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ABSTRACTGut microbiota and related metabolites are both crucial factors that significantly influence how individuals with Crohn’s disease respond to immunotherapy. However, little is known about the interplay among gut microbiota, metabolites, Crohn’s disease, and the response to anti-α4β7-integrin in current studies. Our research utilized 2,4,6-trinitrobenzene sulfonic acid to induce colitis based on the humanized immune system mouse model and employed a combination of whole-genome shotgun metagenomics and non-targeted metabolomics to investigate immunotherapy responses. Additionally, clinical cases with Crohn’s disease initiating anti-α4β7-integrin therapy were evaluated comprehensively. Particularly, 16S-rDNA gene high-throughput sequencing and targeted bile acid metabolomics were conducted at weeks 0, 14, and 54. We found that anti-α4β7-integrin therapy has shown significant potential for mitigating disease phenotypes in remission-achieving colitis mice. Microbial profiles demonstrated that not only microbial composition but also microbially encoded metabolic pathways could predict immunotherapy responses. Metabonomic signatures revealed that bile acid metabolism alteration, especially elevated secondary bile acids, was a determinant of immunotherapy responses. Especially, the remission mice significantly enriched the proportion of the beneficial Lactobacillus and Clostridium genera, which were correlated with increased gastrointestinal levels of BAs involving lithocholic acid and deoxycholic acid. Moreover, most of the omics features observed in colitis mice were replicated in clinical cases. Notably, anti-α4β7 integrin provided sustained therapeutic benefits in clinical remitters during follow-up, and long-lasting remission was linked to persistent changes in the microbial-related bile acids. In conclusion, gut microbiota-mediated bile acid metabolism alteration could play a crucial role in regulating immunotherapy responses to anti-α4β7-integrin in Crohn’s disease. Therefore, the identification of prognostic microbial signals facilitates the advancement of targeted probiotics that activate anti-inflammatory bile acid metabolic pathways, thereby improving immunotherapy responses. The integrated multi-omics established in our research provide valuable insights into potential mechanisms that impact treatment responses in complex diseases.

Abstract Purpose The role and mechanism of zinc finger DHHC protein 11B (ZDHHC11B) in lung adenocarcinoma (LUAD) remain unclear. We, thus, analyzed the expression pattern, biological function, and potential mechanism of ZDHHC11B in LUAD. Methods The expression level and prognostic value of ZDHHC11B were evaluated based on The Cancer Genome Atlas (TCGA) database and further confirmed in LUAD tissues and cells. The effect of ZDHHC11B on the malignant biological progression of LUAD was evaluated in vitro and in vivo. Gene set enrichment analysis (GSEA) and western blot were used to explore the molecular mechanisms of ZDHHC11B. Results In vitro, ZDHHC11B inhibited the proliferation, migration, and invasion of LUAD cells and induced the apoptosis of LUAD cells. In addition, ZDHHC11B inhibited the growth of tumors in nude mice. GSEA revealed that ZDHHC11B expression is positively correlated with epithelial–mesenchymal transition (EMT). Western blot analysis demonstrated that molecular markers of EMT were inhibited under ZDHHC11B overexpression conditions. Conclusions Our findings indicated that ZDHHC11B plays a significant role in inhibiting tumorigenesis via EMT. In addition, ZDHHC11B may be a candidate molecular target for LUAD treatment.

The photocatalytic removal of nitric oxide (NO) is a promising technology used to reduce the level of harmful gaseous pollutants in parts per billion (ppb). As a potential photocatalyst, Bi2Sn2O7 has a low quantum efficiency due to its fast recombination rate of photo-generated carriers. In this paper, Bi/Bi2Sn2O7 was prepared by the in situ deposition of Bi. The structural, electrical, and optical properties of the attained sample were investigated through a series of analyses. The results demonstrate that Bi nanoparticles not only enhance the photoabsorption ability of Bi2Sn2O7 due to their surface plasmon resonance (SPR) effect, but also improve its photocatalytic activity. Photocatalytic performance was evaluated by the oxidation of NO at ppb level under xenon lamp (λ > 400 nm) irradiation. It was found that the photocatalytic NO removal rate increased from 7.2% (Bi2Sn2O7) to 38.6% (Bi/Bi2Sn2O7). The loading of Bi promotes the separation and migration of photo-generated carriers and enhances the generation of •O2− and •OH radicals responsible for the oxidation of NO. The Bi/Bi2Sn2O7 composite photocatalyst also exhibits excellent photocatalytic stability, which makes it a potential candidate for use in air purification systems.

