Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth.

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.

Kinetic networks identify TWIST2 as a key regulatory node in adipogenesis.

Adipocytes contribute to metabolic disorders such as obesity, diabetes, and atherosclerosis. Prior characterizations of the transcriptional network driving adipogenesis have overlooked transiently acting transcription factors (TFs), genes, and regulatory elements that are essential for proper differentiation. Moreover, traditional gene regulatory networks provide neither mechanistic details about individual regulatory element-gene relationships nor temporal information needed to define a regulatory hierarchy that prioritizes key regulatory factors. To address these shortcomings, we integrate kinetic chromatin accessibility (ATAC-seq) and nascent transcription (PRO-seq) data to generate temporally resolved networks that describe TF binding events and resultant effects on target gene expression. Our data indicate which TF families cooperate with and antagonize each other to regulate adipogenesis. Compartment modeling of RNA polymerase density quantifies how individual TFs mechanistically contribute to distinct steps in transcription. The glucocorticoid receptor activates transcription by inducing RNA polymerase pause release, whereas SP and AP-1 factors affect RNA polymerase initiation. We identify Twist2 as a previously unappreciated effector of adipocyte differentiation. We find that TWIST2 acts as a negative regulator of 3T3-L1 and primary preadipocyte differentiation. We confirm that Twist2 knockout mice have compromised lipid storage within subcutaneous and brown adipose tissue. Previous phenotyping of Twist2 knockout mice and Setleis syndrome Twist2 -/- patients noted deficiencies in subcutaneous adipose tissue. This network inference framework is a powerful and general approach for interpreting complex biological phenomena and can be applied to a wide range of cellular processes.

Phase Engineering of Nanomaterials: Transition Metal Dichalcogenides.

Crystal phase, a critical structural characteristic beyond the morphology, size, dimension, facet, etc., determines the physicochemical properties of nanomaterials. As a group of layered nanomaterials with polymorphs, transition metal dichalcogenides (TMDs) have attracted intensive research attention due to their phase-dependent properties. Therefore, great efforts have been devoted to the phase engineering of TMDs to synthesize TMDs with controlled phases, especially unconventional/metastable phases, for various applications in electronics, optoelectronics, catalysis, biomedicine, energy storage and conversion, and ferroelectrics. Considering the significant progress in the synthesis and applications of TMDs, we believe that a comprehensive review on the phase engineering of TMDs is critical to promote their fundamental studies and practical applications. This Review aims to provide a comprehensive introduction and discussion on the crystal structures, synthetic strategies, and phase-dependent properties and applications of TMDs. Finally, our perspectives on the challenges and opportunities in phase engineering of TMDs will also be discussed.

DNA fragility at topologically associated domain boundaries is promoted by alternative DNA secondary structure and topoisomerase II activity.

CCCTC-binding factor (CTCF) binding sites are hotspots of genome instability. Although many factors have been associated with CTCF binding site fragility, no study has integrated all fragility-related factors to understand the mechanism(s) of how they work together. Using an unbiased, genome-wide approach, we found that DNA double-strand breaks (DSBs) are enriched at strong, but not weak, CTCF binding sites in five human cell types. Energetically favorable alternative DNA secondary structures underlie strong CTCF binding sites. These structures coincided with the location of topoisomerase II (TOP2) cleavage complex, suggesting that DNA secondary structure acts as a recognition sequence for TOP2 binding and cleavage at CTCF binding sites. Furthermore, CTCF knockdown significantly increased DSBs at strong CTCF binding sites and at CTCF sites that are located at topologically associated domain (TAD) boundaries. TAD boundary-associated CTCF sites that lost CTCF upon knockdown displayed increased DSBs when compared to the gained sites, and those lost sites are overrepresented with G-quadruplexes, suggesting that the structures act as boundary insulators in the absence of CTCF, and contribute to increased DSBs. These results model how alternative DNA secondary structures facilitate recruitment of TOP2 to CTCF binding sites, providing mechanistic insight into DNA fragility at CTCF binding sites.

Genetic dissection of intercellular interactions in vivo by membrane-permeable protein.

