation of symptoms. Tissue engineering strategies are increasingly recognized as promising modalities for cartilage restoration. Currently, various biological scaffolds utilizing tissue engineering materials are extensively employed in both fundamental and clinical investigations of cartilage repair. In order to optimize the cartilage repair ability of tissue engineering scaffolds, researchers not only optimize the structure and properties of scaffolds from the perspective of materials science and manufacturing technology to enhance their histocompatibility, but also adopt strategies such as loading cells, cytokines, and drugs to promote cartilage formation. This review provides an overview of contemporary tissue engineering strategies employed in cartilage repair, as well as a synthesis of existing preclinical and clinical research. Furthermore, the obstacles faced in the translation of tissue engineering strategies to clinical practice are discussed, offering valuable guidance for researchers seeking to address these challenges.

According to World Health Organization statistics, inappropriate medication has become an important factor affecting the safety of rational medication. In the gray area of medical insurance supervision, such as designated drugstores and medical institutions, there are lots of inappropriate medication phenomena regarding “big prescription for minor ailments.” A traditional clinical decision support system is mostly based on established rules to regulate inappropriate prescriptions, which are not suitable for clinical environments and require intelligent review. In this study, we model the complex relationships between patients, diseases, and drugs based on medical big data to promote appropriate medication use. More specifically, we first construct the medication knowledge graph based on the historical prescription big data of tertiary hospitals and medical text data. Second, based on the medication knowledge graph, we employ a Gaussian mixture model to group patient population representation as physiological features. For diagnostic features, we employ pre-training word vector Bidirectional Encoder Representations from Transformers to enhance the semantic representation between diagnoses. In addition, to reduce adverse drug interactions caused by drug combinations, we employ a graph convolution network to transform drug interaction information into drug interaction features. Finally, we employ the sequence generation model to learn the complex relationships between patients, diseases, and drugs and provide an appropriate medication evaluation for doctor prescriptions in small hospitals from two aspects: drug list and medication course of treatment. In this study, we utilize the MIMIC III dataset alongside data from a tertiary hospital in Fujian Province to validate our model. The results show that our method is more effective than other baseline methods in the accuracy of the medication regimen prediction of rational medication. In addition, it achieved high accuracy in the appropriate medication detection of prescription in small hospitals.

Abstract The role of tumor-resident intracellular microbiota (TRIM) in carcinogenesis has sparked enormous interest. Nevertheless, the impact of TRIM-targeted antibacteria on tumor inhibition and immune regulation in the tumor microenvironment (TME) remains unexplored. Herein, we report long-term relapse-free survival by coordinating antibacteria with antitumor treatment, addressing the aggravated immunosuppression and tumor overgrowth induced by TRIM using breast and prostate cancer models. Combining Ag+ release with a Fenton-like reaction and photothermal conversion, simultaneous bacteria killing and multimodal antitumor therapy are enabled by a single agent. Free of immune-stimulating drugs, the agent restores antitumor immune surveillance and activates immunological responses. Secondary inoculation and distal tumor analysis confirm lasting immunological memory and systemic immune responses. A relapse-free survival of >700 days is achieved. This work unravels the crucial role of TRIM-targeted antibacteria in tumor inhibition and unlocks an unconventional route for immune regulation in TME and a complete cure for cancer.

To evaluate the correlation between the water absorption characteristics of dried chrysanthemums and their structure, water activity (Aw), and storage temperature, two types of powdered chrysanthemums ("Xiaohuangju" and "Gongjuwang") were analyzed through SEM, FTIR, and XPS. The results indicated that the surface of the powdered chrysanthemums was rough and contained a large number of indentations and cavities. In comparison to "Xiaohuangju", "Gongjuwang" powder had smaller particle sizes and more hydrophilic groups on the surface, such as -OH, O-C-O, etc. To examine the water adsorption behavior of two varieties of powdered chrysanthemums, the static gravimetric method was employed at 20, 30, and 40 ℃ and a range of Aw values from 0.112 to 0.976. Model fitting and thermodynamic analysis were conducted to gain insight into the water adsorption mechanism. An increase in water activity (Aw) resulted in a rise in the equilibrium water content (Xe) of powdered chrysanthemums, conversely, the higher the temperature, the lower the Xe values at the equivalent Aw levels. The fitting results demonstrated that the Peleg model was the most suitable model for depicting the water adsorption isotherms. Results from the thermodynamic analysis suggested that the net isosteric heat of adsorption (qst) decreased when the equilibrium water content (Xe) increased, and the qst values of "Xiaohuangju" and "Gongjuwang" powder remained steady in the presence of Xe values greater than 0.14 g/g and 0.24 g/g, respectively. The monolayer water content (Xm) of "Xiaohuangju" at 20, 30, and 40 ℃ were 0.0690, 0.0525, and 0.0505 g/g (d. b), respectively, while those of "Gongjuwang" were 0.0645, 0.0591 and 0.0584 g/g (d. b). When the temperature and water content increased, the effective pore size (rp) of "Xiaohuangju" powder increased, exhibiting mesoporous characteristics when Xe>0.09 g/g (d. b). Conversely, the internal pores of “Gongjuwang” powder shifted from micropore to mesopore only when Xe>0.11 g/g (d. b). The results of the study can be employed as a guide for improving the drying process of chrysanthemums and determining the most suitable storage conditions.