The concept of adenoma-to-cancer transformation in human colorectal cancer (CRC) is widely accepted. However, the relationship between transcriptome features and adenoma to carcinoma transformation in canines is not clear. We collected transcriptome data from 8 normal colon tissues, 4 adenoma tissues, and 15 cancer tissues. Differential analysis was unable to determine the dynamic changes of genes but revealed that PFKFB3 may play a key role in this process. Enrichment analysis explained metabolic dysregulation, immunosuppression, and typical cancer pathways in canine colorectal tumors. MFuzz generated specific dynamic expression patterns of five differentially expressed genes (DEGs). Weighted correlation network analysis showed that DEGs in cluster 3 were associated with malignant tissues, revealing the key role of inflammatory and immune pathways in canine CRC, and the S100A protein family was also found to be involved in the malignant transformation of canine colorectal tumors. By comparing strategies between humans and dogs, we found five novel markers that may be drivers of CRC. Among them, GTBP4 showed excellent diagnostic and prognostic ability. This study was the first systematic exploration of transformation in canine CRC, complemented the molecular characteristics of the development and progression of canine CRC, and provided new potential biomarkers and comparative oncologic evidence for biomarker studies in human colorectal cancer.

BackgroundTo evaluate the ability of tidal volume challenge (VTC)-induced hemodynamic changes to predict fluid responsiveness in patients during one-lung ventilation (OLV).Methods80 patients scheduled for elective thoracoscopic surgery with OLV were enrolled. The inclusion criteria were: age ≥ 18 years, American Society of Anesthesiologists physical status I-III, normal right ventricular function, normal left ventricular systolic function (ejection fraction ≥55%), and normal or slightly impaired diastolic function. The study protocol was implemented 15 min after starting OLV. Simultaneous recordings were performed for hemodynamic variables of diameter of left ventricular outflow tract, velocity time integral (VTI) of aortic valve, and stroke volume (SV), and ΔSV-VTC, ΔVTI-VTC, and ΔMAP-VTC were calculated at four time points: with VT 5 mL/kg (T1); after VT increased from 5 mL/kg to 8 mL/kg and maintained at this level for 2 min (T2); after VT was adjusted back to 5 mL/kg for 2 min (T3); and after volume expansion (250 mL of 0.9% saline infused over 10–15 min) (T4). Patients were considered as responders to fluid administration if SV increased by ≥10%. Receiver operating characteristic (ROC) curves for percent decrease in SV, VTI, and MAP by VTC were generated to evaluate their ability to discriminate fluid responders from nonresponders.ResultsOf the 58 patients analyzed, there were 32 responders (55%) and 26 nonresponders (45%). The basic characteristics were comparable between the two groups (p > 0.05). The area under the curve (AUC) for ΔSV-VTC, ΔVTI-VTC, and ΔMAP-VTC to discriminate responders from nonresponders were 0.81 (95% CI: 0.68–0.90), 0.79 (95% CI: 0.66–0.89), and 0.56 (95% CI: 0.42–0.69). The best threshold for ΔSV-VTC was −16.1% (sensitivity, 78.1%; specificity, 84.6%); the best threshold for ΔVTI-VTC was −14.5% (sensitivity, 78.1%; specificity, 80.8%).ConclusionTidal volume challenge–induced relative change of stroke volume and velocity time integral can predict fluid responsiveness in patients during one-lung ventilation.Clinical Trial Registration: Chinese Clinical Trial Registry, No: chictr210051310.