Unraveling cell-cell interaction is fundamental to understanding many biological processes. To date, genetic tools for labeling neighboring cells in mammals are not available. Here, we developed a labeling strategy based on the Cre-induced intercellular labeling protein (CILP). Cre-expressing donor cells release a lipid-soluble and membrane-permeable fluorescent protein that is then taken up by recipient cells, enabling fluorescent labeling of neighboring cells. Using CILP, we specifically labeled endothelial cells surrounding a special population of hepatocytes in adult mice and revealed their distinct gene signatures. Our results highlight the potential of CILP as a platform to reveal cell-cell interactions and communications in vivo.

The role of HPV11 E7 in modulating STING-dependent interferon ß response in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare benign tumor caused mainly by the infection of the respiratory tract epithelial cells by the human papillomavirus (HPV) type 6/11. However, the specific mechanisms underlying the inhibition of the host's innate immune response by HPV remain unclear. For this purpose, we employed single-cell RNA sequencing to analyze the states of various immune cells in RRP samples post-HPV infection and utilized a cellular model of HPV infection to elucidate the mechanisms by which HPV evades the innate immune system in RRP. The results revealed distinct immune cell heterogeneity in RRP and demonstrated that HPV11 E7 can inhibit the phosphorylation of the stimulator of interferon genes protein, thereby circumventing the body's antiviral response. In vitro co-culture experiments demonstrated that stimulation of macrophages to produce interferon-beta induced the death of HPV-infected epithelial cells, also reducing HPV viral levels. In summary, our study preliminarily identifies the potential mechanisms by which HPV evades the host's antiviral immune response, as well as the latent antiviral functions exhibited by activated macrophages. This research serves as an initial exploration of antiviral immune evasion in RRP, laying a solid foundation for investigating immunotherapeutic approaches for the disease.IMPORTANCESurgical tumor reduction is the most common treatment for recurrent respiratory papillomatosis (RRP). One of the characteristics of RRP is its persistent recurrence, and multiple surgeries are usually required to control the symptoms. Recently, some adjuvant therapies have shown effectiveness, but none of them can completely clear human papillomavirus (HPV) infection, and thus, a localized antiviral immune response is significant for disease control; after all, HPV infection is limited to the epithelium. Inhibition of interferon-beta (IFN-ß) secretion by HPV11 E7 viral proteins in epithelial cells by affecting stimulator of interferon genes phosphorylation may account for the persistence of low-risk HPV replication in the RRP. Moreover, suppression of the IFN-I pathway in RRP cell types might provide clues regarding the hyporeactive function of local immune cells. However, activation of macrophage groups to produce IFN-ß can still destroy HPV-infected cells.

Proteome-wide copy-number estimation from transcriptomics.

Protein copy numbers constrain systems-level properties of regulatory networks, but proportional proteomic data remain scarce compared to RNA-seq. We related mRNA to protein statistically using best-available data from quantitative proteomics and transcriptomics for 4366 genes in 369 cell lines. The approach starts with a protein's median copy number and hierarchically appends mRNA-protein and mRNA-mRNA dependencies to define an optimal gene-specific model linking mRNAs to protein. For dozens of cell lines and primary samples, these protein inferences from mRNA outmatch stringent null models, a count-based protein-abundance repository, empirical mRNA-to-protein ratios, and a proteogenomic DREAM challenge winner. The optimal mRNA-to-protein relationships capture biological processes along with hundreds of known protein-protein complexes, suggesting mechanistic relationships. We use the method to identify a viral-receptor abundance threshold for coxsackievirus B3 susceptibility from 1489 systems-biology infection models parameterized by protein inference. When applied to 796 RNA-seq profiles of breast cancer, inferred copy-number estimates collectively re-classify 26-29% of luminal tumors. By adopting a gene-centered perspective of mRNA-protein covariation across different biological contexts, we achieve accuracies comparable to the technical reproducibility of contemporary proteomics.

The underlying molecular mechanisms of hormonal regulation of fruit color in fruit-bearing plants.