Enhancing photosynthesis is a pivotal strategy for achieving sustainable plant production. Blue and red light facilitate plant growth since these wavelengths are readily absorbed by chlorophyll pigments and power crucial photosynthetic processes. In this investigation, double light conversion films were prepared by incorporating biomass-derived carbon dots into a polyvinyl alcohol matrix (CDs@PVAs). The study conclusively demonstrated that CDs@PVAs can convert ultraviolet and green light from sunlight into blue and red light. Using 2-week-old Athaliana plants as the model organism, the Athaliana plants were covered with CDs@PVAs and then exposed to simulated sunlight (0.57 mW cm−2) for 1 hour. The Fv/Fm value in the presence of the CDs@PVAs was approximately 12% higher than without the film, indicating a significant boost in photosynthesis. Analysis of gene expression showed that the CDs@PVAs cause significant upregulation of genes associated with photosynthesis. These double light conversion films thus emerge as promising contenders for eco-friendly plant cultivation methods that circumvent reliance on electric power. Their potential applications in agriculture are substantial, underscoring their significance in promoting sustainable practices.

Abstract The impairment of sperm maturation is one of the major pathogenic factors in male subfertility, a serious medical and social problem affecting millions of global couples. Regrettably, the existing research on sperm maturation is slow, limited, and fragmented, largely attributable to the lack of a global molecular view. To fill the data gap, we newly established a database, namely the Sperm Maturation Database (SperMD, http://bio-add.org/SperMD ). SperMD integrates heterogeneous multi-omics data (170 transcriptomes, 91 proteomes, and five human metabolomes) to illustrate the transcriptional, translational, and metabolic manifestations during the entire lifespan of sperm maturation. These data involve almost all crucial scenarios related to sperm maturation, including the tissue components of the epididymal microenvironment, cell constituents of tissues, different pathological states, and so on. To the best of our knowledge, SperMD could be one of the limited repositories that provide focused and comprehensive information on sperm maturation. Easy-to-use web services are also implemented to enhance the experience of data retrieval and molecular comparison between humans and mice. Furthermore, the manuscript illustrates an example application demonstrated to systematically characterize novel gene functions in sperm maturation. Nevertheless, SperMD undertakes the endeavor to integrate the islanding omics data, offering a panoramic molecular view of how the spermatozoa gain full reproductive abilities. It will serve as a valuable resource for the systematic exploration of sperm maturation and for prioritizing the biomarkers and targets for precise diagnosis and therapy of male subfertility.

BackgroundPostmenopausal osteoporosis is a prevalent disease that affects the bone health of middle-aged and elderly women. The link between gut microbiota and bone health, known as the gut-bone axis, has garnered widespread attention.MethodsWe employed a two-sample Mendelian randomization approach to assess the associations between gut microbiota with osteoclasts and postmenopausal osteoporosis, respectively. Single nucleotide polymorphisms associated with the composition of gut microbiota were used as instrumental variables. By analyzing large-scale multi-ethnic GWAS data from the international MiBioGen consortium, and combining data from the eQTLGen consortium and the GEFOS consortium, we identified microbiota related to osteoclasts and postmenopausal osteoporosis. Key genes were further identified through MAGMA analysis, and validation was performed using single-cell data GSE147287.ResultsThe outcomes of this study have uncovered significant associations within the gut microbiome community, particularly with the Burkholderiales order, which correlates with both an increase in osteoclasts and a reduced risk of postmenopausal osteoporosis. with an odds ratio (OR) of 0.400, and a P-value of 0.011. Further analysis using single-cell data allowed us to identify two key genes, FMNL2 and SRBD1, that are closely linked to both osteoclasts and osteoporosis.ConclusionThis study utilizing Mendelian randomization and single-cell data analysis, provides new evidence of a causal relationship between gut microbiota and osteoclasts, as well as postmenopausal osteoporosis. It was discovered that the specific microbial group, the Burkholderiales order, significantly impacts both osteoporosis and osteoclasts. Additionally, key genes FMNL2 and SRBD1 were identified, offering new therapeutic strategies for the treatment of postmenopausal osteoporosis.

Objectives This study aimed to investigate the impact of adjuvant chemotherapy (ACT) on survival outcomes in older women with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer (BC).Design A retrospective cohort study using data from the Surveillance, Epidemiology, and End Results database, which contains publicly available information from US cancer registries.Setting and participants The study included 45 762 older patients with BC aged over 65 years diagnosed between 2010 and 2015.Methods Patients were divided into two groups based on age: 65–79 years and ≥80 years. Propensity score matching (PSM) was employed to balance clinicopathological characteristics between patients who received ACT and those who did not. Data analysis used the χ2 test and Kaplan-Meier method, with a subgroup analysis conducted to identify potential beneficiaries of ACT.Outcome measures Overall survival (OS) and cancer-specific survival (CSS).Results Due to clinicopathological characteristic imbalances between patients with BC aged 65–79 years and those aged ≥80 years, PSM was used to categorise the population into two groups for analysis: the 65–79 years age group (n=38 128) and the ≥80 years age group (n=7634). Among patients aged 65–79 years, Kaplan-Meier analysis post-PSM indicated that ACT was effective in improving OS (p

Abstract Photothermal devices and thermoelectric cells hold great promise for energy generation but integration of the two remains a considerable challenge in real‐life power supply for sensors. Here, a novel photo‐thermo‐electric hydrogel (PTEH‐Interlocking) was constructed by the synthesis of a photothermal layer on a thermoelectric hydrogel with the redox pair Fe(CN)63−/Fe(CN)64−. The smart design of using the oxidation of pyrogallic acid by Fe(CN)63− to construct the photothermal layer for photo‐to‐heat conversion protected the redox couple of the thermogalvanic ion pair from ultraviolet damage, as well as triggered the formation of an interlocking structure at the interface of the photothermal layer and the thermoelectric hydrogel. The as‐prepared PTEH‐Interlocking has shown a high Seebeck coefficient and rapid heat transfer, boosting the photo‐thermo‐electric conversion. As a demonstration of a practical application, the PTEH‐Interlocking cells are successfully used as the energy supply for a mechanical sensor.