Monocyte-derived macrophages can be polarized into antitumor M1 phenotype, which inhibited the growth of tumors, and immune-suppressive M2 phenotype, which promoted the development and metastasis of tumors. Plantain polysaccharide (PLP), extracted from the Plantago asiatica, has shown its various biological activities. However, the ability of PLP involved in immune regulation was still obscure. Accordingly, we aimed to investigate whether PLP could polarize macrophages and further inhibit 4T1 tumor cells in vivo and in vitro. In this research, in vitro results showed that PLP displayed the potential in polarizing RAW264.7 macrophages into M1 phenotype and indirect inhibiting migratory effect on 4T1 cells. Furthermore, the phagocytosis and the release of reactive oxygen species (ROS) of macrophages were enhanced. In vivo anti-tumor results demonstrated that PLP could effectively inhibit the growth of 4T1 breast tumors by promoting accumulation of macrophages and T cells in the spleen and lymph node. In conclusion, these findings indicated that PLP inhibited the proliferation and progression of breast tumors by accumulating CD4+, CD8+ T cells and M1-like macrophages in lymph node and spleen, and therefore provided an experimental basis for PLP as a potential antitumor adjunctive therapy in preclinical and clinical trials.

PurposeTo emphasize the importance of tumor-associated macrophages (TAMs) in tumor immunity and to describe the ways in which extracts from Traditional Chinese Medicine (TCM) achieve tumor therapy by modulating macrophages.SignificanceBy summarizing these available data, this review focused on TAMs and TCM and can build the foundation for future research on antitumor therapeutics.MethodsIn this review, we summarized the key functions of TAMs in cancer development and overviewed literature on TCM targeting TAMs together with other immune cells aiming to enhance antitumor immunity.ConclusionsWith an indispensable role in antitumor immunity, TAMs contribute to tumor progression, migration, invasion, angiogenesis, lymphangiogenesis, and immunosuppressive microenvironment. In recent years, TCM has gradually gained attention as a potential antitumor adjunctive therapy in preclinical and clinical trials. TCM is also a regulator of cytokine secretion and cell surface molecule expression in balancing the tumor microenvironment (TME), especially macrophage activation and polarization. Therefore, it is believed that TCM could serve as modifiers with immunomodulatory capability.

The global transition to a renewable-powered economy is gaining momentum as renewable energy becomes more cost-effective and energy-efficient. Renewable-energy-integrated Virtual Power Plants (VPPs) are capable of facilitating renewable transition, reducing distributed generator impacts, and creating value for prosumers and communities by producing renewable energy, engaging in the electricity market, and providing electricity network functions. In this paper, we conducted a case study in the City of Greater Bendigo to evaluate the challenges and opportunities of the community-focused renewable energy transition through establishing VPP with community-based renewable generators and storage systems. A reinforcement learning algorithm was formulated to optimise the energy supply, load shifting, and market trading in the VPP system. The proposed VPP system has great potential to improve the economic value and carbon emission reduction performance of local renewable resources: it can reduce 50–70% of the case study city’s carbon emissions in 10 years and lower the electricity price from the current range of 0.15 AUD/kWh (off-peak) −0.30 AUD/kWh (peak) as provided by Victorian Essential Services Committee to 0.05 AUD/kWh (off-peak) (peak). Overall, this study proposed a comprehensive framework to investigate community-based VPP in a complex urban environment and validated the capability of the VPP in supporting the renewable transition for Australian communities.

An omni-azimuth angle sensor for tilt measuring based on fiber Bragg grating (FBG) array is proposed. It is designed based on the sensitivity of FBG to axial traction. The sensor consists of a mass block and a cube frame connected by an FBG array. The FBG array consists of four FBGs. When the sensor is tilted at different angles, the axial traction of each FBG will change due to the pull of the mass block. The tilt angle of the sensing unit can be obtained by calculating the magnitude and direction of the resultant traction of the four FBGs. The array design and measurement theory of the sensor are introduced, and the sensitivity of the sensor is discussed. Experimental results show that the FBG array can be used to measure the omni-azimuth angle. The angle sensitivity varies unevenly with the tilt angle and the range of variation is 0.08 nm/° to 0.4593 nm/°. Using the spectrometer with an accuracy of 0.01 nm, the angle resolution ranges from 0.125° to 0.0218°. The array effectively extends the measurement range of the tilt sensor, and reduces the number of FBGs as much as possible on the basis of achieving omni-azimuth angle measurement.