Fruit color is a key feature of fruit quality, primarily influenced by anthocyanin or carotenoid accumulation or chlorophyll degradation. Adapting the pigment content is crucial to improve the fruit's nutritional and commercial value. Genetic factors along with other environmental components (i.e., light, temperature, nutrition, etc.) regulate fruit coloration. The fruit coloration process is influenced by plant hormones, which also play a vital role in various physiological and biochemical metabolic processes. Additionally, phytohormones play a role in the regulation of a highly conserved transcription factor complex, called MBW (MYB-bHLH-WD40). The MBW complex, which consists of myeloblastosis (MYB), basic helix-loop-helix (bHLH), and WD40 repeat (WDR) proteins, coordinates the expression of downstream structural genes associated with anthocyanin formation. In fruit production, the application of plant hormones may be important for promoting coloration. However, concerns such as improper concentration or application time must be addressed. This article explores the molecular processes underlying pigment formation and how they are influenced by various plant hormones. The ABA, jasmonate, and brassinosteroid increase anthocyanin and carotenoid formation, but ethylene, auxin, cytokinin, and gibberellin have positive as well as negative effects on anthocyanin formation. This article establishes the necessary groundwork for future studies into the molecular mechanisms of plant hormones regulating fruit color, ultimately aiding in their effective and scientific application towards fruit coloration.

Biomimetic-Structured Cobalt Nanocatalyst Suppresses Aortic Dissection Progression by Catalytic Antioxidation.

As one of the most lethal cardiovascular diseases, aortic dissection (AD) is initiated by overexpression of reactive oxygen species (ROS) in the aorta that damages the vascular structure and finally leads to massive hemorrhage and sudden death. Current drugs used in clinics for AD treatment fail to efficiently scavenge ROS to a large extent, presenting undesirable therapeutic effect. In this work, a nanocatalytic antioxidation concept has been proposed to elevate the therapeutic efficacy of AD by constructing a cobalt nanocatalyst with a biomimetic structure that can scavenge pathological ROS in an efficient and sustainable manner. Theoretical calculations demonstrate that the antioxidation reaction is catalyzed by the redox transition between hydroxocobalt(III) and oxo-hydroxocobalt(V) accompanied by inner-sphere proton-coupled two-electron transfer, forming a nonassociated activation catalytic cycle. The efficient antioxidation action of the biomimetic nanocatalyst in the AD region effectively alleviates oxidative stress, which further modulates the aortic inflammatory microenvironment by promoting phenotype transition of macrophages. Consequently, vascular smooth muscle cells are also protected from inflammation in the meantime, suppressing AD progression. This study provides a nanocatalytic antioxidation approach for the efficient treatment of AD and other cardiovascular diseases.

Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension.

BACKGROUND: The appropriate target for systolic blood pressure to reduce cardiovascular risk in older patients with hypertension remains unclear. METHODS: In this multicenter, randomized, controlled trial, we assigned Chinese patients 60 to 80 years of age with hypertension to a systolic blood-pressure target of 110 to less than 130 mm Hg (intensive treatment) or a target of 130 to less than 150 mm Hg (standard treatment). The primary outcome was a composite of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. RESULTS: Of the 9624 patients screened for eligibility, 8511 were enrolled in the trial; 4243 were randomly assigned to the intensive-treatment group and 4268 to the standard-treatment group. At 1 year of follow-up, the mean systolic blood pressure was 127.5 mm Hg in the intensive-treatment group and 135.3 mm Hg in the standard-treatment group. During a median follow-up period of 3.34 years, primary-outcome events occurred in 147 patients (3.5%) in the intensive-treatment group, as compared with 196 patients (4.6%) in the standard-treatment group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.92; P = 0.007). The results for most of the individual components of the primary outcome also favored intensive treatment: the hazard ratio for stroke was 0.67 (95% CI, 0.47 to 0.97), acute coronary syndrome 0.67 (95% CI, 0.47 to 0.94), acute decompensated heart failure 0.27 (95% CI, 0.08 to 0.98), coronary revascularization 0.69 (95% CI, 0.40 to 1.18), atrial fibrillation 0.96 (95% CI, 0.55 to 1.68), and death from cardiovascular causes 0.72 (95% CI, 0.39 to 1.32). The results for safety and renal outcomes did not differ significantly between the two groups, except for the incidence of hypotension, which was higher in the intensive-treatment group. CONCLUSIONS: In older patients with hypertension, intensive treatment with a systolic blood-pressure target of 110 to less than 130 mm Hg resulted in a lower incidence of cardiovascular events than standard treatment with a target of 130 to less than 150 mm Hg. (Funded by the Chinese Academy of Medical Sciences and others; STEP ClinicalTrials.gov number, NCT03015311.).

mRNA expression insights: Unraveling the relationship between COPD and lung cancer.

BACKGROUND: Lung cancer is a prevalent form of cancer worldwide. A possible link between lung cancer and chronic obstructive pulmonary disease (COPD) has been suggested by recent studies. The objective of our research was to analyze the mRNA expression patterns in both situations, with a specific emphasis on their biological functions and the pathways they are linked to. METHOD: Data on COPD mRNA expression was collected from the NCBI-GEO database, while information regarding lung cancer mRNA was acquired from The Cancer Genome Atlas database. To examine the association of COPD-related scores in lung cancer patients, we utilized the ssGSEA algorithm for single sample gene set enrichment analysis. The possible routes were examined through the utilization of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Risk models were developed using Cox and least absolute shrinkage and selection operator (LASSO) regression analyses. Moreover, a GSEA was performed to investigate significant pathways among various risk groups. RESULT: After identifying 17 genes that were differentially expressed and linked to COPD, we found that they met the criteria of having a false discovery rate < 0.05 and an absolute log2 fold change > 0.585. By utilizing the ssGSEA algorithm, it became possible to classify individuals with lung cancer into two distinct groups based on their COPD status. Consequently, a seven-gene risk model was developed specifically for these patients. The risk score was determined by applying the given formula: risk score = AC022784.1 × 0.0423737993775888 + CRISP3 × 0.0415322046890524 + MELTF × 0.0661848418476596 + MT2P1 × 0.111843227536117 + FAM83A-AS1 × 0.045295939710361 + ZNF506 × -0.309489953363417 + ITGA6 × 0.01813978449589. The risk model associated with COPD showed a notable connection with different immune cells found in the lung cancer sample, including macrophages of M0/M1/M2 types, hematopoietic stem cells, mast cells, NK T cells and regulatory T cells. Overexpression of crucial genes was seen to enhance cell proliferation and invasive potential in the lung cancer sample. In the lung cancer sample, it was observed that an increase in ZNF506 expression enhanced both cell proliferation and invasion. CONCLUSION: In conclusion, this study effectively examines the potential correlation between COPD and lung cancer. A prognostic model based on seven COPD-associated genes demonstrated robust predictive potential in the lung cancer sample. Our analysis offers comprehensive insights for lung cancer patients.

Single-cell RNA sequencing reveals microenvironmental infiltration in non-small cell lung cancer with different responses to immunotherapy.

BACKGROUND: Immunotherapy represents a groundbreaking and monumental achievement in the field of cancer therapy, marking a significant advancement in fighting against this devastating disease. Lung cancer has showed consistent clinical improvements in response to immunotherapy treatments, yet, it is undeniable that challenges such as limited response rates acquire resistance, and the unclear fundamental mechanisms were inevitable problems. METHODS: The cellular composition was defined and distinguished through single-cell RNA sequencing (scRNA-seq) analysis of MPR (major pathologic response) and NMPR (non-major pathologic response) samples in GSE207422, including four primary MPR samples and eight primary NMPR samples. RESULTS: We found obvious difference in CD8+ T cell population between MPR and NMPR samples, with high expression of TYMS, RRM2, and BIRC5 in NPMR samples. Meanwhile, the proportion of macrophages and tumor epithelial cells infiltration increased in the NMPR samples. We discovered biomarkers (ACTN4, ATF3, BRD2, CDKN1A, and CHMP4B) in epithelial cells which were potentially represented worse outcomes. CONCLUSIONS: By exploring the difference of tumor microenvironment (TME) in samples with different corresponding degrees of neoadjuvant immunotherapy, this research introduces a number of novel biomarkers for predicting the response of treatment and a theoretical basis for overcoming immunotherapy resistance.

Rocaglamide promotes infiltration and differentiation of T cells and coordinates with PD-1 inhibitor to overcome checkpoint resistance in multiple tumor models.

Tumor-infiltrating lymphocyte (TIL) deficiency is the most conspicuous obstacle to limit the cancer immunotherapy. Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibody, have achieved great success in clinical practice. However, due to the limitation of response rates of ICIs, some patients fail to benefit from monotherapy. Thus, novel combination therapy that could improve the response rates emerges as new strategies for cancer treatment. Here, we reported that the natural product rocaglamide (RocA) increased tumor-infiltrating T cells and promoted Th17 differentiation of CD4+ TILs. Despite RocA monotherapy upregulated PD-1 expression of TILs, which was considered as the consequence of T cell activation, combining RocA with anti-PD-1 antibody significantly downregulated the expression of PD-1 and promoted proliferation of TILs. Taken together, these findings demonstrated that RocA could fuel the T cell anti-tumor immunity and revealed the remarkable potential of RocA as a therapeutic candidate when combining with the ICIs.