In this paper, an aluminum foam sandwich (AFS) was prepared by the rolling composite-powder metallurgy method, and its fatigue properties were studied. It was compared with an AFS made by the adhesive method to study its fatigue properties more directly. In this experiment, the fatigue performance was investigated by studying the microscopic interface, fatigue life, deflection curve, and failure mode. The results show that the fatigue life of an AFS with the rolling composite-powder metallurgy method is much longer than that with the adhesive method. The failure mode of an AFS made by the rolling composite-powder metallurgy method is shear failure, and that of an AFS made by the adhesive method is shear failure and interface debonding. An AFS with the rolling composite-powder metallurgy method has better fatigue properties. This paper also explored the fatigue damage model using the fatigue modulus method, and the polynomial fitting method has a higher fitting degree.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe neurological event with limited treatment options, and little is known about its pathophysiology. There are few objective tools for predicting outcomes of aSAH patients and further aiding in directing clinical therapeutic programs. This study aimed to determine whether an elevated serum D-dimer/albumin ratio (DAR) reflects disease severity and predicts aSAH outcomes. Methods: We included 178 patients with aSAH. Data included demographics; clinical severity of aSAH (World Federation of Neurological Societies (WFNS) grade and Hunt–Hess grade); levels of D-dimer, albumin, and c-reactive protein (CRP); leukocyte counts on admission; and three-month outcomes. The outcomes were dichotomized into good and poor. The predictive ability of DAR for outcomes was determined using receiver operating characteristic (ROC) curve analysis. Results: Serum DAR showed a positive correlation with disease severity. Univariate analysis revealed that DAR, WFNS grade, Hunt–Hess grade, delayed cerebral infarction (DCI), age, neutrophil-to-lymphocyte ratio (NLR), and CRP/albumin ratio (CAR) were associated with unfavorable outcomes. Multivariate regression analysis further revealed that elevated DAR predicted poor outcomes after adjusting for WFNS grade, Hunt–Hess grade, DCI, age, NLR, and CRP/albumin ratio. Receiver operating characteristic curve analysis revealed that DAR predicted outcomes at a level comparable with NLR and CAR and had superior predictivity than D-dimer alone. Conclusion: DAR is a promising objective tool for aSAH outcome prediction. A high content DAR was associated with disease severity and unfavorable short-term outcomes.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) that mediate T-cell immune responses. Breast cancer is one of the most commonly diagnosed diseases and its mortality rate is higher than any other cancer in both humans and canines. Plantain polysaccharide (PLP), extracted from the whole plant of Plantago asiatica L., could promote the maturation of DCs. In this research, we found that PLP could upregulate the maturation of DCs both in vitro and in vivo. PLP-activated DCs could stimulate lymphocytes’ proliferation and differentiate naive T cells into cytotoxic T cells. Tumor antigen-specific lymphocyte responses were enhanced by PLP and CIPp canine breast tumor cells lysate-pulsed DCs, and PLP and CIPp-cell-lysate jointly stimulated DCs cocultured with lymphocytes having the great cytotoxicity on CIPp cells. In the 4T1 murine breast tumor model, PLP could control the size of breast tumors and improve immunity by recruiting DCs, macrophages, and CD4+ and CD8+ T cells in the tumor microenvironment. These results indicated that PLP could achieve immunotherapeutic effects and improve immunity in the breast tumor model.

In recent years, heavy metal pollution has caused immeasurable harm to the environment. As an emerging technology, phytoremediation technology has gained a place in the treatment of heavy metal pollution with its unique advantages. This study analyzes the toxic effects of mulberry (Morus alba) seeds, seedling growth and silkworm under heavy metal stress of lead (Pb) and cadmium (Cd), and explore the accumulation and migration of Pb and Cd in the soil-mulberry tree-silkworm system. The main results were as follows: (1) Seed germination and potted seedling experiments were conducted under heavy metal Pb and Cd stresses, and it was found that Pb and Cd had inhibitory effects on mulberry seed germination, growth and photosynthesis of mulberry seedlings, and as the concentration of heavy metals increased, the stronger the inhibitory effect. Moreover, Pb and Cd have a synergistic effect under compound stress. (2) The accumulation and transfer rules of Pb and Cd ions in mulberry were different. The content of Pb in mulberry was root > leaf > stem and the content of Cd was root > stem > leaf. The combined stress promoted the transfer of Pb and Cd from the underground part to the aerial portion of mulberry. (3) The silkworm feeds on mulberry leaves contaminated with heavy metals in this experiment and found that: with the increase of silkworm feeding, the heavy metal content in the silkworm body increased significantly, but the content remained in the silkworm body was less, most of it was excreted with silkworm excrement. Combined stress has no significant effect on the detoxification mechanism of silkworm. It is indispensable to think of the synergistic effect of heavy metals on plants germination when seeds are used for phytoremediation.