The determining factors of hydrogen isotope offsets between plants and their source waters.

A fundamental assumption when using hydrogen and oxygen stable isotopes to understand ecohydrological processes is that no isotope fractionation occurs during plant water uptake/transport/redistribution. A growing body of evidence has indicated that hydrogen isotope fractionation occurs in certain environments or for certain plant species. However, whether the plant water source hydrogen isotope offset (δ2 H offset) is a common phenomenon and how it varies among different climates and plant functional types remains unclear. Here, we demonstrated the presence of positive, negative, and zero offsets based on extensive observations of 12 plant species of 635 paired stable isotopic compositions along a strong climate gradient within an inland river basin. Both temperature and relative humidity affected δ2 H offsets. In cool and moist environments, temperature mainly affected δ2 H offsets negatively due to its role in physiological activity. In warm and dry environments, relative humidity mainly affected δ2 H offsets, likely by impacting plant leaf stomatal conductance. These δ2 H offsets also showed substantial linkages with leaf water 18 O enrichment, an indicator of transpiration and evaporative demand. Further studies focusing on the ecophysiological and biochemical understanding of plant δ2 H dynamics under specific environments are essential for understanding regional ecohydrological processes and for conducting paleoclimate reconstructions.

Sex-based outcomes after thoracic endovascular aortic repair: A systematic review and meta-analysis.

OBJECTIVE: As it remains unclear whether there are sex-based differences in clinical outcomes after thoracic endovascular aortic repair (TEVAR), this meta-analysis aimed to evaluate differences in early outcomes and overall survival between female and male patients who underwent TEVAR. METHODS: The PubMed, Embase, Web of Science, and Cochrane Central databases were searched for eligible studies published through June 10, 2023, that reported sex-based differences in clinical outcomes after TEVAR. The primary outcome was operative mortality; second outcomes included stroke, spinal cord ischemia, acute kidney injury, hospital length of stay, and overall survival. Patient characteristics, operative data, and early outcomes were aggregated using the random-effects model, presenting pooled risk ratio (RR) or standardized mean difference along with their corresponding 95% confidence intervals (CIs). Overall survival was assessed by reconstructing individual patient data to generate sex-specific pooled Kaplan-Meier curves. This study was registered in PROSPERO (CRD42023426069). RESULTS: Of the 1785 studies retrieved, 14 studies met all eligibility criteria, encompassing a total of 17,374 patients, comprising 5026 female and 12,348 male patients. Female patients were older, had a smaller maximum aortic diameter, had lower rates of smoking and coronary artery disease, and had higher rates of anemia. Intraoperatively, female patients were more likely to use iliac conduits and require blood transfusions. There were no sex-based differences in operative mortality (RR: 1.12, 95% CI: 0.90-1.40; P = .309), stroke (RR: 1.14, 95% CI: 0.95-1.38; P = .165), spinal cord ischemia (RR: 1.33, 95% CI: 0.83-2.14; P = .234), acute kidney injury (RR: 0.78, 95% CI: 0.52-1.17; P = .228), and hospital length of stay (standardized mean difference: 0.09, 95% CI: -0.03 to 0.20; P = .141). Pooled Kaplan-Meier estimates showed a worse overall survival in female patients compared with male patients (87.2% vs 89.8% at 2 years, log-rank P = .001). CONCLUSIONS: Among patients treated by TEVAR, female sex was not associated with increased risk of operative mortality or major morbidity. However, female patients exhibited a lower overall survival after TEVAR compared with male patients.

Diagnostic potential of soluble ST2 and D-dimer for Stanford Type B aortic dissection and intramural aortic hematoma.

OBJECTIVE: Type B aortic dissection (TBAD) and intramural aortic hematoma (IMH) are common manifestations of Acute Aortic Syndrome (AAS), exhibiting overlapping clinical features. The timely and accurate diagnosis and differentiation between TBAD and IMH are critical for appropriate management. Tumorigenicity 2 (sST2) and D-dimer have been shown to elevate levels in both TBAD and IMH, making them valuable as "rule-out" markers. Hence, we aimed to assess the diagnostic utility of sST2 and D-dimer in distinguishing TBAD from IMH. METHODS: In this retrospective study, we analyzed serum levels of sST2 and D-dimer in 182 AAS patients, comprising 90 TBAD cases, 92 IMH cases, and 90 non-AAS cases. Serial measurements were taken at 1 h, 6 h, 12 h, 24 h, and 72 h post-admission. Comparative analyses were conducted between TBAD and non-AAS cases, IMH and non-AAS cases, and TBAD and IMH cases. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of sST2 and D-dimer in identifying TBAD or IMH cases. RESULTS: Both TBAD and IMH patients displayed elevated levels of sST2 and D-dimer compared to non-AAS cases. Notably, sST2 levels were significantly higher in TBAD patients than in IMH patients, whereas D-dimer levels exhibited moderate differences. TBAD patients tended to exhibit elevated levels of either sST2 or D-dimer, with a modest correlation between the two (Pearson correlation coefficient = 0.3614). In contrast, IMH patients showed elevations in both markers, with a positive correlation between them (Pearson correlation coefficient = 0.6814). The ROC analysis revealed that both sST2 (AUC, 0.657; 95 % CI, 0.552-0.753; cutoff value, 27.54 ng/ml) and D-dimer (AUC, 0.695; 95 % CI, 0.591-0.787, cutoff value, 1.215 ng/ml) demonstrated favorable diagnostic performance for TBAD. sST2 exhibited a sensitivity of 80.92 % and a specificity of 75.00 %, while D-dimer showed a sensitivity of 80.92 % and a specificity of 75.00 %. For the diagnosis of IMH, the combined assessment of sST2 and D-dimer (AUC, 0.674; 95 % CI, 0.599-0.768; sensitivity, 69.20 %; specificity, 80.00 %) proved effective. CONCLUSIONS: Our results indicate that both sST2 and D-dimer show diagnostic potential for TBAD. Elevated levels of either serve as an indicator of TBAD onset. However, concurrent elevation of both markers seems to be indicative of IMH. The combination of increased sST2 and D-dimer levels demonstrates strong diagnostic performance in identifying IMH cases.

Toward a Comprehensive Understanding of the Anomalously Small Contact Angle of Surface Nanobubbles.

Experimental studies have demonstrated that the gas phase contact angle (CA) of a surface nanobubble (SNB) is much smaller than that of a macroscopic gas bubble. This reduced CA plays a crucial role in prolonging the lifetime of SNBs by lowering the bubble pressure and preventing gas molecules from dissolving in the surrounding liquids. Despite extensive efforts to explain the anomalously small CA, a consensus about the underlying reasons is yet to be reached. In this study, we conducted experimental investigations to explore the influence of gas molecules adsorbed at the solid-liquid interface on the CA of SNBs created through the solvent exchange (SE) method and temperature difference (TD). Interestingly, no significant change is observed in the CA of SNBs on highly oriented pyrolytic graphite (HOPG) surfaces. Even for nanobubbles on micro/nano pancakes, the CA only exhibited a slight reduction compared to SNBs on bare HOPG surfaces. These findings suggest that gas adsorption at the immersed solid surface may not be the primary factor contributing to the small CA of the SNBs. Furthermore, the CA of SNBs formed on polystyrene (PS) and octadecyltrichlorosilane (OTS) substrates was also investigated, and a considerable increase in CA was observed. In addition, the effects of other factors including impurity, electric double layer (EDL) line tension, and pinning force upon the CA of SNBs were discussed, and a comprehensive model about multiple factors affecting the CA of SNBs was proposed, which is helpful for understanding the abnormally small CA and the stability of SNBs.

Pivotal Evaluation of Novel Dedicated Venous Stent for Iliofemoral Venous Obstruction: A Prospective Cohort Study.