Although the wider electrochemical window, higher temperature stability, and better battery safety of Li _7 La _3 Zr _2 O _12 (LLZO) electrolytes than organic liquid, organogels, and polyelectrolytes, the limited ionic conductivity still far away from the practical electrochemical applications. Herein, LLZO electrolytes were by solid phase method. In order to further improve its electrochemical performance, aluminum substitution was introduced to replace Li ^+ sites and thus the highly conductive cubic phase was stabilized. The results show that with the increase of the substitution amount, the ion conductivity presents a trend of first increasing and then decreasing. It was found that 0.15Al-LLZO ceramics presented optimized ionic conductivity (1.184 × 10 ^–4 S·cm ^−1 ) and 92.5% of bulk density at 1150 °C for 21 h treatment. On the other hand, with the combination of molecular simulations, the relationship between the influence of aluminum substitution on the differential charge density of the garnet solid electrolyte and the electrochemical performance was investigated. It is believed that such an experimental-modeling combination will expand the fundamental understanding of elements variation/substitution effects on solid electrolytes, especially for lithium metal oxides.

AIMS: We aimed to replicate the association of the rs290487 (IVS3C/T) and rs7903146 (IVS3C/T) polymorphisms of transcription factor 7-like 2 (TCF7L2) and type 2 diabetes mellitus (T2DM) in Han Chinese people in Henan province, China. METHODS: In all, 1,842 patients with T2DM and 7,777 normal glucose-tolerant controls underwent genotyping for the T2DM-associated variants rs7903146 (IVS3C/T) and rs290487 (IVS3C/T). W performed a meta-analysis of the association of the risk alleles of rs7903146 (IVS3C/T) and rs290487 (IVS3C/T) in TCF7L2 and T2DM in Han Chinese by combining previous studies with the present study. RESULTS: We found that T2DM was associated with the CC genotype (1.364, 1.137-1.636, p = 0.001), the recessive model (1.457, 1.156-1.838, p = 0.001) of rs290487 (IVS3C/T) and haplotype CC (1.116, 1.034-1.204, p = 0.004) in Han Chinese. Moreover, our meta-analyses supported the association of the T allele (IVS3C/T) of rs7903146 (1.36, 1.24-1.48; p = 6.404×10(-12)) and T2DM but not the C allele of rs290487 (IVS3C/T) (0.99, 0.85-1.15, p = 0.890) in Han Chinese. We found no interactions between behavioral risk factors (smoking, alcohol drinking, and physical activity) and rs7903146 (IVS3C/T) and rs290487 (IVS3C/T) polymorphisms. CONCLUSIONS: The CC genotype and the recessive model of the variant rs290487 (IVS3C/T) and CC haplotype of rs7903146 (IVS3C/T) and rs290487 (IVS3C/T) in TCF7L2 may be associated with T2DM in Han Chinese people in Henan province, China.

Ubiquitin-specific proteases (USPs) are crucial for controlling cellular proteostasis and signaling pathways but how deubiquitination is selective remains poorly understood, in particular between paralogues. Here, we developed a fusion tag method by mining the Protein Data Bank and trapped USP11, a key regulator of DNA double-strand break repair, in complex with a novel engineered substrate mimetic. Together, this enabled structure determination of USP11 as a Michaelis-like complex that revealed key S1 and S1' binding site interactions with a substrate. Combined mutational, enzymatic, and binding experiments identified Met77 in linear diubiquitin as a significant residue that leads to substrate discrimination. We identified an aspartate “gatekeeper” residue in the S10 site of USP11 as a contributing feature for discriminating against linear diubiquitin. When mutated to a glycine, the corresponding residue in paralog USP15, USP11 acquired elevated activity toward linear diubiquitin in-gel shift assays, but not controls. The reverse mutation in USP15 confirmed that this position confers paralog-specific differences impacting diubiquitin cleavage rates. The results advance our understanding of the molecular basis for the higher selectivity of USP11 compared to USP15 and may aid targeted inhibitor development. Moreover, the reported carrier-based crystallization strategy may be applicable to other challenging targets. [ABSTRACT FROM AUTHOR]