PURPOSE: The purpose was to evaluate the clinical outcomes of a dedicated venous stent with the tripartite composite segments for the treatment of iliofemoral venous obstruction (IVO) in a mixed cohort of nonthrombotic iliac vein lesion (NIVL) and post-thrombotic syndrome (PTS) over a period of 12 months. METHODS: The Grency Trial is a prospective, multicenter, single-arm, open-label, pivotal study, which was conducted at 18 large tertiary hospitals in China from August 2019 to October 2020. A total of 133 hospitalized patients were screened and 110 patients with clinical, etiology, anatomical, and pathophysiology clinical class (CEAP) clinical grade C>3 and iliac vein stenosis >50% or occlusion, including 72 patients with NIVL and 38 patients with PTS, were implanted with Grency venous stents. Primary endpoint was stent patency at 12 months follow-up, and secondary outcomes were technical success; improvement in venous clinical severity score (VCSS) at 3, 6, and 12 month follow-up; and rates of clinical adverse events. RESULTS: Among 110 patients who were implanted with Grency venous stents, 107 patients completed the 12 month follow-up. All 129 stents were successfully implanted in 110 limbs. Twelve-month primary patency rate was 94.39% [95% confidence interval [CI]=88.19%-97.91%] overall, and 100% [94.94%-100%] and 83.33% [67.19%-93.63%] in the NIVL and PTS subgroups, respectively. Venous clinical severity score after iliac vein stenting improved significantly up to 12 months follow-up. There were 3 early major adverse events (1 intracerebral hemorrhage and 2 stent thrombosis events related to anticoagulation therapy), and 7 late major adverse events (1 cardiovascular death, 1 intracranial hemorrhage with uncontrolled hypertension, and 5 in-stent restenosis cases without stent fractures or migration). CONCLUSIONS: The Grency venous stent system appeared excellent preliminary safe and effective for IVO treatment. Further large-scale studies with longer-term follow-up are needed to evaluate long-term patency and durability of stent. CLINICAL IMPACT: The design of venous stents for iliofemoral venous obstruction (IVO) must address engineering challenges distinct from those encountered in arterial stenting. The Grency venous stent, a nitinol self-expanding stent specifically tailored for IVO, features a composite structure designed to meet the stent requirements of various iliac vein segments. The Grency Trial is a prospective, multicenter, single-arm, open-label pivotal study aimed at evaluating the efficacy and safety of the Grency stent system. Following a 12-month follow-up period, the Grency venous stent system has demonstrated both safety and efficacy in treating iliofemoral venous outflow obstruction.

Galectin-9 activates host immune response and improve immunoprotection of Onychostoma macrolepis against Aeromonas hydrophila infection.

Galectin-9 (Gal-9) belongs to a family of the glycan-binding proteins (GBPs) and is known to restrict bacterial activity via interacting with pathogen associated molecular pattern (PAMPs). However, the underlying immune mechanism of endogenous Gal-9 on fish against bacterial infection is still unclear. In this study, effects of Gal-9 from Onychostoma macrolepis (OmGal-9) on expression of immune-related genes were measured by HEK293T. The immune response of O. macrolepis with OmGal-9 overexpression to Aeromonas hydrophila (A. hydrophila) infection (1.65 × 108 CFU/mL) was evaluated by tissue bacterial load, fish survival rate and transcriptome analysis. The results showed that OmGal-9 displayed a punctate distribution in the nucleus and cytoplasm of HEK293T cells. Compared to cells transfected with the empty vector (EV group), recombinant plasmid pEGFP-Gal9 treatment (Gal9 group) significantly down-regulated the expression of immune-related genes TNFα, STAT3, MyD88, LCK, and p52 of HEK293T cells stimulated with LPS at 24 h, while up-regulated IκBα and caspase-1 (P < 0.05). The activities of catalase (CAT), superoxide dismutase (SOD), the total antioxidant capacity (T-AOC), alkaline phosphatase (AKP), acid phosphatase (ACP), and lysozyme (LZM) of O. macrolepis were significantly increased on 7 days in Gal9 group compared to EV group (P < 0.05). The bacterial load of liver, spleen, and kidney of O. macrolepis infected with A. hydrophila in Gal9 group at 24 h was significantly lower than that in EV group (P < 0.05), and the survival rate had increased from 15 % to 35 %. A comparative transcriptome analysis between the Gal9 and EV group identified 305 differentially expressed genes (DEGs). The analysis showed that OmGal-9 might play an important regulatory role in glycolysis/gluconeogenesis, fatty acid degradation, and ascorbate and aldarate metabolism. Moreover, the immune-related DEGs were predominantly enriched in eleven pathways, with the most important three of them being linked to innate immunity: NOD-like, C-type lectin and Toll-like receptor signaling pathway. Taking together, OmGal-9 can enhance the resistance of fish to bacterial diseases by improving immune system function and activating immune-related pathways.